dizocilpine-maleate and Memory-Disorders

Abnormal N-methyl-D-aspartate receptor (NMDAr) function has been linked to oscillopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal/intermediate hippocampus and medial prefrontal cortex (mPFC), administered the NMDAr antagonist MK-801, and recorded oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade disrupted the correlation between oscillations and speed of movement, crucial for internal representations of distance. In the hippocampus, MK-801 increased gamma oscillations and disrupted theta/gamma coupling during spatial working memory. In the mPFC, MK-801 increased the power of theta and gamma, generated high-frequency oscillations (HFO 155-185 Hz), and disrupted theta/gamma coupling. Moreover, the performance of mice in the spatial working memory version of the y-maze was strongly correlated with CA1-PFC theta/gamma co-modulation. Thus, theta/gamma mediated by NMDAr function might explain several of SCZ's cognitive symptoms and might be crucial to explaining hippocampal-PFC interaction.

Topics: Animals; Dizocilpine Maleate; Hippocampus; Memory Disorders; Memory, Short-Term; Mice; Prefrontal Cortex; Receptors, N-Methyl-D-Aspartate; Spatial Memory; Theta Rhythm

Treating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL)). Here, the aim of the experiments was to evaluate the impact of inhibitors of endocannabinoids' enzymatic degradation in the brain: KML-29 (MAGL inhibitor), JZL-195 (MAGL/FAAH inhibitor) and PF-3845 (FAAH inhibitor), on the memory disturbances typical for schizophrenia in an acute N-methyl-D-aspartate (NMDA) receptor hypofunction animal model of schizophrenia (i.e., injection of MK-801, an NMDA receptor antagonist). The memory-like responses were assessed in the passive avoidance (PA) test. A single administration of KML-29 or PF-3845 had a positive effect on the memory processes, but an acute administration of JZL-195 impaired cognition in mice in the PA test. Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids' concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia.

Topics: Amidohydrolases; Animals; Dizocilpine Maleate; Endocannabinoids; Enzyme Inhibitors; Memory Disorders; Mice; Monoacylglycerol Lipases; N-Methylaspartate; Schizophrenia

At present, the research on the prevention of schizophrenia is still in its infancy. Pyrroloquinoline quinone (PQQ) has potential to treat psychological and neurological diseases including schizophrenia. However, the preventive effect of PQQ on schizophrenia remains unclear.. In this study, we aimed to examine the preventive effect of supplementation of dietary PQQ from pregnancy or after birth on dizocilpine (MK-801)-induced schizophrenia-like behaviors in mice.. Supplementation of dietary PQQ from pregnancy could effectively prevent MK-801-induced weight gain decrease, hyperlocomotion, stereotypical behavior, ataxia, exploratory activity decrease, social interaction disorder, memory deficit, and depression in mice. Supplementation of dietary PQQ after birth could effectively prevent MK-801-induced weight gain decrease, stereotypical behavior, ataxia, and memory deficit in mice. Female mice responded to a greater degree than males in preventing MK-801-induced weight gain decrease in both forms of PQQ supplementation. For mice that began PQQ supplementation after birth, females performed better than males in preventing MK-801-induced ataxia, memory deficit, and depression. For mice that began PQQ supplementation from pregnancy, males performed better than females in preventing MK-801-induced memory deficit. In vitro experiments indicated that PQQ supplementation in the earlier stage of life contributed to the growth of neurons and the development of neurites.. Our current study suggested that PQQ supplementation from pregnancy or postpartum could prevent some schizophrenia-like behaviors induced by MK-801 in mice. Our work supported the potential usage of dietary supplement of PQQ in preventing or alleviating symptoms associated with schizophrenia.

Topics: Animals; Ataxia; Dietary Supplements; Dizocilpine Maleate; Female; Male; Memory Disorders; Mice; PQQ Cofactor; Pregnancy; Schizophrenia; Weight Gain

Few treatments exist for the cognitive symptoms of schizophrenia. Pharmacological agents resulting in glutamate N-methyl-d-aspartate (NMDA) receptor hypofunction, such as MK-801, mimic many of these symptoms and disrupt neural activity. Recent evidence suggests that deep brain stimulation (DBS) of the medial septal nucleus (MSN) can modulate medial prefrontal cortex (mPFC) and hippocampal activity and improve spatial memory.. Here, we examine the effects of acute MK-801 administration on oscillatory activity within the septohippocampal circuit and behavior. We also evaluate the potential for MSN stimulation to improve cognitive behavioral measures following MK-801 administration.. 59 Sprague Dawley male rats received either acute intraperitoneal (IP) saline vehicle injections or MK-801 (0.1 mg/kg). Theta (5-12 Hz), low gamma (30-50 Hz) and high frequency oscillatory (HFO) power were analyzed in the mPFC, MSN, thalamus and hippocampus. Rats underwent MSN theta (7.7 Hz), gamma (100 Hz) or no stimulation during behavioral tasks (Novel object recognition (NOR), elevated plus maze, Barnes maze (BM)).. Injection of MK-801 resulted in frequency-specific changes in oscillatory activity, decreasing theta while increasing HFO power. Theta, but not gamma, stimulation enhanced the anxiolytic effects of MK-801 on the elevated plus maze. While MK-801 treated rats exhibited spatial memory deficits on the Barnes maze, those that also received MSN theta, but not gamma, stimulation found the escape hole sooner.. These findings demonstrate that acute MK-801 administration leads to altered neural activity in the septohippocampal circuit and impaired spatial memory. Further, these findings suggest that MSN theta-frequency stimulation improves specific spatial memory deficits and may be a possible treatment for cognitive impairments caused by NMDA hypofunction.

Topics: Animals; Deep Brain Stimulation; Dizocilpine Maleate; Hippocampus; Male; Memory Disorders; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Septal Nuclei; Spatial Memory

Schizophrenia is a chronic mental disorder that disturbs feelings and behavior. The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive. Cognitive symptoms are characterized by memory loss or attentional deficits, and are especially difficult to treat. Thus, there is intense research into the development of new treatments for schizophrenia-related responses. One of the possible strategies is connected with cannabidiol (CBD), a cannabinoid compound. This research focuses on the role of CBD in different stages of memory (acquisition, consolidation, retrieval) connected with fear conditioning in the passive avoidance (PA) learning task in mice, as well as in the memory impairment typical of cognitive symptoms of schizophrenia. Memory impairment was provoked by an acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (animal model of schizophrenia). Our results revealed that an acute injection of CBD (30 mg/kg; intraperitoneally (i.p.) improved all phases of long-term fear memory in the PA test in mice. Moreover, the acute injection of non-effective doses of CBD (1 or 5 mg/kg; i.p.) attenuated the memory impairment provoked by MK-801 (0.6 mg/kg; i.p.) in the consolidation and retrieval stages of fear memory, but not in the acquisition of memory. The present findings confirm that CBD has a positive influence on memory and learning processes in mice, and reveals that this cannabinoid compound is able to attenuate memory impairment connected with hypofunction of glutamate transmission in a murine model of schizophrenia.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cannabidiol; Disease Models, Animal; Dizocilpine Maleate; Locomotion; Male; Memory; Memory Disorders; Mice; Schizophrenia

The spontaneous object recognition (SOR) task is one of the most widely used behavioral protocols to assess visual memory in animals. However, only recently was it shown that nonhuman primates also perform well on this task. Here we further characterized this new monkey recognition memory test by assessing the performance of adult marmosets after an acute systemic administration of two putative amnesic agents: the competitive muscarinic acetylcholine receptor antagonist scopolamine (SCP; 0.05 mg/kg) and the noncompetitive N-methyl-d-aspartate glutamate receptor antagonist MK-801 (0.015 mg/kg). We also determined whether the acetylcholinesterase inhibitor donepezil (DNP; 0.50 mg/kg), a clinically-used cognitive enhancer, reverses memory deficits caused by either drug. The subjects had an initial 10 min sample trial where two identical neutral objects could be explored. After a 6 h retention interval, recognition was based on an exploratory preference for a new rather than familiar object during a 10 min test trial. Both SCP and MK-801 impaired the marmosets' performance on the SOR task, as both objects were explored equivalently. Co-administration of 0.50 mg/kg of DNP reversed the SCP- but not the MK-801-induced memory deficit. These results indicate that cholinergic and glutamatergic pathways mediate object recognition memory in the monkey SOR task.

Topics: Acetylcholinesterase; Animals; Callithrix; Dizocilpine Maleate; Donepezil; Excitatory Amino Acid Antagonists; Female; Haplorhini; Male; Memory; Memory Disorders; Muscarinic Antagonists; Nootropic Agents; Open Field Test; Receptors, Muscarinic; Recognition, Psychology; Scopolamine

MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Nitric Oxide; Scopolamine

N-Methyl-D-Aspartate (NMDA) receptors are critically involved in the learning and memory formation and dizocilpine (MK-801) is an antagonist of NMDA receptor. Ghrelin plays a crucial role in learning and memory processes. The present study was conducted to the evaluation of ghrelin effect on passive avoidance memory impairment induced by MK801. In this experimental study, 24 male wistar rats were randomly distributed into 3 groups of 8 each. Passive avoidance tests of animals were evaluated using Shuttle Box apparatus. One week after the surgery, ghrelin (3 nmol) was injected intra-hippocampally, 5 min before the MK-801administration. MK-801 (0.15 mg/kg) was injected intraperitoneally (i.p.), 10 min before the test session. Pre-test injection of MK-801 significantly decreased STL (step through latency) at 24 h and 48 h (P < 0.001) and 10 days (P < 0.01) and increased TDC (time spent in dark compartment) at 24 h, 48 h and 10 days (P < 0.001) after training in comparison with control group. Pre-test injection of ghrelin + MK-801 significantly increased STL at 24 h (P < 0.01), 48 h and 10 days (P < 0.001) and decreased TDC at 24 h, 48 h and 10 days (P < 0.001) after training in comparison with MK-801 received group. It is concluded that pre-test injection of MK-801 impaired passive avoidance memory. Administration of ghrelin before MK-801 ameliorated memory impairment induced by MK-801. It is assumed that this compensative effect of ghrelin was mediated by NMDA receptor.

Topics: Animals; Avoidance Learning; CA1 Region, Hippocampal; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ghrelin; Male; Memory Disorders; Rats; Rats, Wistar

MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 μg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 μg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 μg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 μg/rat, baclofen at the doses of 0.001 and 0.01 μg/rat, and phaclofen at the doses of 0.001 and 0.01 μg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 μg/rat) and phaclofen (0.0001 μg/rat) restored the impairment effect of MK-801 (0.5 μg/rat) on memory. Also, both baclofen (0.0001 μg/rat) potentiated the impairment effect of MK-801 (0.125 μg/rat) and phaclofen (0.0001 μg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 μg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.

Topics: Animals; Avoidance Learning; Baclofen; Basolateral Nuclear Complex; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Male; Memory Disorders; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N-methyl d-aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia.

Topics: Animals; Anxiety; Behavior, Animal; Chelating Agents; Corpus Callosum; Cuprizone; Dizocilpine Maleate; Hyperkinesis; Injections, Intraperitoneal; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Spatial Memory; White Matter

Reelin, a large extracellular matrix protein, helps to regulate neuronal plasticity and cognitive function. Several studies have shown that Reelin dysfunction, resulting from factors such as mutations in gene RELN or low Reelin expression, is associated with schizophrenia (SCZ). We previously reported that microinjection of Reelin into cerebral ventricle prevents phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear whether and how Reelin ameliorates behavioral abnormalities in the animal model of SCZ. In the present study, we evaluated the effect of recombinant Reelin microinjection into the medial prefrontal cortex (mPFC) on abnormal behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Microinjection of Reelin into the mPFC prevented impairment of recognition memory of MK-801-treated mice in the novel object recognition test (NORT). On the other hand, the same treatment had no effect on deficits in sensory-motor gating and short-term memory in the pre-pulse inhibition and Y-maze tests, respectively. To establish the neural substrates that respond to Reelin, the number of c-Fos-positive cells in the mPFC was determined. A significant increase in c-Fos-positive cells in the mPFC of MK-801-treated mice was observed when compared with saline-treated mice, and this change was suppressed by microinjection of Reelin into the mPFC. A K2360/2467A Reelin that cannot bind to its receptor failed to ameliorate MK-801-induced cognitive deficits in NORT. These results suggest that Reelin prevents MK-801-induced recognition memory impairment by acting on its receptors to suppress neural activity in the mPFC of mice.

Topics: Animals; Behavior, Animal; Cells, Cultured; Dizocilpine Maleate; Male; Memory Disorders; Mice, Inbred C57BL; Microinjections; Neurons; Neuroprotective Agents; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Reelin Protein

Schizophrenia is a neuropsychiatric condition that reaches around 1% of people worldwide. Because taurine exerts a neuroprotective role in the brain, this molecule is a promising candidate to reduce schizophrenia-like symptoms. Here, we investigated a possible neuroprotective role of taurine against MK-801-induced memory deficit and hyperlocomotion in zebrafish using the inhibitory avoidance task and the novel tank diving test, respectively. First, we assessed the influence of different MK-801 doses (0.1, 0.3, 0.5, 1 and 2 mg/kg, i.p.) on memory consolidation. Although all MK-801 doses tend to reduce the retention index, only 2 mg/kg MK-801 showed robust amnesic effects. Then, we evaluated whether taurine pretreatments (42, 150 and 400 mg/L for 60 min) prevent MK-801-induced cognitive impairment. Immediately after the training, animals were exposed to non-chlorinated water or taurine and subsequently challenged with 2 mg/kg MK-801, i.p. The test session was performed 24 h after training. Although taurine alone did not change memory retention when compared with control, taurine pretreatments prevented MK-801-induced memory deficit. Importantly, no locomotor changes were observed 24 h after the training session. In the novel tank diving test, MK-801 induced hyperlocomotion and disrupted vertical activity, while 400 mg/L taurine pretreatment prevented these effects. Overall, our novel findings indicate a neuroprotective role of taurine against MK-801-induced memory deficit and hyperlocomotion, reinforcing the growing utility of zebrafish models to investigate the beneficial effects of different compounds against glutamate excitotoxicity.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Gait Disorders, Neurologic; Male; Memory Disorders; Neuroprotective Agents; Taurine; Zebrafish

NMDA receptors (NMDAr) are widely expressed throughout the brain on many cell types, and loss of function of these receptors (ie: NMDAr hypofunction) is a candidate mechanism explaining working memory impairment in schizophrenia. However, the cellular source driving the working memory deficits caused by NMDAr hypofunction has not been explored. The aim of this study was to assess the contribution of NMDAr on pyramidal cells and parvalbumin (PV+) interneurons to impairments in working memory induced by NMDAr hypofunction. We excised GluN1 - the gene encoding the obligatory subunit of the NMDAr - from PV + interneurons or CaMKIIα+ pyramidal cells using Cre-lox technology. Adult male PV GluN1 KO (n = 10) and CaMKIIα GluN1 KO mice (n = 9) and WT controls (n = 10 and n = 13) were trained to perform the Trial-Unique Nonmatching-to-Location (TUNL) task of working memory. Once trained, mice received the NMDAr antagonist MK-801 (0.1 and 0.3 mg/kg ip), and working memory assessed. Neither task acquisition nor working memory differed between the two transgenic lines and WT littermates. MK-801 dose-dependently decreased working memory accuracy in all strains (p < 0.001). PV GluN1 KO mice were sensitised to the impairing effects of MK-801 (p = 0.04), whereas CaMKIIα GluN1 KO mice showed equivalent working memory deficits as WT. Developmental NMDAr hypofunction at either PV+ interneurons or forebrain pyramidal cells is not sufficient to impair working memory, and neither of these cell types exclusively mediates working memory impairment caused by NMDAr antagonism. Reduced NMDAr signalling at PV+ interneurons could predispose circuits to NMDAr hypofunction magnifying deficits in working memory.

Topics: Animals; Animals, Genetically Modified; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Interneurons; Male; Memory Disorders; Memory, Short-Term; Mice; Nerve Tissue Proteins; Parvalbumins; Prosencephalon; Pyramidal Cells; Receptors, N-Methyl-D-Aspartate

Topics: Animals; Antidepressive Agents; Aripiprazole; Benzazepines; Biogenic Monoamines; Citalopram; Dizocilpine Maleate; Dopamine Antagonists; Frontal Lobe; Memory Disorders; Piperazines; Pyridines; Rats; Recognition, Psychology; Serotonin Antagonists

Abnormalities in neural oscillations that occur in the gamma frequency range (30-80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists.. We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR. C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus.. MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130-180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment.. NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cognitive Dysfunction; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hippocampus; Male; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Prefrontal Cortex; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate

Research in Alzheimer's disease is going through a big turnaround. New palliative therapies are being reconsidered for the effective management of disease because of setbacks in the development of disease-modifying therapies. Serotonin 6 (5-HT6) receptor has long been pursued as a potential target for the symptomatic treatment of Alzheimer's disease. SUVN-502 is a novel 5-HT6 receptor antagonist (Ki=2.04 nmol/l) with high receptor affinity and high degree of selectivity. SUVN-502 at doses ranging from 1 to 10 mg/kg, per os (p.o.) demonstrated procognitive effects in various behavioral animal models (object recognition task, water maze, and radial arm maze), and it acts on three phases of cognition, viz., acquisition, consolidation, and retention (object recognition task). SUVN-502 (3 and 10 mg/kg, p.o.) modulated glutamate levels when administered alone (microdialysis). At doses ranging from 1 to 10 mg/kg p.o., SUVN-502 potentiated the effects of donepezil (microdialysis). SUVN-502 [1 mg/kg, intravenous (i.v.)] also potentiated pharmacological effects of memantine (1 mg/kg, i.v.) and/or donepezil (0.3 mg/kg, i.v.) (θ modulation). The beneficial effects of SUVN-502 on learning and memory might be mediated through the modulation of cholinergic and/or glutamatergic neurotransmission in relevant brain regions. In summary, behavioral, neurochemical, and electrophysiological outcomes indicate that SUVN-502 may augment the beneficial effects of donepezil and memantine combination.

Topics: Acetylcholine; Animals; Behavior, Animal; Brain; Brain Waves; CHO Cells; Cricetulus; Culture Media, Serum-Free; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Electroencephalography; Glutamic Acid; Indoles; Male; Maze Learning; Memantine; Memory Disorders; Microdialysis; Nootropic Agents; Piperazines; Rats; Rats, Wistar; Receptors, Serotonin; Recognition, Psychology; Scopolamine; Serotonin; Serotonin Antagonists

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Dizocilpine Maleate; Hippocampus; Humans; Interneurons; Locomotion; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Nootropic Agents; Prepulse Inhibition; Rats, Sprague-Dawley; Schizophrenia; Sensory Gating; Synaptic Transmission; Thiazoles; Xenopus

To explore the reversion of the excitatory amino acid receptor antagonists against the impairment of learning-memory and the hyperphosphorylation of protein Tau induced by fetal intrauterine distress in neonatal rats.. The analysis of variance of factorial design set up two intervention factors, fetal intrauterine distress (two levels: no fetal intrauterine distress and a course of fetal intrauterine distress) and the excitatory amino acid receptor antagonists (three levels: Saline; NMDA receptor antagonist MK-801; astragalosides). Forty-eight pregnant rats were randomly divided into six experimental groups (n=8, in each group). After the end of the fetal intrauterine distress, the pregnant rats continued until the birth of newborn rats. When the neonatal rats grow to 12W, the Morris water maze test started in order to evaluate learning-memory. The hippocampus was removed from newborn rats within 1 day after the Morris water maze test finished. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. Besides, the content of protein Tau including Tau5 (total protein Tau), p-PHF1Ser396/404, p-AT8Ser199/202, p-12E8Ser262 in the hippocampus of rats, was examined with the method of immunohistochemistry (IHC) staining (SP).. Fetal intrauterine distress and the glutamate ionic receptor blockers could induce the impairment of learning-memory in neonatal rats, extending the evasive latency time and shorten the space exploration time. Both influences present subtract effect. Fetal intrauterine distress could significantly up-regulate the content of glutamate in the hippocampus of neonatal rats, which was not affected by the glutamate ionic receptor blockers. Fetal intrauterine distress and the glutamate ionic receptor blockers did not affect the total protein Tau in the hippocampus of rats. Moreover, fetal intrauterine distress could increase the hyperphosphorylation of protein Tau in the hippocampus of neonatal rats, which were reduced by the glutamate ionic receptor blockers. Both influences presented subtract effect.. We showed that fetal intrauterine distress upregulates the content of glutamate in the hippocampus of neonatal rats, up-regulating the hyperphosphorylation of protein Tau and inducing the impairment of learning-memory in neonatal rats.

Topics: Animals; Animals, Newborn; Dizocilpine Maleate; Female; Hippocampus; Male; Maze Learning; Memory Disorders; Phosphorylation; Pregnancy; Rats; Rats, Sprague-Dawley; Signal Transduction; tau Proteins; Uterus

The adipokinetic and red pigment-concentrating hormone (AKH/RPCH) family of peptides controls fat, carbohydrate, and protein metabolism in insects. In our previous study, we showed that AKH possesses antidepressant, anxiolytic, and analgesic effects, causes hyperlocomotion, and exerts neuroprotective effects and increased brain neurotrophic factors in mice. The aim of this study was to investigate the effects of Anax imperator AKH (Ani-AKH), Libellula auripennis AKH (Lia-AKH), and Phormia-Terra hypertrehalosemic hormone (Pht-HrTH) on MK-801-induced memory deterioration in the active allothetic place avoidance test (AAPA) and MK-801-induced sensorimotor gating deficit in the prepulse inhibition test (PPI). In the AAPA task, Long-Evans rats were treated with Ani-AKH (2 mg/kg), Lia-AKH (2 mg/kg), Pht-HrTH (2 mg/kg), MK-801 (0.15 mg/kg), and the combination of MK-801 with the hormones subchronically. In the prepulse inhibition test, Wistar albino rats were treated with Ani-AKH (1 mg/kg), Lia-AKH (1 mg/kg), Pht-HrTH (1 mg/kg), MK-801 (0.1 mg/kg), or the combination of MK-801 with hormones acutely before the test. In our study, Ani-AKH (2 mg/kg), Lia-AKH (2 mg/kg), and Pht-HrTH (2 mg/kg) reversed MK-801 (0.15 mg/kg)-induced cognitive memory impairment effects in the AAPA task. Lia-AKH (1 mg/kg) significantly potentiated the MK-801-induced PPI disruption, while Ani-AKH (1 mg/kg) partially potentiated the impairment caused by MK-801, and Pht-HrTH did not modify the effect of MK-801. In conclusion, AKH had no effect in sensorimotor gating deficits in the PPI test in schizophrenia model while AKH improved memory in the schizophrenia model of MK-801.

Topics: Animals; Anti-Anxiety Agents; Disease Models, Animal; Dizocilpine Maleate; Insect Hormones; Male; Memory; Memory Disorders; Neuropeptides; Neuroprotective Agents; Oligopeptides; Peptides; Pyrrolidonecarboxylic Acid; Rats; Rats, Long-Evans; Rats, Wistar; Schizophrenia

Atypical antipsychotic drugs have some efficacy in alleviating the negative and some cognitive symptoms of schizophrenia but those effects are small and mechanisms of this action are still unknown A few clinical reports have suggested that antidepressants (ADs), are able to augment the activity of atypical antipsychotic drugs. Thus, in the present study, we aimed to evaluate the effect of ADs, escitalopram (ESC) or mirtazapine (MIR) and aripiprazole (an atypical antipsychotic drug) given separately or jointly, on the MK-801-induced positive and cognitive symptoms of schizophrenia in mice.. The experiments were conducted on male Albino Swiss mice. ADs and aripiprazole were given 30min before MK-801 injection. Locomotor hyperactivity induced by MK-801 (0.3mg/kg) was measured for 30min, starting 30min after MK-801 administration. In the novel object recognition test, MK-801 (0.2mg/kg) was given 30min before the first introductory session. Memory retention was evaluated for 5min, starting 90min after the introductory session.. Aripiprazole (0.3mg/kg) reduced the locomotor hyperactivity induced by MK-801(0.3mg/kg). Co-treatment with an inactive dose of aripiprazole and ESC or MIR inhibited the effect of MK-801. Moreover, MK-801 (0.2mg/kg) decreased the memory retention. Aripiprazole (0.3mg/kg) reversed that effect. Co-treatment with an inactive dose of aripiprazole and ESC or MIR abolished the deficit of object recognition memory induced by MK-801.. The obtained results suggest that ADs may enhance the antipsychotic-like effect of aripiprazole in the animal tests used for evaluation of some positive and cognitive symptoms of schizophrenia.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Citalopram; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Drug Therapy, Combination; Hyperkinesis; Male; Memory Disorders; Mianserin; Mice; Mirtazapine; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology

Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies.. We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis.. To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms.. Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay.. These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.

Topics: Acetamides; Animals; Association Learning; Benzamides; Calcium Channel Blockers; Calcium Channels, T-Type; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Locomotion; Male; Memory Disorders; Piperidines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Effect of prenatal exposure to lambda-cyhalothrin (LCT) has been assessed on the integrity of NMDA receptors and associated post-synaptic signalling in hippocampus of developing rats. Decrease in the binding of [3H]-MK 801, known to label NMDA receptors was observed in hippocampus of rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22, compared to controls. Consistent with this, decrease in the mRNA and protein expression of NR1 and NR2B subunits of NMDA receptors was evident in rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22. There was no change in mRNA and protein expression of NR2A subunit of NMDA receptors. Prenatal exposure to LCT (1 and 3mg/kg body weight) decreased the expression of positive regulators (PSD95, pERK1/2, CaMKIIα & pCREB) and increased the expression of negative regulators (Cdk5 & SynGAP) associated with NMDA receptor dependent synaptic plasticity in hippocampus and impaired learning and memory of rats on PD22. The neurobehavioral changes continued to persist in rats exposed to LCT at high dose (3mg/kg body weight) while exhibited trend of recovery in those exposed at moderate dose (1mg/kg body weight) on PD45, compared to controls. No change in any of the neurobehavioral endpoint was observed in developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45. The results exhibit that alterations in NMDA receptors on prenatal exposure to LCT may affect postsynaptic signalling associated with impaired learning and memory in developing rats.

Topics: Age Factors; Animals; Animals, Newborn; Dizocilpine Maleate; Female; Fungicides, Industrial; Gene Expression Regulation; Hippocampus; Male; Maze Learning; Memory Disorders; Nitriles; Pregnancy; Prenatal Exposure Delayed Effects; Pyrethrins; Radioligand Assay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses

A previous study reported biotransformation of a citrus peel polymethoxyflavone, nobiletin, by Aspergillus enabling production of 4'-demethylnobiletin, and the product's antimutagenic activity. However, the effects of fermented citrus peel on the basal forebrain-hippocampal system remain unidentified. Citrus reticulata (ponkan) fruit squeezed draffs are generated as mass waste in beverage factories. In this study using PC12D cells and cultured central nervous system neurons, we therefore examined whether Aspergillus kawachii-fermented citrus fruit squeezed draff could affect cAMP response element (CRE)- and choline acetyltransferase gene (ChAT) promoter region-mediated transcriptional activities relevant to memory formation and cholinergic function. Our current fermentation yielded approximately 80% nobiletin bioconversion, and a sample of hot-water extract of the fermented fruit squeezed draff was stronger than that of the unfermented one in facilitating CRE-mediated transcription in cultured hippocampal neurons as well as in PC12D cells. A sample of 0-80% ethanol-eluted fraction of Diaion HP-20 column-adsorbed components of the preparation obtained by the fermentation concentration-dependently and more strongly facilitated CRE-mediated transcription than did the fraction of the unfermented one in both cell culture systems. In a separate study, this polymethoxyflavone-rich fraction of the fermented fruit squeezed draff showed a potent ability to facilitate CRE-mediated and ChAT transcription in a co-culture of hippocampal neurons and basal forebrain neurons. Repeated oral gavage of mice with the fermented fraction sample prevented MK801-impaired memory formation in mice. These findings suggest that the 4'-demethylnobiletin-rich fraction prepared from the Aspergillus-fermented ponkan squeezed draff has a potential anti-dementia effect.

Topics: Animals; Aspergillus; Brain; Cell Culture Techniques; Choline O-Acetyltransferase; Citrus; Cyclic AMP Response Element-Binding Protein; Dementia; Dizocilpine Maleate; Fermentation; Flavones; Fruit; Hippocampus; Memory Disorders; Mice; Neurons; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Transcription, Genetic

Choline is essential to the development and function of the central nervous system and supplemental choline during development is neuroprotective against a variety of insults, including neurotoxins like dizocilpine (MK-801). MK-801 is an NMDA receptor antagonist that is frequently used in rodent models of psychological disorders, particularly schizophrenia. At low doses, it causes cognitive impairments, and at higher doses it induces motor deficits, anhedonia, and neuronal degeneration. The primary goals of the present study were to investigate whether prenatal choline supplementation protects against the cognitive impairments, motor deficits, and neuropathologies that are precipitated by MK-801 administration in adulthood. Adult male Sprague-Dawley rats were fed a standard or supplemented choline diet prenatally. Using the novelty preference test of object recognition, we found that only prenatal standard-fed rats displayed memory consolidation deficits induced by low-dose MK-801 administered immediately following study of sample objects; all other groups, including prenatal choline supplemented rats given MK-801, showed intact memory. Following high-dose MK-801, prenatal choline supplementation significantly alleviated rats' motor response to MK-801, particularly ataxia. Using doublecortin and Ki67 to mark neurogenesis and cell division, respectively, in the hippocampus, we found that prenatal choline supplementation, in the face of MK-801 toxicity, protected against reduced hippocampal plasticity. Taken together, the current findings suggest that prenatal choline supplementation protects against a variety of behavioral and neural pathologies induced by the neurotoxin, MK-801. This research contributes to the growing body of evidence supporting the robust neuroprotective capacity of choline.

Topics: Aging; Animals; Choline; Dizocilpine Maleate; Doublecortin Protein; Female; Hippocampus; Male; Memory; Memory Disorders; Motor Activity; Neurotoxins; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley

Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3mg/kg of MK-801 was most effective in inducing locomotion. 0.3mg/kg of MK-801 was most effective in decreasing PPI. 0.03mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03mg/kg MK-801 can establish a "pure" memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC.

Topics: Amino Acids; Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Locomotion; Male; Memory Disorders; Neurotransmitter Agents; Oncogene Protein v-akt; Prefrontal Cortex; Prepulse Inhibition; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Reflex, Startle; Sensory Gating; Thalamus

The cognitive symptoms observed in schizophrenia are not consistently alleviated by conventional antipsychotics. Following a recent pilot study, sodium nitroprusside (SNP) has been identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.. The present experiments were designed to explore the effects of SNP on the highly translatable trial-unique, delayed nonmatching-to-location (TUNL) task in rats with and without acute MK-801 treatment.. SNP (0.5, 1.0, 2.0, 4.0, and 5.0 mg/kg) and MK-801 (0.05, 0.075, and 0.1 mg/kg) were acutely administered to rats trained on the TUNL task.. Acute MK-801 treatment impaired TUNL task accuracy. Administration of SNP (2.0 mg/kg) with MK-801 (0.1 mg/kg) failed to rescue performance on TUNL. SNP (5.0 mg/kg) administration nearly 4 h prior to MK-801 (0.05 mg/kg) treatment had no preventative effect on performance impairments. SNP (2.0 mg/kg) improved performance on a subset of trials.. These results suggest that SNP may possess intrinsic cognitive-enhancing properties but is unable to block the effects of acute MK-801 treatment on the TUNL task. These results are inconsistent with the effectiveness of SNP as an adjunct therapy for working memory impairments in schizophrenia patients. Future studies in rodents that assess SNP as an adjunct therapy will be valuable in understanding the mechanisms underlying the effectiveness of SNP as a treatment for schizophrenia.

Topics: Animals; Antihypertensive Agents; Antipsychotic Agents; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Memory Disorders; Memory, Short-Term; Nitroprusside; Nootropic Agents; Pilot Projects; Psychomotor Performance; Rats; Rats, Long-Evans; Schizophrenia; Vasodilator Agents

Swertisin, a plant-derived C-glucosylflavone, is known to have antidiabetic, anti-inflammatory and antioxidant effects. In the present study, we investigated in mice the effects of swertisin on glutamatergic dysfunction induced by dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate receptor antagonist. In the Acoustic Startle Response test, their MK-801-induced (given 0.2 mg/kg i.p.) pre-pulse inhibition deficit was significantly attenuated by the administration of swertisin (30 mg/kg p.o.). In the Novel Object Recognition Test, the recognition memory impairments that were induced by MK-801 (0.2 mg/kg, given i.p.) were also reversed by administration of swertisin (30 mg/kg p.o.). In addition, swertisin normalized the MK-801-induced elevation of phosphorylation levels of Akt and GSK-3β signaling molecules in the prefrontal cortex. These results indicated that swertisin may be useful in managing the symptoms of schizophrenia, including sensorimotor gating disruption and cognitive impairment, and that these behavioral outcomes may be related to Akt-GSK-3β signaling in the prefrontal cortex.

Topics: Acoustic Stimulation; Animals; Apigenin; Cognitive Dysfunction; Dizocilpine Maleate; Flavonoids; Glycogen Synthase Kinase 3; Male; Memory Disorders; Mice; Mice, Inbred ICR; Phosphorylation; Prefrontal Cortex; Proto-Oncogene Proteins c-akt; Reflex, Startle; Schizophrenia; Sensory Gating; Signal Transduction

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction plays an important role in schizophrenia. Positive allosteric modulators of α7 nAChR have emerged as a promising therapeutic approach to manage cognitive deficits that are inadequately treated in schizophrenic patients. The aim of the present study was to evaluate the ability of type I (CCMI) and type II (PNU120596) α7 nAChR positive allosteric modulators to counteract MK-801-induced cognitive and sensorimotor gating deficits. The activity of these compounds was compared with the action of the α7 nAChR agonist A582941. CCMI, PNU120596 and A582941 reversed the sensorimotor gating impairment evoked by MK-801 based on the prepulse inhibition of the startle response. Additionally, no MK-801-evoked working memory deficits were observed with α7 nAChR ligand pretreatment as assessed in a discrete paired-trial delayed alternation task. However, these compounds did not affect the rats' attentional performances in the five-choice serial reaction time test. The α7 nAChR agents demonstrated a beneficial effect on sensorimotor gating and some aspects of cognition tested in a rat model of schizophrenia. Therefore, these results support the use of α7 nAChR positive allosteric modulators as a potential treatment strategy in schizophrenia.

Topics: Acetylcholine; Allosteric Regulation; alpha7 Nicotinic Acetylcholine Receptor; Animals; Attention; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Isoxazoles; Male; Memory Disorders; Memory, Short-Term; Nicotinic Agonists; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia; Sensory Gating

The present study was carried out to evaluate whether the combined administration of sarcosine with risperidone possess any advantageous effects on dopaminergic and NMDA receptor-mediated glutamatergic neurotransmissions as compared to single drug administration in rats. The Wistar rats were divided into 7 groups each with different treatments. MK-801 (0.1 mg/kg, i.p.) was injected as single dose on 14th day for inducing learning and memory deficits in animals. Sarcosine (300 and 600 mg/kg, i.p.) and risperidone (0.2 mg/kg, i.p.) were administered daily for 14 days. Spatial habituation learning and hole board tests were performed on 14th day followed by measurement of GABA and 5-HT levels in brain tissues of rats. Pretreatment of sarcosine (600 mg/kg, i.p.) non-significantly improved learning and memory deficits induced by non-competitive NMDA receptor antagonist MK-801, significantly increased the GABA and decreased the 5-HT levels (p<0.05). Combined administration of sarcosine (300 mg/kg, i.p.) with risperidone (0.1 mg/kg, i.p.) synergistically improved cognitive deficits significantly, decreased % errors in hole board learning test, and increased centre time, corner time in spatial habituation learning test (p<0.05). The combined administration also potentiated the GABA and decreased 5-HT levels, indicating that the increased synaptic glycine concentrations may enhance NMDA receptor function which is directly linked with increased GABAergic transmission in striatum region and decreased 5-HT levels showed antagonistic action hence, enhancing the cognition. Our results suggest that combined administration of sarcosine with risperidone may strengthen glutamatergic tone in striatum. Thus, it may be a novel regime to improve psychotic symptoms and cognitive deficit in schizophrenia.

Topics: Animals; Antipsychotic Agents; Dizocilpine Maleate; gamma-Aminobutyric Acid; Glycine; Glycine Plasma Membrane Transport Proteins; Learning Disabilities; Male; Memory Disorders; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Risperidone; Sarcosine; Serotonin

Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.

Topics: Animals; Avoidance Learning; Benzothiazoles; Cholinesterase Inhibitors; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Histamine H3 Antagonists; Indans; Male; Memory; Memory Disorders; Nootropic Agents; Phenoxypropanolamines; Piperidines; Pyrilamine; Pyrroles; Quinazolines; Random Allocation; Rats, Wistar; Receptors, Histamine H3

Atypical antipsychotic drugs have some efficacy in alleviating the negative and some cognitive symptoms of schizophrenia but those effects are small and mechanisms of this action are still unknown. A few clinical reports have suggested that the antidepressant drugs, especially selective serotonin reuptake inhibitors (SSRI) are able to augment the activity of atypical antipsychotic drugs, thus effectively improving treatment of the negative and some cognitive symptoms of schizophrenia.. In the present study, we evaluated the effect of escitalopram (SSRI) and risperidone (an atypical antipsychotic drug), given separately or jointly, on the effect of MK-801 (a NMDA receptor antagonist) given before to the first introductory session, in the object recognition memory test. The mice were tested for the ability to discriminate between an old, familiar and a novel object. Escitalopram and risperidone were given 30min before MK-801, and MK-801 was administered 30min before the first introductory session. Memory retention was evaluated 90min after the introductory session.. The obtained results showed that MK-801 (0.2mg/kg) decreased memory retention when given before the introductory session. Risperidone at a higher dose (0.1mg/kg) reversed that effect. Co-treatment with an ineffective dose of risperidone (0.01mg/kg) and escitalopram (5 or 10mg/kg) abolished the deficit of object recognition memory induced by MK-801.. The obtained results suggest that escitalopram may enhance the antipsychotic-like effect of risperidone in the animal tests used for evaluation of some cognitive symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Citalopram; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Exploratory Behavior; Male; Memory Disorders; Mice; Recognition, Psychology; Risperidone; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended.

Topics: Aging; Animals; Anti-Anxiety Agents; Chlorpyrifos; Cholinesterase Inhibitors; Cues; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Maze Learning; Memory Disorders; Memory, Long-Term; Movement; Neuroprotective Agents; Photic Stimulation; Physical Stimulation; Rats; Rats, Wistar; Spatial Behavior; Time Factors

There is a near correlation between N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid (GABA) receptors in the modulation of learning and memory in the basolateral amygdala (BLA). In this study, we investigated the involvement of GABAA receptors in the BLA in amnesia induced by (+)-MK-801, a noncompetitive antagonist of NMDA receptors, in male Wistar rats. After guide cannulae were bilaterally placed in the BLA, animals were trained in a step-through type passive avoidance task and then tested 24h after training to measure memory retrieval and locomotor activity. Post-training intra-BLA microinjection of (+)-MK-801 (0.5 μg/rat) and GABAA receptor agonists (muscimol at doses 0.05 and 0.1 μg/rat) or antagonist (bicuculline at doses 0.05 and 0.1 μg/rat) decreased step-through latency during retrieval but did not alter locomotor activity. Results also showed that a subthreshold dose of muscimol (0.025 μg/rat) potentiated impairment induced by (+)-MK-801, whereas bicuculline (0.025 μg/rat) restored it. Furthermore, the highest dose of muscimol (0.5 μg/rat) increased locomotor activity induced by (+)-MK-801. Isobologram analysis showed that there was an additive but not synergistic effect between muscimol and (+)-MK-801 on memory retention deficits in the BLA. In conclusion, muscimol and bicuculline decreased retention of memory formation in the BLA, and GABAA receptors in the BLA may be involved in the additive effect on (+)-MK-801-induced memory retention deficits.

Topics: Animals; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; GABA-A Receptor Agonists; Male; Memory Disorders; Muscimol; Rats; Rats, Wistar; Receptors, GABA-A

Limitations of preclinical models of human memory contribute to the pervasive view that rodent models do not adequately predict therapeutic efficacy in producing cognitive impairments or improvements in humans. We used a source-memory model (i.e., a representation of the origin of information) we developed for use in rats to evaluate possible drug-induced impairments of both spatial memory and higher order memory functions in the same task. Memory impairment represents a major barrier to use of NMDAR antagonists as pharmacotherapies. The scaffolding protein postsynaptic density 95kDa (PSD95) links NMDARs to the neuronal enzyme nitric oxide synthase (nNOS), which catalyzes production of the signaling molecule nitric oxide (NO). Therefore, interrupting PSD95-nNOS protein-protein interactions downstream of NMDARs represents a novel therapeutic strategy to interrupt NMDAR-dependent NO signaling while bypassing unwanted side effects of NMDAR antagonists. We hypothesized that the NMDAR antagonist MK-801 would impair source memory. We also hypothesized that PSD95-nNOS inhibitors (IC87201 and ZL006) would lack the profile of cognitive impairment associated with global NMDAR antagonists. IC87201 and ZL006 suppressed NMDA-stimulated formation of cGMP, a marker of NO production, in cultured hippocampal neurons. MK-801, at doses that did not impair motor function, impaired source memory under conditions in which spatial memory was spared. Thus, source memory was more vulnerable than spatial memory to impairment. By contrast, PSD95-nNOS inhibitors, IC87201 and ZL006, administered at doses that are behaviorally effective in rats, spared source memory, spatial memory, and motor function. Thus, PSD95-nNOS inhibitors are likely to exhibit favorable therapeutic ratios compared to NMDAR antagonists.

Topics: Aminosalicylic Acids; Animals; Benzylamines; Cells, Cultured; Chlorophenols; Cyclic GMP; Disease Models, Animal; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Embryo, Mammalian; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hippocampus; Intracellular Signaling Peptides and Proteins; Male; Maze Learning; Membrane Proteins; Memory Disorders; N-Methylaspartate; Neurons; Nitric Oxide Synthase Type I; Rats; Rats, Long-Evans; Triazoles

Cognitive deficits are core symptoms of schizophrenia, but effective treatments are still lacking. Previous studies have reported that the brain-derived neurotrophic factor (BDNF) signaling is closely involved in learning and memory. Monosialotetrahexosylganglioside (GM1) is a ganglioside with wide-ranging pharmacologic effects that enhances the BDNF signaling cascade. This study aimed to assess the effects of GM1 on schizophrenia-related cognitive impairments. A brief disruption of N-methyl-D-aspartate receptors with MK801 was used to generate the animal model for cognitive deficits in schizophrenia. It was found that MK801-treated mice showed significant deficits in memory ability compared with control mice in different behavior tests, and this was accompanied by decreased hippocampal BDNF signaling pathway. Consecutive administration of GM1 fully restored the MK801-induced cognitive deficits and the impaired BDNF signaling in the hippocampus. Furthermore, a BDNF system inhibitor abolished the effects of GM1 in the MK801 model. Taken together, our results show that GM1 could reverse the MK801-induced cognitive deficits, suggesting a potential usefulness of GM1 in treating the schizophrenia-related cognitive impairments.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; G(M1) Ganglioside; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Signal Transduction

A plethora of studies have indicated that enriched environment (EE) paradigm provokes plastic and morphological changes in astrocytes with accompanying increments of their density and positively affects the behavior of rodents. We also previously documented that EE could be employed to preclude several behavioral abnormalities, mainly cognitive deficits, attributed to postnatal N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) treatment, as a rodent model of schizophrenia (SCH) aspects. Given this, the current study quantitatively investigated the number of cells, presumed to be astrocytes, expressing two astroglia-associated proteins (S100B and glial fibrillary acidic protein (GFAP)) by immunohistochemistry in the prefrontal cortex (PFC), along with anxiety and passive avoidance (PA) learning behaviors by utilizing elevated plus maze (EPM) and shuttle-box tests, in MK-801-treated male wistar rats submitted to EE and non-EE rats. Following a treatment regime of sub-chronic MK-801 (1.0mg/kg i.p. daily for five consecutive days from postnatal day (P) 6), S-100B-positive cells and anxiety level were markedly increased, while the GFAP-positive cells and PA learning were notably attenuated. The trend of diminished GFAP-immunopositive cells and elevated S100B-immunostained cells in the PFC was reversed in the SCH-like rats by exposure of animals to EE, commencing from birth up to the time of experiments on P28-85. Additionally, EE exhibited an ameliorating effect on the behavioral abnormalities evoked by MK-801. Overall, present findings support that improper astrocyte functioning and behavioral changes, reminiscent of the many facets of SCH, occur consequential to repetitive administration of MK-801 and that raising rat pups in an EE mitigates these alterations.

Topics: Animals; Anxiety; Astrocytes; Avoidance Learning; Dizocilpine Maleate; Environment; Excitatory Amino Acid Antagonists; Glial Fibrillary Acidic Protein; Locomotion; Male; Memory Disorders; Prefrontal Cortex; Rats; Rats, Wistar; S100 Calcium Binding Protein beta Subunit

Amphetamine (AMPH) induces deficits in cognition, and depressive-like behavior following withdrawal. The aim of the present study was to investigate whether pre-treatment with memantine (5mg/kg, i.p.), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, attenuates memory impairment induced by withdrawal from a 1 day binge regimen of AMPH (2mg/kg, four times every 2h, i.p.), in the novel object recognition test in rats. Herein, the influence of scopolamine (0.1mg/kg), an antagonist of the muscarinic cholinergic receptors, and the impact of MK-801 (0.1mg/kg), an antagonist of the NMDA receptors, on the memantine effect, were ascertained. Furthermore, the impact of memantine (5; 10; 20mg/kg, i.p.) was measured on depression-like effects of abstinence, 14 days after the last AMPH treatment (2mg/kg×1×14 days), in the forced swim test. In this test, the efficacy of memantine was compared to that of tricyclic antidepressant imipramine (10; 20; 30mg/kg, i.p.). Our study indicated that withdrawal from a binge regimen of AMPH impaired recognition memory. This effect was attenuated by administration of memantine at both 72h and 7 days of withdrawal. Moreover, prior administration of scopolamine, but not MK-801, decreased the memantine-induced recognition memory improvement. In addition, memantine reversed the AMPH-induced depressive-like behavior in the forced swim test in rats. The antidepressant-like effects of memantine were stronger than those of imipramine. Our study indicates that memantine constitutes a useful approach towards preventing cognitive deficits induced by withdrawal from an AMPH binge regimen and by depressive-like behavior during AMPH abstinence.

Topics: Amphetamine; Amphetamine-Related Disorders; Animals; Antidepressive Agents; Central Nervous System Stimulants; Depression; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Imipramine; Male; Memantine; Memory Disorders; Muscarinic Antagonists; Nootropic Agents; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Scopolamine; Substance Withdrawal Syndrome

The aim of study was to investigate the effects of pyrroloquinoline quinone (PQQ) combined with d-serine on the modulation of glycine sites in the brain of rats using social recognition test. Rats were divided into seven groups (n=10) and given repeated intraperitoneal (ip) injections of saline, MK-801 (0.5mg/kg), clozapine (1mg/kg), haloperidol (0.1mg/kg), d-serine (0.8g/kg), PQQ (2.0μg/kg), or d-serine (0.4g/kg) combined with PQQ (1.0μg/kg) for seven days. A social recognition test, including assessment of time-dependent memory impairment, was performed. A non-competitive NMDA receptor antagonist, MK-801, significantly impaired social memory, and this impairment was significantly repaired with an atypical antipsychotic (clozapine) but not with a typical antipsychotic (haloperidol). Likewise, d-serine combined with PQQ significantly improved MK-801-disrupted cognition in naïve rats, whereas haloperidol was ineffective. The present results show that the co-agonist NMDA receptor treated with PQQ and d-serine enhances social memory and may be an effective approach for treating the cognitive dysfunction observed in schizophrenic patients. PQQ stimulates glycine modulatory sites by which it may antagonize indirectly by removing glycine from the synaptic cleft or by binding the unsaturated site with d-serine in the brain, providing the insights into future research of central nervous system and drug discovery.

Topics: Animals; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Drug Contamination; Drug Synergism; Glycine; Haloperidol; Male; Memory; Memory Disorders; Neuroprotective Agents; PQQ Cofactor; Rats; Rats, Sprague-Dawley; Serine; Social Behavior; Time Factors

Cognitive deficits are a core symptom of schizophrenia. It is controversial whether antidepressants could improve cognitive symptoms in schizophrenia patients. The present study was designed to identify the therapeutic effect of antidepressants on cognitive deficits in schizophrenia. In the present study, adolescent rats were repeatedly exposed to dizocilpine, which can induce cognitive deficits associated with schizophrenia. Then these rats were treated by six antidepressants (fluvoxamine, sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine) or vehicle. The rats in the control group were exposed to vehicle during the study. Lastly, all rats' spatial memory (a major part of cognition) was assessed using the Morris water maze (MWM) test, and the density of hippocampal parvalbumin (PV) interneurons was evaluated to explore possible mechanisms underlying spatial memory change in schizophrenia. The results of the present study supported the hypothesis of a therapeutic effect of fluvoxamine and escitalopram on spatial memory deficit induced by dizocilpine. Additionally, the data of the present study suggested that fluvoxamine and escitalopram remitted hippocampal PV interneuron reduction induced by dizocilpine. The neuroprotective effect of fluvoxamine and escitalopram may partly explain the therapeutic effect of antidepressants on spatial memory deficit in schizophrenia patients.

Topics: Animals; Antidepressive Agents; Cell Count; Citalopram; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluvoxamine; Hippocampus; Interneurons; Male; Maze Learning; Memory Disorders; Mianserin; Mirtazapine; Paroxetine; Rats; Rats, Sprague-Dawley; Schizophrenia; Schizophrenic Psychology; Sertraline; Spatial Memory; Venlafaxine Hydrochloride

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1-0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5-20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.

Topics: Animals; Antipsychotic Agents; Cannabinoid Receptor Modulators; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Endocannabinoids; Excitatory Amino Acid Antagonists; Male; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Mice; Motor Activity; Oleic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Schizophrenia; Schizophrenic Psychology

High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10mg/kg/day BM orally for 21weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory (p<0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p<0.05), however, no changes were seen in the hippocampus (p>0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p<0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus.

Topics: Animals; Autoradiography; Diet, High-Fat; Disease Models, Animal; Dizocilpine Maleate; Drug Administration Schedule; Exploratory Behavior; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oleanolic Acid; Prefrontal Cortex; Protein Binding; Recognition, Psychology; Signal Transduction; Statistics, Nonparametric; Tritium

Topics: Animals; Antipsychotic Agents; Cognition; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Male; Memory Disorders; Motor Activity; Nootropic Agents; Random Allocation; Rats, Sprague-Dawley; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology

Many peripheral diseases are associated with a decline in cognitive function. In this regard, there have been reports of patients with inflammatory bowel disease and an otherwise unexplained memory impairment.. We sought to assess the memory performance of mice with colitis. We also investigated the roles of N-methyl D-aspartate (NMDA) receptors and nitric oxide (NO) as possible mediators of colitis-induced amnesia.. To induce colitis, male NMRI mice were intrarectally injected with a solution containing dinitrobenzene sulfonic acid (DNBS; 4 mg in 100 μl) under anesthesia. Three days after intrarectal DNBS instillation, spatial recognition and associative memories were assessed by the Y-maze and passive avoidance tasks, respectively. The NMDA antagonists, MK-801 and memantine, and the inducible NO synthase (iNOS) inhibitor, aminoguanidine, were injected intraperitoneally 45 min before the Y-maze task.. Induction of colitis by DNBS impaired spatial recognition memory in the Y-maze task but had no effect on step through latencies in the passive avoidance test. Colitis-induced amnesia was reversed by administering specific doses of MK-801 and memantine (30 μg/kg and 1 mg/kg, respectively) suggesting dysregulated NMDA receptor activation as an underlying mechanism. No effect was seen with lower and higher doses of these drugs, resulting in a bell-shaped dose response curve. Colitis-induced amnesia was also inhibited by aminoguanidine (50 mg/kg), implicating a role for iNOS activation and neuroinflammation in this phenomenon.. DNBS-induced colitis impairs memory through NMDA receptor overstimulation and NO overproduction.

Topics: Animals; Avoidance Learning; Benzenesulfonates; Cognition; Colitis; Dizocilpine Maleate; Guanidines; Male; Memantine; Memory Disorders; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Receptors, N-Methyl-D-Aspartate; Spatial Memory

The present study aimed to examine the neurophysiological mechanisms of the 2,6-diisopropylphenol and N-methyl-D-aspartate (NMDA) receptor antagonist against learning and memory impairment, induced by electroconvulsive therapy (ECT). A total of 48 adult depressed rats without olfactory bulbs were randomly divided into six experimental groups: i) saline; ii) 10 mg/kg MK‑801; iii) 10 mg/kg MK‑801 and a course of ECT; iv) 200 mg/kg 2,6‑diisopropylphenol; v) 200 mg/kg 2,6‑diisopropylphenol and a course of ECT; and vi) saline and a course of ECT. The learning and memory abilities of the rats were assessed using a Morris water maze 1 day after a course of ECT. The hippocampus was removed 1 day after assessment using the Morris water maze assessment. The content of glutamate in the hippocampus was detected using high‑performance liquid chromatography. The expression levels of p‑AT8Ser202 and GSK‑3β1H8 in the hippocampus were determined using immunohistochemical staining and western blot analysis. The results demonstrated that the 2,6‑diisopropylphenol NMDA receptor antagonist, MK‑801 and ECT induced learning and memory impairment in the depressed rats. The glutamate content was significantly upregulated by ECT, reduced by 2,6‑diisopropylphenol, and was unaffected by the NMDA receptor antagonist in the hippocampus of the depressed rats. Tau protein hyperphosphorylation in the hippocampus was upregulated by ECT, but was reduced by 2,6‑diisopropylphenol and the MK‑801 NMDA receptor antagonist. It was also demonstrated that 2,6‑diisopropylphenol prevented learning and memory impairment and reduced the hyperphosphorylation of the Tau protein, which was induced by eECT. GSK‑3β was found to be the key protein involved in this signaling pathway. The ECT reduced the learning and memory impairment, caused by hyperphosphorylation of the Tau protein, in the depressed rats by upregulating the glutamate content.

Topics: Animals; Depressive Disorder; Dizocilpine Maleate; Electroconvulsive Therapy; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Learning Disabilities; Male; Maze Learning; Memory Disorders; Propofol; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Reportedly, negative modulation of α5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of α5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of α5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia.

Topics: Amphetamine; Animals; Behavior, Animal; Benzodiazepines; Cognition Disorders; Dizocilpine Maleate; Hyperkinesis; Male; Maze Learning; Memory Disorders; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Schizophrenia

To explore the possible neurophysiologic mechanisms of propofol and N-methyl-D- aspartate (NMDA) receptor antagonist against learning-memory impairment of depressed rats without olfactory bulbs.. Models of depressed rats without olfactory bulbs were established. For the factorial design in analysis of variance, two intervention factors were included: electroconvulsive shock groups (with and without a course of electroconvulsive shock) and drug intervention groups [intraperotoneal (ip) injection of saline, NMDA receptor antagonist MK-801 and propofol. A total of 60 adult depressed rats without olfactory bulbs were randomly divided into 6 experimental groups (n=10 per group): ip injection of 5 ml saline; ip injection of 5 ml of 10 mg/kg MK-801; ip injection of 5 ml of 10 mg/kg MK-801 and a course of electroconvulsive shock; ip injection of 5 ml of 200 mg/kg propofol; ip injection of 5 ml of 200 mg/kg propofol and a course of electroconvulsive shock; and ip injection of 5 ml saline and a course of electroconvulsive shock. The learning-memory abilities of the rats was evaluated by the Morris water maze test. The content of glutamic acid in the hippocampus was detected by high-performance liquid chromatography. The expressions of p-AT8Ser202 in the hippocampus were determined by Western blot analysis.. Propofol, MK-801 or electroconvulsive shock alone induced learning-memory impairment in depressed rats, as proven by extended evasive latency time and shortened space probe time. Glutamic acid content in the hippocampus of depressed rats was significantly up-regulated by electroconvulsive shock and down-regulated by propofol, but MK-801 had no significant effect on glutamic acid content. Levels of phosphorylated Tau protein p-AT8Ser202 in the hippocampus was up-regulated by electroconvulsive shock but was reduced by propofol and MK-801 alone. Propofol prevented learning-memory impairment and reduced glutamic acid content and p-AT8Ser202 levels induced by electroconvulsive shock.. Electroconvulsive shock might reduce learning-memory impairment caused by protein Tau hyperphosphorylation in depressed rats by down-regulating glutamate content.

Topics: Animals; Depression; Dizocilpine Maleate; Electroshock; Glutamic Acid; Learning Disabilities; Male; Memory Disorders; Phosphorylation; Propofol; Rats; Rats, Sprague-Dawley; tau Proteins

Targeting group II metabotropic glutamate receptors (mGluR2/3) has been proposed to correct the dysfunctional glutamatergic system, particularly NMDA receptor (NMDAR) hypofunction, for treatment of schizophrenia. However, how activation of mGluR2/3 affects NMDAR function in adult animals remains elusive. Here we show the effects of LY395756 (LY39), a compound acting as both an mGluR2 agonist and mGluR3 antagonist, on the NMDAR expression and function of normal adult rat prefrontal cortex (PFC) as well as working memory function in the MK801 model of schizophrenia. We found that in vivo administration of LY39 significantly increased the total protein levels of NMDAR subunits and NR2B phosphorylationin the PFC, along with the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSC) in the prefrontal cortical neurons. Moreover, LY39 also significantly increased mTOR and pmTOR expression, but not ERK1/2, Akt, and GSK3β, suggesting an activation of mTOR signaling. Indeed, the mTOR inhibitor rapamycin, and actinomycin-D, a transcription inhibitor, blocked the enhanced effects of LY39 on NMDAR-mEPSCs. These results indicate that LY39 regulates NMDAR expression and function through unidentified mTOR-mediated protein synthesis in the normal adult rat PFC. However, this change is insufficient to affect working memory function in normal animals, nor to reverse the MK801-induced working memory deficit. Our data provide the first evidence of an in vivo effect of a novel compound that acts as both an mGluR2 agonist and mGluR3 antagonist on synaptic NMDAR expression and function in the adult rat PFC, although its effect -on PFC-dependent cognitive function remains to be explored.

Topics: Amino Acids, Dicarboxylic; Animals; Attention; Bridged Bicyclo Compounds; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agents; Gene Expression Regulation; Immunosuppressive Agents; In Vitro Techniques; Male; MAP Kinase Signaling System; Memory Disorders; Memory, Short-Term; Patch-Clamp Techniques; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sirolimus; Synaptic Membranes; Synaptic Potentials

Blockade of the N-methyl-d-aspartate receptors (NMDARs) during the neonatal period has been reported to induce long-term behavioral and neurochemical alterations that are relevant to schizophrenia. In this study, we examined the effects of such treatment on recognition memory and hippocampal excitatory and inhibitory (E/I) balance in both adolescence and adulthood. After exposure to the NMDAR antagonist, MK-801, at postnatal days (PND) 5-14, male Sprague-Dawley rats were tested for object and object-in-context recognition memory during adolescence (PND 35) and adulthood (PND 63). The parvalbumin-positive (PV+) γ-aminobutyric acid (GABA)-ergic interneurons and presynaptic markers for excitatory and inhibitory neurons, vesicular glutamate transporter-1 (VGLUT1) and vesicular GABA transporter (VGAT) were examined in the hippocampus to reflect the E/I balance. We found that rats receiving MK-801 treatment showed deficits of recognition memory, reduction in PV+ cell counts and upregulation of the VGLUT1/VGAT ratio in both adolescence and adulthood. Notably, the changes of the VGLUT1/VGAT ratio at the two time points exhibited distinct mechanisms. These results parallel findings of hippocampal abnormalities in schizophrenia and lend support to the usefulness of neonatal NMDAR blockade as a potential neurodevelopmental model for the disease.

Topics: Animals; Animals, Newborn; Cell Count; Disease Models, Animal; Dizocilpine Maleate; Exploratory Behavior; gamma-Aminobutyric Acid; Hippocampus; Immunohistochemistry; Male; Memory Disorders; Neurons; Parvalbumins; Random Allocation; Rats, Sprague-Dawley; Recognition, Psychology; Vesicular Glutamate Transport Protein 1; Vesicular Inhibitory Amino Acid Transport Proteins

Acute administration of the N-methyl-d-aspartate (NMDA) non-competitive antagonist, MK-801, impairs novel object recognition (NOR), locomotor activity in open field (OF) and conditioned taste aversion (CTA) in rodents. NMDAR partial agonist d-cycloserine (DCS) reverses these effects in NOR and CTA via modulation of glutamatergic, cholinergic and dopaminergic systems.. To test this hypothesis, we investigated the effects of DCS, a partial NMDAR agonist, on NOR memory, locomotor activity, and CTA memory in Wistar rats on NMDA-glutamate receptor antagonism by MK-801. The potential involvement of dopaminergic and cholinergic systems in improving cognitive functions was explored. MK-801-induced cognitive deficits were assessed using NOR, OF and CTA paradigms. MK-801-induced dopamine release increase in acetylcholinesterase (AChE), mono amine oxidase (MAO) activity and increase in c-fos expression were also investigated.. The effects caused by MK-801 (0.2 mg/kg) were inhibited by administration of the NMDA receptor agonist DCS (15 mg/kg). NOR and CTA paradigms inhibited by MK-801 were attenuated by DCS administration. Moreover, DCS also blocked the MK-801-induced abnormal increase in dopamine content, AChE activity and MAO activity. However, c-fos overexpression was controlled to some extent only.. Based on the NMDAR hypo function hypothesis in some neuropsychiatric disorders, our finding suggests that improving NMDAR hypo function by agonist DCS may play a significant role.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Conditioning, Psychological; Cycloserine; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Exploratory Behavior; Female; Memory Disorders; Monoamine Oxidase; Nootropic Agents; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Taste Perception

Pre- and early postnatal stress can cause dysfunction of the N-methyl-d-aspartate receptor (NMDAR) and thereby promote the development of hippocampus memory-dependent schizoid abnormalities of navigation in space, time, and knowledge. An enriched environment improves mental abilities in humans and animals. Whether an enriched environment can prevent the development of schizoid symptoms induced by neonatal NMDAR dysfunction was the central question of our paper. The experimental animals were Wistar rats. Early postnatal NMDAR dysfunction was created by systemic treatment of rat pups with the NMDAR antagonist MK-801 at PD10-20 days. During the development period (PD21-90 days), the rats were reared in cognitively and physically enriched cages. Adult age rats were tested on navigation based on pattern separation and episodic memory in the open field and on auto-hetero-associations based on episodic and semantic memory in a step-through passive avoidance task. The results showed that postnatal NMDAR antagonism caused abnormal behaviors in both tests. An enriched environment prevented deficits in the development of navigation in space based on pattern separation and hetero-associations based on semantic memory. However, an enriched environment was unable to rescue navigation in space and auto-associations based on episodic memory. These data may contribute to the understanding that an enriched environment has a limited capacity for therapeutic interventions in protecting the development of schizoid syndromes in children and adolescents.

Topics: Age Factors; Animals; Animals, Newborn; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Environment; Excitatory Amino Acid Antagonists; Fear; Female; Hippocampus; Male; Memory Disorders; Pregnancy; Rats; Rats, Wistar; Reaction Time; Receptors, N-Methyl-D-Aspartate; Schizoid Personality Disorder

Polymorphisms in the metabotropic glutamate receptor 3 (mGluR3) encoding gene GRM3 have been linked to schizophrenia and cognitive performance in humans. Our aim was to analyze the role of mGluR3 in basal working memory and attentional processes, and also when these functions were distracted by the psychotomimetic N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801). mGluR3 knockout (KO) mice were used. Spontaneous alternation in a T-maze test was significantly reduced in mGluR3-KO mice compared to wildtype (WT) mice, particularly after a low dose of MK-801 (0.03 mg/kg, i.p., 30 min). In a Y-maze novelty discrimination test, the locomotor stimulatory effect of MK-801 (0.1mg/kg) was enhanced in mGluR3-KO mice. Interestingly, mGluR3-KO mice showed the significantly reduced alternation in the spontaneous alternation T-maze test and the significantly enhanced sensitivity to MK-801 in the Y-maze test only when forced to enter the right arm first, not when the forced arm was on the left. A side-biased response was also found in a rewarded alternation T-maze test, where mGluR3-KO mice made significantly more incorrect visits to the left arm than the right arm after a 25-s delay. No genotype difference was found in the novelty discrimination in the Y-maze test, rewarded alternation with a 5-s delay, preference for left or right when free to enter either arm or in MK-801-induced circling. Our findings indicate cognitive disturbance and left-right asymmetry in certain behavioral responses of mGluR3-KO mice. This novel observation warrants further elucidation, and should also be considered in other studies of mGluR3 in brain functions.

Topics: Analysis of Variance; Animals; Attention; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Functional Laterality; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Knockout; Receptors, Metabotropic Glutamate

Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use. Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated, reconsolidation of memories of physiologically relevant social rewards has received little attention. Social play, the most characteristic social behaviour displayed by young mammals, is highly rewarding, illustrated by the fact that it can induce conditioned place preference (CPP). Here, we investigated the role of signalling mechanisms implicated in memory processes, including reconsolidation, namely glucocorticoid, mineralocorticoid, NMDA glutamatergic and CB1 cannabinoid receptors, in the reconsolidation of social play-induced CPP in rats. Systemic treatment with the glucocorticoid receptor antagonist mifepristone before, but not immediately after, retrieval disrupted the reconsolidation of social play-induced CPP. Mifepristone did not affect social play-induced CPP in the absence of memory retrieval. Treatment with the NMDA receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP. However, the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and CB1 cannabinoid receptor antagonists spironolactone and rimonabant, respectively. We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats. These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories.

Topics: Analysis of Variance; Animals; Cannabinoid Receptor Antagonists; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hormone Antagonists; Male; Memory Disorders; Mifepristone; Mineralocorticoid Receptor Antagonists; Neuroprotective Agents; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reward; Rimonabant; Social Behavior; Spironolactone

It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B- but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation.

Topics: Animals; Association Learning; Basolateral Nuclear Complex; Conditioning, Psychological; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fear; Histone-Lysine N-Methyltransferase; Histones; Male; MAP Kinase Signaling System; Memory Disorders; Memory, Long-Term; Methylation; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reflex, Startle

The N-methyl-D-aspartate (NMDA) receptor is a subtype of ionotropic glutamate receptor that is involved in synaptic mechanisms of learning and memory, and mediates excitotoxic neuronal injury. In this study, we tested the hypothesis that NMDA receptor subunit gene expression is altered in cortex and hippocampus of OKA induced memory impairment. Therefore in the present study, we checked the effect of OKA (ICV) on NMDA receptor regulation and synapse function. The memory function anomalies and synaptosomal calcium ion (Ca(2+)) level were increased in OKA treated rats brain; which was further protected by MK801 (0.05mg/kg. i.p) treatment daily for 13days. To elucidate the involvement of NMDA receptor, we estimated NR1, NR2A and NR2B (subunits) expression in rat brain. Results showed that expression of NR1 and NR2B were significantly increased, but expression of NR2A had no significant change in OKA treated rat brain. We also observed decrease in synapsin-1 mRNA and protein expression which indicates synapse dysfunction. In addition, we detected an increase in MDA and nitrite levels and a decrease in GSH level in synapse preparation which indicates synapse altered redox stress. Moreover, neuronal loss was also confirmed by nissl staining in periventricular cortex and hippocampus. Altered level of oxidative stress markers along with neuronal loss confirmed neurotoxicity. Further, MK801 treatment restored the level of NR1, NR2B and synapsin-1 expression, and protected from neuronal loss and synapse redox stress. In conclusion, Okadaic acid (OKA) induced expression of NR1 and NR2B deteriorates synapse function in rat brain which was confirmed by the neuroprotective effect of MK801.

Topics: Animals; Base Sequence; Behavior, Animal; Dizocilpine Maleate; DNA Primers; Excitatory Amino Acid Antagonists; Hippocampus; Injections, Intraventricular; Male; Memory Disorders; Okadaic Acid; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; Synapses

Schizophrenia is a severe neuropsychiatric disorder that is characterized by core psychiatric symptoms, including positive, negative, and cognitive symptoms. Current treatments for schizophrenia have an effect on positive symptoms but have a limited efficacy on negative or cognitive symptoms. Oleanolic acid is a plant-derived pentacyclic terpenoid that is known to exhibit anti-oxidative and anti-inflammatory activities. Here, we investigated the effects of oleanolic acid on schizophrenia-like behaviors in mice elicited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. A single administration of oleanolic acid blocked MK-801-induced hyperlocomotion in the open field test. In the acoustic startle response test, oleanolic acid itself did not have any effects on the acoustic startle response or prepulse inhibition (PPI) level, whereas the MK-801-induced PPI deficit was ameliorated by oleanolic acid. In the novel object recognition test, the attention and recognition memory impairments induced by MK-801 were reversed by a single administration of oleanolic acid. Additionally, oleanolic acid normalized the MK-801-induced alterations of signaling molecules including phosphorylation levels of Akt and GSK-3β in the frontal cortex. These results suggest that oleanolic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, and cognitive impairments.

Topics: Animals; Antipsychotic Agents; Attention; Disease Models, Animal; Dizocilpine Maleate; Frontal Lobe; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hyperkinesis; Male; Memory Disorders; Mice, Inbred ICR; Oleanolic Acid; Phosphorylation; Prepulse Inhibition; Proto-Oncogene Proteins c-akt; Recognition, Psychology; Reflex, Startle; Schizophrenia

Neuropeptide S (NPS), the endogenous ligand of NPSR, has been shown to promote arousal and anxiolytic-like effects. According to the predominant distribution of NPSR in brain tissues associated with learning and memory, NPS has been reported to modulate cognitive function in rodents. Here, we investigated the role of NPS in memory formation, and determined whether NPS could mitigate memory impairment induced by selective N-methyl-D-aspartate receptor antagonist MK801, muscarinic cholinergic receptor antagonist scopolamine or Aβ₁₋₄₂ in mice, using novel object and object location recognition tasks. Intracerebroventricular (i.c.v.) injection of 1 nmol NPS 5 min after training not only facilitated object recognition memory formation, but also prolonged memory retention in both tasks. The improvement of object recognition memory induced by NPS could be blocked by the selective NPSR antagonist SHA 68, indicating pharmacological specificity. Then, we found that i.c.v. injection of NPS reversed memory disruption induced by MK801, scopolamine or Aβ₁₋₄₂ in both tasks. In summary, our results indicate that NPS facilitates memory formation and prolongs the retention of memory through activation of the NPSR, and mitigates amnesia induced by blockage of glutamatergic or cholinergic system or by Aβ₁₋₄₂, suggesting that NPS/NPSR system may be a new target for enhancing memory and treating amnesia.

Topics: Amyloid beta-Peptides; Animals; Dizocilpine Maleate; Infusions, Intraventricular; Male; Memory; Memory Disorders; Mice; Neuropeptides; Peptide Fragments; Receptors, Neuropeptide; Recognition, Psychology; Scopolamine

Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. Both the stimulation of the metabotropic glutamate (mGlu) 2/3 receptor and the blockade of the mGlu1 receptor have been shown to be effective in a number of animal models of schizophrenia. However, the efficacy for social cognition, which is poorly managed by current medication, has not been fully addressed. The present study evaluated the effects of an mGlu2/3-receptor agonist and an mGlu1-receptor antagonist on social memory impairment in rats. Pretreatment with an mGlu2/3-receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1-receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) without affecting the social interactions. In addition, the intraperitoneal administration of an mGlu2-receptor potentiator, 3'-[[(2-cyclopentyl-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-5-yl)oxy]methyl]-[1,1'-biphenyl]-4-carboxylic acid (BINA), also improved the MK-801-induced impairment of social memory, which was blocked by pretreatment with an mGlu2/3-receptor antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). These findings indicate that both the stimulation of the mGlu2 receptor and the inhibition of an mGlu1 receptor improve social memory impairment elicited by MK-801, and both manipulations could be effective approaches for the treatment of certain cognitive dysfunctions observed in schizophrenic patients.

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Memory Disorders; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Recognition, Psychology; Xanthenes

The spontaneous response to novelty is the basis of one-trial object recognition tests for the study of object recognition memory (ORM) in rodents. We describe an object recognition task for the rabbit, based on its natural tendency to scent-mark ("chin") novel objects. The object recognition task comprised a 15min sample phase in which the rabbit was placed into an open field arena containing two similar objects, then removed for a 5-360min delay, and then returned to the same arena that contained one object similar to the original ones ("Familiar") and one that differed from the original ones ("Novel"), for a 15min test phase. Chin-marks directed at each of the objects were registered. Some animals received injections (sc) of saline, ketamine (1mg/kg), or MK-801 (37μg/kg), 5 or 20min before the sample phase. We found that chinning decreased across the sample phase, and that this response showed stimulus specificity, a defining characteristic of habituation: in the test phase, chinning directed at the Novel, but not Familiar, object was increased. Chinning directed preferentially at the novel object, which we interpret as novelty-induced sensitization and the behavioral correlate of ORM, was promoted by tactile/visual and spatial novelty. ORM deficits were induced by pre-treatment with MK-801 and, to a lesser extent, ketamine. Novel object discrimination was not observed after delays longer than 5min. These results suggest that short-term habituation and sensitization, not long-term memory, underlie novel object discrimination in this test paradigm.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Ketamine; Male; Memory Disorders; Rabbits; Recognition, Psychology; Sex Characteristics; Statistics, Nonparametric; Time Factors

The objective of this study was to assess the effects of phosphodiesterase type 2 (PDE2) and type 10 (PDE10) inhibition on memory function in the object recognition task using the scopolamine- and MK-801-induced memory deficit model. The effects of the PDE2 inhibitor BAY 60-7550 and the PDE10 inhibitor PQ-10 on object recognition performance were investigated in the scopolamine (0.1mg/kg, i.p.) or MK-801 (0.125 mg/kg, i.p.) model. BAY 60-7550 was tested at a dose of 0.3-3mg/kg (p.o.) in both models; PQ-10 was tested at doses of 0.1-1mg/kg (p.o.) in the scopolamine model and 0.3-3mg/kg in the MK-801 model. All compounds were injected 30 min before the learning trial. Both BAY 60-7550 (1mg/kg) and PQ-10 (0.3mg/kg) attenuated the scopolamine-induced memory deficit. The MK-801-induced memory deficit was reversed after treatment with each PDE inhibitor at a dose of 1mg/kg or higher. PQ10 was highly brain penetrant, whereas 60-7550 levels in the brain were very low after oral treatment. We concluded that since BAY 60-7550 and PQ10 reversed both scopolamine- and MK-801-induced memory deficits, this supports the notion that dual substrate PDE inhibitors might be suitable candidates for cognition enhancement.

Topics: Animals; Blood-Brain Barrier; Brain; Cyclic Nucleotide Phosphodiesterases, Type 2; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Imidazoles; Male; Memory; Memory Disorders; Muscarinic Antagonists; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Recognition, Psychology; Scopolamine; Spectrometry, Mass, Electrospray Ionization; Triazines

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT₄R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.

Topics: AIDS-Related Complex; Analysis of Variance; Animals; Avoidance Learning; Benzopyrans; Brain-Derived Neurotrophic Factor; Citalopram; Depression; Disease Models, Animal; Dizocilpine Maleate; Emotions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Hippocampus; Immunoprecipitation; MAP Kinase Signaling System; Memory Disorders; Prefrontal Cortex; Rats; Rats, Mutant Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin; Swimming

The purpose of this study was to determine the effects of alstonine, an indole alkaloid with putative antipsychotic effects, on working memory by using the step-down inhibitory avoidance paradigm and MK801-induced working memory deficits in mice. Additionally, the role of serotonin 5-HT2A/C receptors in the effects of alstonine on mouse models associated with positive (MK801-induced hyperlocomotion), negative (MK801-induced social interaction deficit), and cognitive (MK801-induced working memory deficit) schizophrenia symptoms was examined. Treatment with alstonine was able to prevent MK801-induced working memory deficit, indicating its potential benefit for cognitive deficits now seen as a core symptom in the disease. Corroborating previously reported data, alstonine was also effective in counteracting MK801-induced hyperlocomotion and social interaction deficit. Ritanserin, a 5-HT2A/C receptor antagonist, prevented alstonine's effects on these three behavioral parameters. This study presents additional evidence that 5-HT2A/C receptors are central to the antipsychotic-like effects of alstonine, consistently seen in mouse models relevant to the three dimensions of schizophrenia symptoms.

Topics: Animals; Antipsychotic Agents; Dizocilpine Maleate; Hyperkinesis; Male; Memory Disorders; Mice; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Secologanin Tryptamine Alkaloids

Stigmasterol, a kind of phytosterol, is present in small amounts in various foods. In the present study, we investigated the effects of stigmasterol on scopolamine-induced memory impairments using the passive avoidance and the Morris water maze tasks in mice. In addition, changes in memory-related molecules, including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were examined following the administration of stigmasterol. Scopolamine-induced memory impairments were significantly attenuated by the administration of stigmasterol (10mg/kg) in the passive avoidance task. In the Morris water maze task, the escape latencies were significantly decreased in the stigmasterol-treated group compared to the scopolamine-treated group during the training phase. The swimming times within the target zone during the probe trial were significantly increased as compared to scopolamine-treated mice. Furthermore, the ameliorating effect of stigmasterol on scopolamine-induced memory dysfunction was blocked by a sub-effective dose of dizocilpine (MK-801), an NMDA receptor antagonist, and tamoxifen, an estrogen receptor antagonist, in the passive avoidance task. In addition, the expression levels of phosphorylated ERK and CREB in the hippocampus were significantly increased by stigmasterol, which was blocked by tamoxifen or MK-801 with scopolamine. These results suggest that stigmasterol-induced cognitive ameliorative effects are mediated by the enhancement of cholinergic neurotransmission system via the activation of estrogen or NMDA receptors.

Topics: Animals; Avoidance Learning; Cognition; Cyclic AMP Response Element-Binding Protein; Dizocilpine Maleate; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Phosphorylation; Scopolamine; Stigmasterol; Tamoxifen

Several years after the diagnosis of Parkinson's disease (PD), 20-30% of PD patients develop dementia, known as Parkinson's disease dementia (PDD), the features of which include impairment of short-term memory and recognition function. Hyperactivation of the glutamatergic system is implicated in the neurodegeneration seen in PD. The aim of this study was to determine the effects of MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, on short-term memory and object recognition in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat animal model. MPTP was injected stereotaxically into the substantia nigra pars compacta (SNc) of male Wistar rats, then, starting 1 day later (day 1), the rats were injected daily with MK-801 (0.2 mg/kg/day, i.p.) and rats underwent a bar test on days 1-7, a T-maze test on days 8-10, and object recognition test on days 12-14. On day 1, the animals showed motor dysfunction, which recovered to control levels on day 7. MPTP-lesioned rats showed impairment of working memory in the T-maze test and of recognition in the object recognition test, both of which were prevented by MK-801 treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all improved by MK-801 treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunction.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Analysis of Variance; Animals; Brain; Disease Models, Animal; Dizocilpine Maleate; Gene Expression Regulation; Male; Maze Learning; Memory Disorders; MPTP Poisoning; Neurodegenerative Diseases; Neuroprotective Agents; Rats; Rats, Wistar; Recognition, Psychology; Time Factors; Tyrosine 3-Monooxygenase

This study combined two neurodevelopmental manipulations, neonatal MK-801 treatment and isolation rearing, to produce a 'two-hit' model and determine whether two hits induce a more robust behavioural phenotype of an animal model of aspects of schizophrenia compared with individual manipulations alone. The effect of clozapine was also assessed. Male Sprague-Dawley rats received 0.2 mg/kg MK-801 or saline intraperitoneally (i.p.) once daily on postnatal days (PNDs) 7-10 and were assigned to group or isolation rearing at weaning (PND 21). From PND 77, they received a vehicle or 5 mg/kg clozapine (i.p.) treatment regimen and were subjected to three prepulse inhibition (PPI) tests, a locomotor activity assessment and a novel object recognition task. MK-801-treated rats reared in isolation displayed robust PPI disruptions which were consistently manifested in all three tests. PPI deficits were also detected in saline-treated rats reared in isolation but not in all tests. Only the two-hit rats demonstrated hyperlocomotion and impaired object recognition memory. Clozapine restored PPI anomalies in the two-hit rats. The two-hit model showed greater psychotic-like effects than either neonatal MK-801 or isolation rearing alone. The preliminary predictive validity shown with clozapine suggests this model may be useful for predicting the efficacy of putative antipsychotics.

Topics: Akathisia, Drug-Induced; Animals; Animals, Newborn; Antipsychotic Agents; Behavior, Animal; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Injections, Intraperitoneal; Male; Maternal Deprivation; Memory Disorders; Neural Inhibition; Neurotoxicity Syndromes; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Pioglitazone, a peroxisome proliferator activated receptor γ (PPARγ) agonist, is widely used in clinical medicine as a treatment for type 2 diabetes and is recently proved to have beneficial effects on improving cognition in early stages of Alzheimer's disease (AD). Moreover, it has been shown that pioglitazone reduces N-methyl-D-aspartate (NMDA, a glutamate agonist) mediated calcium currents and transients. Since enhanced calcium transients are present in AD models, we tested the hypothesis whether pioglitazone manifests its acquisition memory enhancement role through glutamatergic pathway.. Memory performance was evaluated in a two-trial recognition Y-maze test and passive avoidance in mice. Pioglitazone (20 or 40 mg/kg, p.o.) was administered 2h before each trial, NMDA (75 mg/kg i.p.), 15 min before pioglitazone, and scopolamine, an M1 (muscarinic) receptor antagonist (0.3 or 1.0 mg/kg i.p.) and MK-801 (dizocilpine) (0.01, 0.03 or 0.1 mg/kg, i.p.), the highly selective, non-competitive NMDA antagonist--30 min beforehand.. (1) We induced the memory impairment by scopolamine or MK-801 before trials. (2) Pioglitazone did not improve the memory impairment induced by MK-801. (3) Pioglitazone significantly improved the memory impairment induced by scopolamine. (4) Subeffective dose of MK-801 nullified the beneficial effects of pioglitazone in scopolamine induced memory impaired mice. (5) NMDA promoted the effects of subeffective dose of pioglitazone on memory impaired by scopolamine.. In conclusion, the present study suggests that glutamatergic pathway is involved in the pioglitazone induced memory performance.

Topics: Animals; Avoidance Learning; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hypoglycemic Agents; Maze Learning; Memory; Memory Disorders; Mice; Muscarinic Antagonists; Pioglitazone; Receptors, N-Methyl-D-Aspartate; Scopolamine; Thiazolidinediones

Hypofunction of brain N-methyl-d-aspartate (NMDA) receptors has been implicated in psychiatric disorders such as schizophrenia and Alzheimer's disease. Inhibition of glycine transporter-1 (GlyT1) is expected to increase glycine, a co-agonist of the NMDA receptor and, consequently, to facilitate NMDA receptor function. We have identified ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole) as a novel GlyT1 inhibitor, and here describe our in vitro and in vivo characterization of this compound. ASP2535 potently inhibited rat GlyT1 (IC(50)=92 nM) with 50-fold selectivity over rat glycine transporter-2 (GlyT2). It showed minimal affinity for many other receptors except for μ-opioid receptors (IC(50)=1.83 μM). Oral administration of ASP2535 dose-dependently inhibited ex vivo [(3)H]-glycine uptake in mouse cortical homogenate, suggesting good brain permeability. This profile was confirmed by pharmacokinetic analysis. We then evaluated the effect of ASP2535 on animal models of cognitive impairment in schizophrenia and Alzheimer's disease. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both attenuated by ASP2535 (0.3-3mg/kg, p.o. and 0.3-1mg/kg, p.o., respectively). ASP2535 (1-3mg/kg, p.o.) also improved the PCP-induced deficit in prepulse inhibition in rats. Moreover, the working memory deficit in scopolamine-treated mice and the spatial learning deficit in aged rats were both attenuated by ASP2535 (0.1-3mg/kg, p.o. and 0.1mg/kg, p.o., respectively). These studies provide compelling evidence that ASP2535 is a novel and centrally-active GlyT1 inhibitor that can improve cognitive impairment in animal models of schizophrenia and Alzheimer's disease, suggesting that ASP2535 may satisfy currently unmet medical needs for the treatment of these diseases.

Topics: Administration, Oral; Alzheimer Disease; Animals; Brain; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Glycine Plasma Membrane Transport Proteins; Humans; Inhibitory Concentration 50; Male; Memory Disorders; Mice; Oxadiazoles; Permeability; Rats; Rats, Wistar; Schizophrenia; Triazoles

In the present study we investigate the effect of Withania somnifera (WS) root extract and Withanolide A (WA) in restoring spatial memory deficit by inhibiting oxidative stress induced alteration in glutamergic neurotransmission. We demonstrate significant cellular loss in hippocampus of epileptic rats, visualized through decreased TOPRO stained neurons. Impaired spatial memory was observed in epileptic rats after Radial arm maze test. Treatment with WS and WA has resulted in increased number of TOPRO stained neurons. Enhanced performance of epileptic rats treated with WS and WA was observed in Radial arm maze test. The antioxidant activity of WS and WA was studied using superoxide dismutase (SOD) and Catalase (CAT) assays in the hippocampus of experimental rats. The SOD activity and CAT activity decreased significantly in epileptic group, treatment with WS and WA significantly reversed the enzymatic activities to near control. Real time gene expression studies of SOD and GPx showed significant up-regulation in epileptic group compared to control. Treatment with WS and WA showed significant reversal to near control. Lipid peroxidation quantified using TBARS assay, significantly increased in epileptic rats. Treatment with WS and WA showed significant reversal to near control. NMDA receptor expression decreased in epileptic rats. The treatment with WS and WA resulted in physiological expression of NMDA receptors. This data suggests that oxidative stress effects membrane constitution resulting in decreased NMDA receptor density leading to impaired spatial memory. Treatment with WS and WA has ameliorated spatial memory deficits by enhancing antioxidant system and restoring altered NMDA receptor density.

Topics: Animals; Catalase; Cognition Disorders; Dizocilpine Maleate; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Transporter 1; Hemostasis; Immunohistochemistry; Male; Maze Learning; Memory Disorders; Oxidative Stress; Plant Roots; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate; Space Perception; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Withania; Withanolides

This study explored the effect of the excitatory amino acid receptor antagonists on the impairment of learning-memory and the hyperphosphorylation of Tau protein induced by electroconvulsive shock (ECT) in depressed rats, in order to provide experimental evidence for the study on neuropsychological mechanisms improving learning and memory impairment and the clinical intervention treatment. The analysis of variance of factorial design set up two intervention factors which were the electroconvulsive shock (two level: no disposition; a course of ECT) and the excitatory amino acid receptor antagonists (three level: iv saline; iv NMDA receptor antagonist MK-801; iv AMPA receptor antagonist DNQX). Forty-eight adult Wistar-Kyoto (WKY) rats (an animal model for depressive behavior) were randomly divided into six experimental groups (n = 8 in each group): saline (iv 2 mL saline through the tail veins of WKY rats ); MK-801 (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats) ; DNQX (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats ); saline + ECT (iv 2 mL saline through the tail veins of WKY rats and giving a course of ECT); MK-801 + ECT (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats and giving a course of ECT); DNQX + ECT (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats and giving a course of ECT). The Morris water maze test started within 1 day after the finish of the course of ECT to evaluate learning and memory. The hippocampus was removed from rats within 1 day after the finish of Morris water maze test. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. The contents of Tau protein which included Tau5 (total Tau protein), p-PHF1(Ser396/404), p-AT8(Ser199/202) and p-12E8(Ser262) in the hippocampus of rats were detected by immunohistochemistry staining (SP) and Western blot. The results showed that ECT and the glutamate ionic receptor blockers (NMDA receptor antagonist MK-801 and AMPA receptor antagonist DNQX) induced the impairment of learning and memory in depressed rats with extended evasive latency time and shortened space exploration time. And the two factors presented a subtractive effect. ECT significantly up-regulated the content of glutamate in the hippocampus of depressed rats which were not affected by the glutamate ionic receptor blockers. ECT and the glutamate ionic receptor blockers did not affect the total Tau protein in the hippocampus of rats. ECT up-regul

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Learning; Memory; Memory Disorders; Phosphorylation; Quinoxalines; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; tau Proteins

Artemisia princeps var. orientalis (Compositae) is widely distributed in China, Japan and Korea and is known to have anti-inflammatory and anti-oxidative activities. The ethyl acetate fraction of ethanolic extract of A. princeps var. orientalis (AEA) was found to inhibit acetylcholinesterase activity in a dose-dependent manner in vitro (IC(50) value: 541.4 ± 67.5 μg/ml). Therefore, we investigated the effects of AEA on scopolamine-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. AEA (100 or 200 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (p < 0.05). In the Morris water maze task, AEA (200 mg/kg, p.o.) significantly shortened escape latencies in training trials and increased both swimming time spent in the target zone and probe crossing numbers during the probe trial as compared with scopolamine-treated mice (p < 0.05). Additionally, the ameliorating effect of AEA on scopolamine-induced memory impairment was antagonized by a subeffective dose of MK-801. These results suggest that AEA could be an effective treatment against cholinergic dysfunction and its effect is mediated by the enhancement of the cholinergic neurotransmitter system via NMDA receptor signaling or acetylcholinesterase inhibition.

Topics: Animals; Artemisia; Avoidance Learning; Behavior, Animal; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Receptors, N-Methyl-D-Aspartate; Scopolamine; Signal Transduction; Swimming

Sepsis is characterized by an intense inflammatory reaction with potential neurotoxic effects in the central nervous system and damage to memory and learning ability. We assessed the effects of acute low dose of MK-801 on the memory impairment, hippocampal BDNF levels and DARPP-32 expression ten days after sepsis. Under anesthesia, male Wistar rats underwent either cecal ligation and perforation (CLP) or sham. Then, the animals received either a single systemic injection of MK-801 (0.025 mg/kg) or saline solution. Ten days after CLP, the animals were submitted to the step-down inhibitory avoidance and object recognition tests. Also, the hippocampal BDNF protein levels and DARPP-32 expression were evaluated. MK-801 prevented cognitive impairment, but did not affect the hippocampal BDNF levels. DARPP-32 expression was significantly different only in the animals submitted to sepsis that received MK-801 treatment. Thus, we demonstrated that a single low dose of MK-801 prevented memory impairment without altering hippocampal DARPP-32 expression and BDNF levels.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Dizocilpine Maleate; Dopamine and cAMP-Regulated Phosphoprotein 32; Hippocampus; Male; Memory Disorders; Neuroprotective Agents; Rats; Rats, Wistar; Sepsis

We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT(7) antagonist and 5-HT(1A) partial agonist activities, is superior to other antipsychotics in improving the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT(7) and 5-HT(1A) receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT(7) and 5-HT(1A) receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models.

Topics: Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Isoindoles; Learning Disabilities; Lurasidone Hydrochloride; Male; Maze Learning; Memory Disorders; Rats; Rats, Wistar; Reaction Time; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Serotonin Agents; Thiazoles; Time Factors

The aim of this study was to investigate the effects of an atypical antipsychotic risperidone (RIS; 0.06, 0.125 or 0.25 mg/kg, intraperitoneal, i.p.) on learning and memory processes, both in naive and MK-801-treated (0.15 mg/kg, i.p.) rats.. Modified elevated plus maze (mEPM), passive avoidance (PA) and Morris water maze (MWM) tasks were used.. In the mEPM test, RIS (0.125 or 0.25 mg/kg) significantly decreased the transfer latency and reversed MK-801-induced prolongation in the transfer latency of rats on the 2nd day. In the PA test, RIS (0.125 or 0.25 mg/kg) slightly decreased step-through latency (retention latency) but this finding did not reach statistical significance in naive rats. RIS had no effect on MK-801-induced reduction of retention latency. In the MWM test, RIS (0.06, 0.125 or 0.25 mg/kg, i.p.) neither affected the time spent in the escape platform quadrant, nor the distance to the platform in naive rats. It (0.125 mg/kg) tended to increase MK-801-induced reduction of time spent in the escape platform quadrant, but this finding was insignificant. RIS (0.125 mg/kg) significantly shortened MK-801-induced elongation in the distance to the platform. RIS had no effect on the swimming speed of the animals.. RIS might be effective in treating cognitive dysfunctions associated with schizophrenia.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Dizocilpine Maleate; Learning; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Motor Activity; Rats; Rats, Wistar; Risperidone

A primary objective in developing a neural prosthesis is to replace neural circuitry in the brain that no longer functions appropriately. Such a goal requires artificial reconstruction of neuron-to-neuron connections in a way that can be recognized by the remaining normal circuitry, and that promotes appropriate interaction. In this study, the application of a specially designed neural prosthesis using a multi-input/multi-output (MIMO) nonlinear model is demonstrated by using trains of electrical stimulation pulses to substitute for MIMO model derived ensemble firing patterns. Ensembles of CA3 and CA1 hippocampal neurons, recorded from rats performing a delayed-nonmatch-to-sample (DNMS) memory task, exhibited successful encoding of trial-specific sample lever information in the form of different spatiotemporal firing patterns. MIMO patterns, identified online and in real-time, were employed within a closed-loop behavioral paradigm. Results showed that the model was able to predict successful performance on the same trial. Also, MIMO model-derived patterns, delivered as electrical stimulation to the same electrodes, improved performance under normal testing conditions and, more importantly, were capable of recovering performance when delivered to animals with ensemble hippocampal activity compromised by pharmacologic blockade of synaptic transmission. These integrated experimental-modeling studies show for the first time that, with sufficient information about the neural coding of memories, a neural prosthesis capable of real-time diagnosis and manipulation of the encoding process can restore and even enhance cognitive, mnemonic processes.

Topics: Algorithms; Animals; Behavior, Animal; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Cerebral Cortex; Computer Systems; Dizocilpine Maleate; Electrodes, Implanted; Excitatory Amino Acid Antagonists; Memory; Memory Disorders; Models, Neurological; Neural Pathways; Neurons; Nonlinear Dynamics; Online Systems; Prostheses and Implants; Prosthesis Design; Psychomotor Performance; Rats; Rats, Long-Evans; User-Computer Interface

We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test. Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5mg/kg; s.c.) or clozapine (0.5 and 1mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Imidazoles; Indoles; Learning; Male; Memory Disorders; Mice; Mice, Inbred BALB C; Motor Activity; Olanzapine; Recognition, Psychology; Visual Perception

The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Glutamic Acid; Male; Memory Disorders; Memory, Short-Term; Phenols; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Sulfonamides; Synaptic Transmission

The current study was undertaken to determine the role of dorsal hippocampal N-methyl-d-aspartate (NMDA) receptors in nicotine's effect on impairment of memory by ethanol.. Adult male mice were cannulated in the CA1 regions of dorsal hippocampi and trained on a passive avoidance learning task for memory assessment.. We found that pre-training intraperitoneal (i.p.) administration of ethanol (0.5 and 1g/kg) decreased memory retrieval when tested 24h later. Pre-test administration of ethanol reversed the decrease in inhibitory avoidance response induced by pre-training ethanol. Similar to ethanol, pre-test administration of nicotine (0.125-0.75 mg/kg, s.c.) prevented impairment of memory by pre-training ethanol. In the animals that received ethanol (1g/kg, i.p) before training and tested following intra-CA1 administration of different doses of NMDA (0.0005-0.005 microg/mouse), no significant change was observed in the retrieval latencies. Co-administration of the same doses of NMDA with an ineffective dose of nicotine (0.125 mg/kg, s.c.) significantly improved the memory retrieval and mimicked the effects of pre-test administration of a higher dose of nicotine. Pre-test intra-CA1 microinjection of MK-801 (0.25-1 microg/mouse), which had no effect alone, in combination with an effective dose of nicotine (0.75 mg/kg, s.c.) prevented the improving effect of nicotine on memory impaired by pre-training ethanol. Moreover, intra-CA1 microinjection of MK-801 reversed the NMDA-induced potentiation of the nicotine response.. The results suggest the importance of NMDA glutamate system(s) in the CA1 regions of dorsal hippocampus for improving the effect of nicotine on the ethanol-induced amnesia.

Topics: Animals; Avoidance Learning; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Male; Memory; Memory Disorders; Mice; N-Methylaspartate; Nicotine; Nicotinic Agonists; Receptors, N-Methyl-D-Aspartate

Interaction of cholinergic and glutamatergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is a topic of great interest. In the present study the effect of intra-VTA administration of a nonselective muscarinic acetylcholine antagonist, scopolamine, and N-methyl-d-aspartate (NMDA) receptor agents by themselves as well as their interactions on consolidation and retrieval of inhibitory avoidance (IA) memory have been investigated. A step-through inhibitory avoidance task was used for memory assessment in male Wistar rats. The results showed that intra-VTA administration of scopolamine (1 and 2microg/rat) and NMDA receptor antagonist, MK-801 (0.75 and 1microg/rat) immediately after training, impaired consolidation of IA memory. Interestingly, co-administration of an ineffective dose of MK-801 (0.5microg/rat) with ineffective doses of scopolamine (0.25 and 0.5microg/rat) significantly decreased the consolidation process. Post-training intra-VTA injections of NMDA (0.001 and 0.01microg/rat) had no effects by itself, whereas its co-administration with scopolamine (2microg/rat) prevented the effect of the later drug. The results also showed that pre-test intra-VTA administration of scopolamine (3 and 4microg/rat) and MK-801 (1 and 2microg/rat) impaired retrieval of the IA memory. Moreover, co-administration of an ineffective dose of MK-801 (0.5microg/rat) with ineffective doses of scopolamine (1 and 2microg/rat) increasingly reduced the retrieval of the IA memory. On the contrary to its post-training treatment, pre-test administration of NMDA either alone or in combination with scopolamine caused no significant effect on retrieval of IA memory. It can be concluded that muscarinic acetylcholine and NMDA glutamate receptors in the VTA are involved in the mechanism(s) underlying consolidation and retrieval of the IA memory.

Topics: Acetylcholine; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Memory; Memory Disorders; Muscarinic Antagonists; N-Methylaspartate; Neuropsychological Tests; Rats; Rats, Wistar; Receptors, Muscarinic; Receptors, N-Methyl-D-Aspartate; Scopolamine; Ventral Tegmental Area

Heterozygous rolling Nagoya (rol/+) mice carrying Ca(V)2.1 alpha(1) mutation demonstrated normal behavior in Y maze test. Similar spontaneous alternation patterns were noted in wild-type and rol/+ mice injected with N-methyl-D-aspartate (NMDA; 0-50mg/kg, sc). Systemic injection of NMDA receptor blocker (MK-801; 0.05 mg/kg, ip) or intrahippocampal injection of MK-801 (0.5 microg/side), which had no effect in wild-type controls, decreased spatial cognition in rol/+ mice. These results indicate that Ca(V)2.1 alpha(1) mutation probably through decrease in Ca(2+) influx lowers the threshold for learning impairment. The combination subthreshold pharmacological and genetic approach is useful to study functional pathways in neuronal circuits.

Topics: Animals; Calcium Channels, N-Type; Calcium Channels, P-Type; Calcium Channels, Q-Type; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Heterozygote; Hippocampus; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Mutant Strains; Mutation; N-Methylaspartate; Neuropsychological Tests; Receptors, N-Methyl-D-Aspartate; Space Perception; Time Factors

There is consistent experimental evidence that noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, such as ketamine, MK-801, and phencyclidine (PCP), impair cognition and produce psychotomimetic effects in rodents. Nitric oxide (NO) is considered as an intracellular messenger in the brain. The implication of NO in learning and memory is well documented. This study was designed to investigate the ability of the NO synthase inhibitor L-NAME to antagonize recognition and spatial memory deficits produced by the NMDA receptor antagonists, MK-801 and ketamine, in the rat. L-NAME (1-3 mg/kg) counteracted MK-801- (0.1 mg/kg) and ketamine (3 mg/kg)-induced performance impairments in the novel object recognition task. L-NAME (10 mg/kg) attenuated ketamine (15 mg/kg)-induced spatial working memory and retention deficits in the radial water maze paradigm. L-NAME, applied at 3 mg/kg, however, disrupted rodents' performance in this spatial memory task. The present findings indicate (1) that L-NAME is sensitive to glutamate hypofunction produced by other than PCP NMDA antagonists such as MK-801 and ketamine and (2) that L-NAME alone differentially affects rodents' spatial memory.

Topics: Animals; Dizocilpine Maleate; Drug Interactions; Ketamine; Male; Maze Learning; Memory Disorders; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology

The possible involvement of N-methyl-D-aspartate (NMDA) receptors of the nucleus accumbens (NAc) in amnesia induced by scopolamine was investigated. An inhibitory (passive) avoidance task was used for memory assessment in male Wistar rats. The results revealed that intra-NAc administration of a nonselective muscarinic acetylcholine antagonist, scopolamine (1 and 2 g/rat) impaired memory consolidation in the animals when tested 24 h later. Post-training intra-NAc administration of NMDA (0.005 and 0.01 g/rat) also impaired memory consolidation, whereas post-training intra-NAc administration of the NMDA receptor antagonist, MK-801 (0.5, 1 and 1.5 g/rat) did not. Intra-NAc co-administration of an ineffective dose of NMDA with ineffective doses of scopolamine (0.25 and 0.5 g/rat) after training had no significant effect on memory consolidation, but intra-NAc injections of effective doses of NMDA (0.005 and 0.01 g/rat) prevented the amnesic effect of an effective dose of scopolamine (2 g/rat). In contrast, intra-NAc co-administration of MK-801 (0.5, 1 and 1.5 g/rat) along with an effective dose of scopolamine (2 g/rat) did not prevent the effect of the latter drug. It can be concluded that NMDA receptors in the NAc are involved in the modulation of memory consolidation that was affected by scopolamine.

Topics: Animals; Avoidance Learning; Cholinergic Antagonists; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Inhibition, Psychological; Male; Memory Disorders; Microinjections; N-Methylaspartate; Nucleus Accumbens; Rats; Rats, Wistar; Scopolamine

Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic-interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function. SynGAP mutant mice exhibited nonhabituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. An NMDAR antagonist, MK-801, induced hyperactivity in normal mice but SynGAP mutants were less responsive, suggesting that NMDAR hypofunction contributes to this behavioral abnormality. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation. Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia. Because SynGAP interacts with NMDARs, and the signaling activity of this protein is regulated by these channels, our data in dicate that SynGAP lies downstream of NMDARs and is a required intermediate for normal neural circuit function and behavior. Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Behavioral Symptoms; Clozapine; Cross-Over Studies; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Inhibition, Psychological; Locomotion; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuropsychological Tests; ras GTPase-Activating Proteins; Reflex, Startle; Schizophrenia; Social Behavior; Stereotyped Behavior

The biochemical and pharmacological activities of nobiletin, including neurotrophic and memory-enhancing action, in both in vitro and in vivo systems are well established. However, whether its metabolites do have such beneficial effects like nobiletin remains to be examined. Here we, for the first time, report that 2-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one (4'-demethylnobiletin), a major metabolite of nobiletin identified in the urine of rats and mice, stimulates the phosphorylation of ERK and CREB and enhances CRE-mediated transcription by activating a PKA/MEK/ERK pathway, like nobiletin, in cultured hippocampal neurons. Since NMDA receptor-mediated ERK signaling is involved in memory processing, including associative memories, we also examined whether 4'-demethylnobiletin, by activating ERK signaling, could restore learning impairment. Chronic intraperitoneal (ip) treatment of the mice with 10 or 50 mg of 4'-demethylnobiletin/kg rescued the NMDA receptor antagonist MK-801-induced learning impairment, accompanied by improvement of the MK-801-induced decrease in the level of ERK phosphorylation in the hippocampus of the animals. Consistently, 4'-demethylnobiletin also restored MK-801-induced inhibition of NMDA-stimulated phosphorylation of not only ERK but also PKA substrates in cultured rat hippocampal neurons. Moreover, we actually detected 4'-demethylnobiletin in the brain of mice following acute ip administration, demonstrating that the metabolite can cross the blood-brain barrier to reach the brain and thereby exert its effects to reverse learning impairment. Therefore, these results suggest that 4'-demethylnobiletin, a bioactive metabolite of nobiletin, may serve as a potential therapeutic agent, at least, for memory disorders associated with a dysregulated NMDA receptor ERK signaling, like nobiletin.

Topics: Animals; Behavior, Animal; Cells, Cultured; Conditioning, Classical; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Dizocilpine Maleate; Enzyme Activation; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Fear; Flavones; Hippocampus; Learning; Male; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Memory Disorders; Mice; Molecular Structure; Neurons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound that is constantly present in the brain, and that exhibits neuroprotective activity. Our earlier study has suggested that 1MeTIQ may play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. It is well known that central nervous system stimulants such as: amphetamine, cocaine, phencyclidine, and selective NMDA receptor antagonists, e.g., MK-801 produce neuropsychotoxicity (psychosis, addiction) that is indistinguishable from paranoid type schizophrenia. In rodents, phencyclidine and MK-801 are often used to evoke schizophrenia-like behavioral abnormalities which are inhibited by neuroleptics. The present study was designed to further investigate potential antipsychotic properties of 1MeTIQ by using both behavioral and neurochemical studies in the rat. We investigated the influence of 1MeTIQ (25 and 50 mg/kg ip) on locomotor hyperactivity, disruptions of prepulse inhibition (PPI), and working memory impairment induced by the NMDA receptor antagonist, MK-801 (0.2-0.3 mg/kg ip). In addition in the biochemical study, we analyzed the effect of 1MeTIQ on the changes in dopamine metabolism in different brain structures and in extraneuronal release of dopamine and glutamate in the rat frontal cortex, produced by MK-801. The concentration of dopamine (DA) and its metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA), as well as the extraneuronal concentration of dopamine and glutamate were established by HPLC. MK-801 (0.25 mg/kg ip) evoked significant disruptions of PPI and working memory impairment, and co-administration of 1MeTIQ at two investigated doses of 25 and 50 mg/kg ip did not antagonize these effects. On the other hand hyperactivity evoked by MK-801 as well as a rise in dopamine metabolism in specific brain structures and glutamate release in the frontal cortex was completely antagonized by pretreatment with 1MeTIQ. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that 1MeTIQ will show efficacy in treating this condition. In conclusions, the present study suggests that 1MeTIQ, an endogenous neuroprotective compound, exhibits also antipsychotic-like efficacy in some animal tests, and may be useful in clinical practice as a psychosis-attenuating drug in schizophrenic patients. Howeve

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Brain; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Glutamic Acid; Hyperkinesis; Inhibition, Psychological; Male; Maze Learning; Memory Disorders; Microdialysis; Motor Activity; Neurochemistry; Prefrontal Cortex; Rats; Rats, Wistar; Reflex, Startle; Tetrahydroisoquinolines

N-methyl-D-aspartate (NMDA) receptor hypofunction is believed to comprise a central factor in the cognitive symptoms of psychotic illnesses such as schizophrenia. In the MK801 model of psychosis in rats, NMDA hypofunction also occurs, and animals display a profound impairment of both hippocampus-dependent learning and synaptic plasticity. The NMDA receptor may thus comprise a useful target for therapeutic amelioration of the symptoms of psychosis. However, direct activation of the receptor could lead to disturbed synaptic information storage. One possibility, however, is to enhance NMDA receptor function indirectly through elevation of glycine levels. We investigated the effects of inhibition of the glycine transporter-1, GlyT1, on long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus of freely behaving rats that had been treated previously with MK801. LTP, but not LTD, was impaired in MK801-treated animals. Systemic application of the GlyT1-inhibitor N[3-(4'-flurophenyl)-3-(4'-phenylphenoxy) propyl]sarcosine (NFPS) rescued LTP but had no effect on LTD in MK801-treated animals. Application of the antagonist to vehicle-treated controls resulted in a disruption of LTP but not LTD. NFPS significantly ameliorated reference memory deficits in a radial maze that occurred following MK801 treatment. NFPS-treated controls performed less well, however, than vehicle-injected controls. These data support that treatment with a glycine transporter inhibitor can ameliorate deficits in both LTP and learning that occur in a rat model of psychosis, and may therefore prove a useful strategy to address cognitive disruption in psychotic illnesses. Use of the inhibitor in healthy subjects is neither beneficial to synaptic plasticity nor hippocampus-dependent learning.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Glycine Plasma Membrane Transport Proteins; Hippocampus; Learning Disabilities; Long-Term Potentiation; Long-Term Synaptic Depression; Male; Maze Learning; Memory Disorders; Psychotic Disorders; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Sarcosine

We have previously shown that lurasidone, a novel atypical antipsychotic, potently reverses learning impairment induced by the N-methyl-D-aspartate receptor antagonist MK-801 in the rat passive avoidance test. However, the effects of lurasidone in other learning and memory tasks remain to be investigated. We investigated the effects of lurasidone and other marketed antipsychotics (risperidone, clozapine, aripiprazole, and haloperidol) on MK-801-induced impairment of learning and memory in the Morris water maze (MWM) and radial-arm maze (RAM) tests in rats. Learning and memory impairment in the MWM test, as measured by escape latency, escape distance, and diving behavior, and in the RAM test, as measured by reference and working memory errors, was induced by MK-801 (i.p.) at doses of 0.15 and 0.2 mg/kg, respectively. In the MWM test, lurasidone (1 and 3 mg/kg p.o.) potently reversed MK-801-induced learning impairment. In the RAM test, lurasidone (1 and 3 mg/kg p.o.) potently reversed MK-801-induced reference memory impairment and moderately but not significantly attenuated MK-801-induced working memory impairment. Risperidone (0.3 and 1mg/kg p.o.), clozapine (3 and 10 mg/kg p.o.), aripiprazole (0.3 and 1mg/kg p.o.), and haloperidol (0.3 and 1mg/kg p.o.) did not reverse MK-801-induced impairment of learning and memory in both tasks. Lurasidone, but not the other antipsychotics tested in this study, reverses MK-801-induced impairment of learning and memory in both the MWM test and the RAM test. These results suggest that lurasidone would be more effective in treating schizophrenics with cognitive dysfunction than current antipsychotics.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Isoindoles; Learning Disabilities; Lurasidone Hydrochloride; Male; Maze Learning; Memory Disorders; Rats; Rats, Wistar; Reaction Time; Swimming; Thiazoles

Spatial memory impairments observed in Alzheimer's disease and schizophrenia have been attributed to many factors, including glutamate hypofunction and reduced hippocampal volume. Clonidine, a non-specific alpha(2) adrenergic receptor agonist, improves spatial memory in animals treated with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine; however, its effects on memory deficits produced by other NMDA antagonists or hippocampal damage have not been fully characterized. The purpose of this study was to determine if clonidine could alleviate memory deficits produced by the NMDA antagonist, MK-801, or by excitotoxic hippocampal damage. In the first phase of the study, male rats were pretreated with clonidine (0.01 or 0.05 mg/kg) or saline, and treated with MK-801 (0.1 mg/kg) or saline prior to discrete-trial delayed alternation or radial-arm maze testing. MK-801 impaired delayed alternation performance and increased the number of arm revisits in the radial-arm maze. Clonidine pretreatment significantly alleviated these drug-induced deficits. In the second phase of the study, excitotoxic damage was produced in the dorsal hippocampus with NMDA. Hippocampal damage produced a significant impairment in the delayed alternation task, yet pretreatment with clonidine did not alleviate this damage-induced deficit. Taken together, the data indicate that clonidine alleviates memory impairments produced by glutamate hypofunction, but not by hippocampal damage. This caveat may be important in designing treatments for memory disorders not linked to a single pathophysiological mechanism.

Topics: Adrenergic alpha-Agonists; Animals; Attention; Clonidine; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Memory Disorders; N-Methylaspartate; Psychomotor Performance; Rats; Rats, Long-Evans; Reinforcement Schedule; Space Perception

Schizophrenia is mostly a progressive psychiatric illness. Although cognitive changes in chronic schizophrenia have been investigated, little is known about the consequences of a single psychotic episode on memory mechanisms and formation. We investigated changes in hippocampal long-term potentiation (LTP) and spatial memory in a rat model of an acute psychotic episode. Application of NMDA receptor antagonists, such as MK801 (dizolcilpine) in rats, have been shown to give rise to an acute and short-lasting behavioral state, which mirrors many symptoms of schizophrenia. Furthermore, NMDA antagonist-intake in humans elicits symptoms of schizophrenia such as hallucinations, delusions, and affective blunting. We therefore treated animals with a single systemic injection of MK801 (5 mg/kg). Increased stereotypy, locomotion, and ataxia were evident immediately after MK801-treatment, with effects disappearing within 24 h. MK801-treatment caused a disruption of prepulse inhibition of the acoustic startle reflex, 1 day but not 7 or 28 days after treatment. These effects were consistent with the occurrence of an acute psychotic episode. LTP was profoundly impaired in freely moving rats 7 days after MK801 application. Four weeks after treatment, a slight recovery of LTP was seen, however marked deficits in long-term spatial memory were evident. These data suggest that treatment with MK801 to generate an acute psychotic episode in rats, gives rise to grave disturbances in synaptic plasticity and is associated with lasting impairments with the ability to form spatial memory.

Topics: Acute Disease; Animals; Ataxia; Defecation; Dentate Gyrus; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Grooming; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Motor Activity; Neuronal Plasticity; Psychotic Disorders; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia; Smell

Adenosine A2A receptor antagonists alleviate memory deficits caused by aging or by administration of beta-amyloid peptides in rodents, which is in accordance with the beneficial effects of caffeine consumption (an adenosine receptor antagonist) on memory performance in aged individuals and in preventing Alzheimer's disease. We now tested if A2A receptor blockade affords a general beneficial effect in different experimental paradigms disturbing memory performance in rodents. The beta-amyloid fragment present in patients with Alzheimer's disease (Abeta1-42, 2 nmol, icv) decreased spontaneous alternation in the Y-maze after 15 days (29%) to an extent similar to the decrease of memory performance caused by scopolamine (2 mg/kg, ip) or MK-801 (0.25 mg/kg, ip) after 30 min (28% and 39%, respectively). The selective A2A receptor antagonist SCH58261 (0.05 mg/kg, ip every 24 h, starting 30 min before the noxious stimuli) prevented Abeta1-42-induced amnesia, but failed to modify scopolamine- or MK-801-induced amnesia. Similar conclusions were reached when testing another A2A receptor antagonist (KW6002, 3 mg/kg, ip). These results indicate that A2A receptors do not affect general processes of memory impairment but instead play a crucial role restricted to neurodegenerative conditions involving an insidious synaptic deterioration leading to memory dysfunction.

Topics: Adenosine A2 Receptor Antagonists; Amyloid beta-Peptides; Analysis of Variance; Animals; Behavior, Animal; Dizocilpine Maleate; Drug Interactions; Male; Maze Learning; Memory Disorders; Motor Activity; Neuroprotective Agents; Peptide Fragments; Purines; Pyrimidines; Rats; Rats, Wistar; Scopolamine; Triazoles

Alpha2-adrenoreceptor (alpha(2)-AR) antagonists have been shown to improve, while alpha(2)-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) alpha(2)-AR agonists attenuate the cognitive impairments. The effect with alpha(2)-AR antagonists remains unclear.. We investigated the effects of the alpha(2)-AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist dizocilpine or a combination of dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function.. Female Sprague-Dawley rats (n=12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination.. Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with dizocilpine, but it did block the nicotine reversal of the dizocilpine-induced memory impairment. Three rats after 10-12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block alpha(2)-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.

Topics: Adrenergic alpha-Antagonists; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Idazoxan; Maze Learning; Memory; Memory Disorders; Memory, Short-Term; Nicotine; Nicotinic Agonists; Norepinephrine; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission

The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the nucleus accumbens (NAc) in nicotine's effect on impairment of memory by morphine was investigated. A passive avoidance task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 10 mg/kg) after training impaired memory performance in the animals when tested 24 h later. Pretest administration of the same doses of morphine reversed impairment of memory because of post-training administration of the opioid. Moreover, administration of nicotine (0.2 and 0.4 mg/kg, s.c.) before the test prevented impairment of memory by morphine (5 mg/kg) given after training. Impairment of memory performance in the animals because of post-training administration of morphine (5 mg/kg) was also prevented by pretest administration of a noncompetitive NMDA receptor antagonist, MK-801 (0.75 and 1 microg/rat). Interestingly, an ineffective dose of MK-801 (0.5 microg/rat) in combination with low doses (0.075 and 0.1 mg/kg) of nicotine, which had no effects alone, synergistically improved memory performance impaired by morphine given after training. On the other hand, pretest administration of NMDA (0.1 and 0.5 microg/rat), which had no effect alone, in combination with an effective dose (0.4 mg/kg, s.c.) of nicotine prevented the improving effect of nicotine on memory impaired by pretreatment morphine. The results suggest a possible role for NMDA receptors of the NAc in the improving effect of nicotine on the morphine-induced amnesia.

Topics: Animals; Dizocilpine Maleate; Male; Memory Disorders; Morphine; Neuroprotective Agents; Nicotine; Nucleus Accumbens; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Brain glutamatergic system is involved in synaptic plasticity as a base for learning and neural development. This study investigated the effects of neonatal and adult chronic antagonism of N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptors, on learning and/or memory. Rats were trained in the radial-maze learning, which is known as a measure of spatial working memory capacities, in adulthood after neonatal or adult repeated treatment of MK-801 (dizocilpine; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine), a non-competitive antagonist, or neonatal repeated treatment of CGS 19755 (cis-4-phosphonomethyl-2-piperadine carboxilic acid), a competitive antagonist. Neonatal repeated treatment of MK-801 or CGS 19755 markedly impaired the radial-arm maze learning. In addition, the treatment altered activities differently in the radial-maze and in the open-field. On the other hand, adult repeated treatment with MK-801 affected neither the radial-maze learning nor activities. Results suggest that chronic blockade of NMDA receptors in a neonatal stage may produce long-lasting deteriorative effects on spatial working memory in adulthood.

Topics: Aging; Animals; Animals, Newborn; Brain; Brain Chemistry; Dizocilpine Maleate; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Glutamic Acid; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Pipecolic Acids; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Time

Smoking marijuana causes working and short-term memory deficits, an effect that is mediated by cannabinoid receptor (CB1) activation in the brain. While this may be due to the main psychoactive constituent Delta9-tetrahydrocannabinol (Delta9-THC), plant extracts also contain other cannabinoid and terpenoid compounds with unknown properties. Towards this end, we have recently shown that high concentrations of plant extracts rich in cannabidiol (CBD) can reverse working memory deficits induced by Delta9-THC which is a remaining contaminant of this extract [Fadda P, Robinson L, Fratta W, Pertwee RG, Riedel G. Differential effects of THC- and CBD-rich cannabis-extracts on working memory in rats. Neuropahrmacology 2004;47:1170-9]. Since this effect was dose-dependent and indicative of memory enhancing qualities of the CBD-rich extract, this prompted a wider investigation into the effects of CBD on other forms of amnesia in order to determine the mechanism of action and to reveal its potency against anticholinergic and antiglutamatergic agents. We employed a spatial delayed matching to position task in the open-field water maze. Both scopolamine (0.2 mg/kg i.p.) and dizocilpine (MK801: 0.1mg/kg i.p.) impaired working memory at delays of 30 s and 4 h. Two doses of CBD-rich extracts (5 and 10 mg/kg), which did not affect working memory when given alone, were unable to reverse these deficits when co-administered with scopolamine or MK801. These data suggest that reversal of working memory deficits by CBD-rich extracts are specific to the cannabinoid system and do not compensate for acutely induced cholinergic or glutamatergic receptor hypoactivity.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cannabinoids; Dizocilpine Maleate; Drug Interactions; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Plant Extracts; Rats; Reaction Time; Scopolamine; Time Factors

We used lipopolysaccharide (LPS) to activate microglia that play an important role in the brain immune system. LPS injected into the rat hippocampus CA1 region activated microglial cells resulting in an increased production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in the hippocampus during the initial stage of treatment. Immunostaining for IL-1beta was increased at 6 hr after LPS injection. IL-1beta-immunopositive cells were co-localized with immunostaining for CD11b. Subacute treatment with LPS by the same route for 5 days caused long-term activation of microglia and induced learning and memory deficits in animals when examined with a step-through passive avoidance test, but histochemical analysis showed that neuronal cell death was not observed under these experimental conditions. The increased expression of the heme oxygenase-1 (HO-1) gene, an oxidative stress maker, was observed. However, the genetic expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, decreased during the course of LPS treatment. We found decreases in [3H]MK801 binding in the hippocampus CA1 region by LPS-treatment for 5 days. The data shows that glutamatergic transmission was attenuated in the LPS-treated rats. These results suggest that long-term activation of microglia induced by LPS results in a decrease of glutamatergic transmission that leads to learning and memory deficits without neuronal cell death. The physiologic significance of these findings is discussed.

Topics: Animals; Avoidance Learning; Blotting, Northern; Brain-Derived Neurotrophic Factor; Cell Death; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Heme Oxygenase-1; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Interleukin-1; Learning Disabilities; Lipopolysaccharides; Memory Disorders; Microglia; Motor Activity; Neurons; Psychomotor Performance; Rats; Receptor, trkB; Tumor Necrosis Factor-alpha

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.

Topics: Animals; Avoidance Learning; Brain; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Hyperkinesis; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Orientation; Rats; Rats, Long-Evans; Rats, Wistar; Receptors, Glutamate; Space Perception; Species Specificity; Synaptic Transmission

Gustatory neophobia dissipates with repeated exposures to an initially novel taste solution. The aim of the present study was to determine whether NMDA receptors in the insular cortex are involved in this experience-dependent process. Results showed that acute microinfusion of MK-801 into the insular cortex prevented the attenuation of gustatory neophobia indicating that this process is an NMDA receptor-dependent phenomenon.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Memory Disorders; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Aggregated 40-residue amyloid-beta peptide (beta40, 4 microg/microl), and 2 days later, ibotenate (NMDA receptor agonist, 0.3 microg/0.5 microl), were bilaterally injected into the hippocampus of rats. Five to six weeks after the beta40 injection, the rats showed learning deficits in the Morris water maze task and neuronal damage in the hippocampus, although the injection of beta40 or ibotenate alone did not result in cognitive deficits and hippocampal damage. Memantine (10, 20 mg/kg/day s.c. infusion for 6 weeks starting 24 h before the beta40 injection) significantly prevented learning deficits as measured for 4 days from 5 weeks after the beta40 injection, while a lower dose of memantine (5 mg/kg/day) and MK-801 (0.312, 0.624 mg/kg/day) did not have inhibitory effects on the learning deficits. The neuronal damage in the hippocampus, assessed as an elevation of the levels of the peripheral-type benzodiazepine-binding site (a gliosis marker for neuronal damage) produced by sequential intra-hippocampal injections of beta40 and ibotenate, at 6 weeks (39 days) after the beta40 injection, was significantly attenuated by memantine (10, 20 mg/kg/day) and MK-801 (0.624 mg/kg/day). These protective effects were also confirmed by histochemical examination (Cresyl violet staining of brain slices). In naive rats, MK-801 produced a significant learning impairment in the water maze task at a dose of 0.624 mg/kg/day, while memantine (20 mg/kg/day s.c. infusion) did not, although the beta40 plus ibotenate-induced hippocampal damage was lessened by both treatments. These results suggest that memantine and MK-801 exert protective effects on progressive neuronal damage, but that only memantine prevents memory impairment in hippocampal-lesioned rats, and that memantine may be a beneficial agent for the treatment of progressive cognitive dysfunction including Alzheimer's disease-type dementia.

Topics: Amyloid beta-Peptides; Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Ibotenic Acid; Male; Maze Learning; Memantine; Memory; Memory Disorders; Neurons; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate

Evidence that NMDA receptors contribute to synaptic plasticity in the hippocampus has stimulated research on their role in behavioral learning and memory. Recent studies indicate that NMDA antagonists decrease use of place strategies by rats in a T-maze task that can be solved using either a "place" or "response" strategy. In the present study, rats were given MK-801 before maze exposure and/or training on this redundant strategy T-maze task. MK-801 did not impair rats' ability to learn the task, but did change the strategies they used on a probe trial administered after learning. MK-801 decreased use of place strategies only when administered before both maze exposure and training; rats given MK-801 only before maze exposure or only before training tended to use place strategies on the probe trial. These results show that MK-801 does not prevent rats from utilizing previously acquired spatial information, but does appear to impair the acquisition of spatial information needed for place strategies.

Topics: Analysis of Variance; Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Maze Learning; Memory Disorders; Rats; Rats, Long-Evans; Reaction Time; Spatial Behavior

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D(1)R binding is increased, whereas D(2)R binding is not.

Topics: Animals; Behavior, Animal; Benzazepines; Benzofurans; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Glutamic Acid; Macaca mulatta; Male; Memory Disorders; Memory, Short-Term; Microdialysis; Positron-Emission Tomography; Prefrontal Cortex; Protein Binding; Pyrrolidines; Radioligand Assay; Receptors, Dopamine D1; Salicylamides; Time Factors; Tritium; Wakefulness

The effects of acute nicotine were determined on dopamine (DA) D(1) (D(1)R) and D(2) (D(2)R) receptor binding in the neocortex of conscious monkeys under control conditions as well as after chronic pretreatment with MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Extrastriatal neocortical D(1)R and D(2)R binding was evaluated with [(11)C]NNC112 and [(11)C]FLB457 with high-specific radioactivity using positron emission tomography (PET). Acute administration of nicotine bitartrate, given as an intravenous (i.v.) bolus plus infusion for 30 min at doses of 32 microg/kg+0.8 microg/kg/min or 100 microg/kg+2.53 microg/kg/min as base, induced slight but significant dose-dependent increases of DA in the extracellular fluid of prefrontal cortex (PFC) as determined by microdialysis. However, acute nicotine did not affect either [(11)C]NNC112 or [(11)C]FLB457 binding to D(1)R or D(2)R, respectively, in any cortical region. Chronic MK-801 (0.03 mg/kg, intramuscularly (i.m.), twice daily for 13 days) increased [(11)C]NNC112 binding to D(1)R in PFC. No significant changes were detected in [(11)C]FLB457 binding to PFC D(2)R. Although chronic MK-801 lowered baseline DA and glutamate levels in PFC, acute nicotine normalized reduced DA to control levels. Acute nicotine dose-dependently normalized the increased binding of [(11)C]NNC112 to D(1)R produced by chronic MK-801 but [(11)C]FLB457 binding to PFC D(2)R did not change. Working memory performance, impaired after chronic MK-801, was partially improved by acute nicotine. These results demonstrate that acute nicotine normalizes MK-801-induced PFC abnormality of D(1)R in PFC.

Topics: Animals; Benzazepines; Benzofurans; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamic Acid; Macaca mulatta; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Microdialysis; Nicotine; Nicotinic Agonists; Positron-Emission Tomography; Prefrontal Cortex; Pyrrolidines; Receptors, Dopamine D1; Salicylamides

Ginkgo biloba extract is widely used as a herbal medicine or dietary supplement in Europe, since Ginkgo biloba extract is effective in facilitation of learning and recollection of memories. However, little is known about the mechanism of the action of Ginkgo biloba extract on learning and memory enhancements. On the other hand, it is well known that cholinergic, histaminergic and glutamatergic systems play a crucial role in learning and memory in animals. Therefore, in order to elucidate the mechanism of Ginkgo biloba extract on memory, we studied and clarified the effect of Ginkgo biloba extract on spatial memory deficits induced by scopolamine, diphenhydramine or MK-801 using eight-arm radial maze performance. It was found that Ginkgo biloba extract improved the spatial memory deficits induced by scopolamine. Ginkgo biloba extract also caused repair to spatial memory deficits induced by diphenhydramine. On the other hand, no significant effect was observed with MK-801-induced spatial memory deficits. These findings suggest that the effect of Ginkgo biloba extract is mediated not only by the cholinergic system but also by the histaminergic system to induce learning and memory enhancements.

Topics: Animals; Diphenhydramine; Dizocilpine Maleate; Ginkgo biloba; Male; Memory Disorders; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Scopolamine

To investigate the role of histamine in memory deficits induced by MK-801 infusion into the ventral hippocampus in rats.. An 8-arm radial maze (4 arms baited) was used to assess spatial memory.. Bilateral ventral intrahippocampal (ih) infusion of MK-801 (0.3 microg/site), an N-methyl-D-aspartate (NMDA) antagonist, impaired the retrieval process in both working memory and reference memory. Intrahippocampal injection of histamine (25 or 50 ng/site) or intraperitoneal (ip) injection of histidine (25, 50 or 100 mg/kg) markedly ameliorated the spatial memory deficits induced by MK-801. Both the histamine H1 antagonist pyrilamine (0.5 or 1.0 microg/site, ih) and the H2 antagonist cimetidine (2.5 microg/site, ih) abolished the ameliorating effect of histidine (100 mg/kg, ip) on reference memory deficits, but not that on working memory deficits induced by MK-801.. The results indicate that histamine in the ventral hippocampus can ameliorate MK-801-induced spatial memory deficits, and that histamine's effect on reference memory is mediated by postsynaptic histamine H1 and H2 receptors.

Topics: Animals; Cimetidine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Histidine; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Pyrilamine; Rats; Rats, Sprague-Dawley

The spatial memory impairment and expression of apoptotic cells in hippocampal CA1 cells were investigated in rats using single and repeated ischemia models. The neuroprotective and memory-improving effect of YM-90K, an alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor antagonist, was compared to MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist. Twice-repeated ischemia, but not single ischemia, impaired the spatial memory and increased expression of apoptotic cells. YM-90K, given before and 6 h after the second reperfusion, significantly improved the memory and reduced the apoptotic cells 7 days after the second reperfusion in repeated ischemia. MK-801 neither improved the spatial memory nor reduced apoptotic cells. The present study showed that delayed expression of apoptotic cells is mediated by mechanisms involving AMPA receptors, but not by NMDA receptor, during the late phase after reperfusion. YM-90K could provide neuroprotective activity and improve the spatial memory impaired by repeated ischemia.

Topics: Animals; Apoptosis; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Memory Disorders; Nerve Degeneration; Neurons; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Reperfusion Injury

A significant impairment of learning and memory-related behavior was induced in mice on the 7th and 14th days after olfactory bulbectomy (OBX), as measured by a passive avoidance task. The involvement of the N-methyl-D-aspartate (NMDA) receptor ion-channel complex for learning and memory-related behavior impairment was examined by the intracerebroventricular administration of several NMDA receptor-related agonists and in combination with antagonists. The NMDA receptor agonist NMDA (1 ng/mouse) and the polyamine site agonist spermidine (1 micro g/mouse) improved learning and memory-related behavior impairment. In contrast, the glycine agonist D-cycloserine (0.2, 1 and 5 micro g/mouse) had no effect on learning and memory-related behavior impairment. The improved effects by NMDA and spermidine were reversed by the coadministration of D-APV, a competitive NMDA receptor antagonist, MK-801, an NMDA ion-channel blocker and ifenprodil, a polyamine site antagonist, respectively. These results suggest that the degeneration of NMDA receptors and polyamine sites in the NMDA receptor ion-channel complex may be involved in the OBX-induced impairment of learning and memory-related behavior.

Topics: 2-Amino-5-phosphonovalerate; Animals; Avoidance Learning; Cycloserine; Disease Models, Animal; Dizocilpine Maleate; Drug Therapy, Combination; Injections, Intraventricular; Male; Memory Disorders; Mice; N-Methylaspartate; Olfactory Bulb; Piperidines; Receptors, N-Methyl-D-Aspartate; Spermidine; Time Factors

This study was performed to investigate whether or not the histamine H3-antagonist clobenpropit can ameliorate spatial memory deficits induced by MK-801 (0.3 microg per site) as evaluated by an eight-arm radial maze task of rats. A bilateral intrahippocampal (i.h.) injection of clobenpropit (5, 10 microg per site, dose-dependent) markedly improved the working and reference memory deficits induced by MK-801. Its ameliorating effect was potentiated by histidine, but completely antagonized by immepip (2.5 microg per site), a selective H3-agonist. alpha-Fluoromethylhistidine (FMH, 25 microg per site), a selective histidine decarboxylase inhibitor prevented the ameliorating effect of clobenpropit on the working memory deficits induced by MK-801. In addition, the H(1-antagonist pyrilamine, but not the H2-antagonist cimetidine, also inhibited the procognitive effects of clobenpropit. Both FMH and pyrilamine did not significantly modulate the effect of clobenpropit on reference memory. Therefore, the results of this study suggest that the procognitive effects of clobenpropit in MK-801-induced working memory deficits is mediated by increasing endogenous histamine release. In addition, the ameliorating effect of clobenpropit on reference memory might be due to the increased release of neurotransmitters other than histamine.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Histamine Antagonists; Imidazoles; Male; Maze Learning; Memory Disorders; Piperidines; Rats; Rats, Sprague-Dawley; Spatial Behavior; Thiourea

The effects of adenosine A3 agonist IB-MECA on scopolamine- and MK-801-induced impairment of spontaneous alternation and learning abilities were examined using Y-maze and passive avoidance tasks in mice. IB-MECA given 20 min before test had no effect on spontaneous alternation performance. Similarly learning abilities tested in passive avoidance were not disturbed after IB-MECA administration before training session. IB-MECA significantly diminished scopolamine- and MK-801-induced impairment of spontaneous alternation in Y-maze and learning abilities in passive avoidance task as well as reduced higher locomotor activity in MK-801-treated group. This ameliorating effect of IB-MECA was not antagonised by adenosine A1 antagonists CPX. Obtained results indicate that adenosine A3 receptor stimulation may ameliorate spatial memory and long term memory impairments in terms of cholinergic and glutamatergic deficits induced by scopolamine and MK-801, respectively.

Topics: Adenosine; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Maze Learning; Memory; Memory Disorders; Mice; Motor Activity; Muscarinic Antagonists; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Receptor, Adenosine A3; Scopolamine; Theophylline

A blockade of N-methyl-D-aspartate (NMDA)-type of glutamate receptor in rodents is believed to provide a pharmacological model of schizophrenia-related psychosis. Since neurodevelopmental abnormality, at least partly, could contribute to the pathogenesis of schizophrenia, the aim of this study was to recapitulate cognitive impairments accompanying this disorder in rats by a chronic neonatal treatment with a noncompetitive NMDA antagonist MK-801. Rat pups were treated with a low dose of MK-801 (0.05 mg/kg s.c.) chronically from early postnatal period (PD 7-49) known to be critical for glutamatergic system maturation. Locomotor activity in the "open-field" test, anxiety level in the elevated plus-maze test, and learning capacity in food rewarded spatial task were examined in young animals. Chronic MK-801 treatment produced a decrease of spontaneous motor and exploratory activity in 16- to 28-day-old rats. At the same time, a hyperlocomotion in response to acute administration of MK-801 was observed as well. Spatial learning of MK-801-treated rats was found to be negatively affected. Treated rats were able to respond to stress stimuli in the adequate manner but their anxiety level was found to be lower than in controls. Behavioral disturbances appeared to be temporary, and no such abnormalities could be detected at the age of 16 weeks. Thus, even mild chronic neonatal blockade of NMDA receptors may lead to a specific pattern of cognitive abnormalities presumably resulting from impairments of sensory information processing at the cortical-basal ganglia level.

Topics: Animals; Animals, Newborn; Dizocilpine Maleate; Learning; Male; Memory Disorders; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Nicotinic acetylcholine and NMDA glutamate receptors play critical roles in memory function. The brain areas involved in their interaction are still under investigation. One likely area is the hippocampus. Ventral hippocampal administration of nicotinic antagonists impair memory. Hippocampal administration of NMDA antagonists also cause memory impairments. We evaluated the importance of ventral hippocampal NMDA receptors for nicotinic actions on memory by testing the impact of systemic nicotine on memory with and without administration of the NMDA antagonist dizocilpine into the ventral hippocampus. Sprague-Dawley rats (N=11) trained on the 16-arm radial maze were bilaterally implanted with local infusion cannulae in the ventral hippocampus. The effects on memory function of ventral hippocampal infusions of 0, 2, 6 and 18 microg per side of dizocilpine were examined with and without acute systemic nicotine administration (0 or 0.4 mg/kg). The dizocilpine doses tested did not cause memory deficits by themselves but only did so when given in combination with systemic nicotine. Blocking NMDA ventral hippocampal actions revealed an impairing action of nicotine on memory. Nicotine effects on other non-NMDA hippocampal receptor systems or extra-hippocampal systems may have been left unchecked by the diminished nicotinic effect on ventral hippocampal NMDA receptors.

Topics: Animals; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Hippocampus; Maze Learning; Memory; Memory Disorders; Neural Pathways; Neurons; Nicotine; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Synaptic Transmission

MK-801 impaired social recognition potency of adult male rats when given immediately after the initial interaction with a juvenile rat. Administration of kynurenic acid prior to the initial interaction protected the adults against recognition deficits induced by MK-801. When re-exposed at a delay of 30 min to the familiar juvenile, social investigation in the adults was significantly reduced. Thus, the adults are able to remember olfactory stimuli emitted by juvenile con-specifics.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Kynurenic Acid; Male; Memory Disorders; Olfactory Pathways; Rats; Rats, Wistar; Recognition, Psychology; Social Behavior

An interaction between N-methyl-D-aspartate (NMDA) and MK-801 was examined in mice using a modified elevated plus-maze paradigm that allows assessment of the adaptive form of spatial memory. NMDA administered (s.c.) immediately after the acquisition session protected the animals against the amnesia induced by MK-801 given shortly before the retention session. Behavioral performance, expressed as the transfer latency, and therefore spatial memory potency of NMDA plus MK-801 treated animals was comparable with that of both NMDA-treated animals and the controls.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Maze Learning; Memory Disorders; Mice; Mice, Inbred Strains; N-Methylaspartate

To investigate whether or not histamine is involved in spatial memory deficits induced by dizocilpine (MK-801) as evaluated by 8-arm radial maze of rats.. 8-Arm (4-arm baited) radial maze was used to measure spatial memory in rats.. Bilaterally intrahippocampal (ih) injection of MK-801 (0.3 microg/site) impaired working memory and reference memory in rats. Both histamine (50, 100 ng/site, ih) and intraperitoneal (ip) injection of histidine (100, 200 mg/kg) markedly improved the spatial memory deficits induced by MK-801. On the other hand, the ameliorating effect of histidine (100 mg/kg, ip) was completely antagonized by alpha-fluoromethylhistidine (alpha-FMH, 5 microg/site, ih), a potent and selective histidine decarboxylase (HDC) inhibitor, and H1-antagonist pyrilamine (1 microg/site, ih), but not by H2-antagonist cimetidine, even at a high dose (2.5 microg/site, ih).. The hippocampal histamine plays an important role in the ameliorating effect on MK-801-induced spatial memory deficits, and its action is mediated through postsynaptic H1-receptor.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Histamine; Histidine; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Rats; Rats, Sprague-Dawley

Effects of MK-801 (a NMDA receptor blocker) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; a non-NMDA receptor blocker) on several neurotoxic responses induced by kainic acid (KA) were examined in ICR mice. In a lethality test, intracerebroventricular (i.c.v.) pretreatment of MK-801 (1 microg), but not CNQX (0.5 microg), attenuated the time to lethality induced by KA (0.5 microg) administered i.c.v. In the memory test (a passive avoidance test), MK-801, but not CNQX, prevented the memory loss induced by KA (0.1 microg). The damage induced by KA (0.1 microg) administered i.c.v. in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. Both MK-801 and CNQX blocked the pyramidal cell death in CA3 hippocampal region induced by KA. In the immunocytochemical study, KA dramatically increased the phosphorylated ERK (p-ERK) and decreased the phosphorylated CREB (p-CREB) in the hippocmapus. Both MK-801 and CNQX attenuated, in part, the increased p-ERK and the decreased p-CREB induced by KA. In addition, both MK-801 and CNQX partially reduced the increased c-Fos and c-Jun protein expression in hippocampus induced by KA. Our results suggest that both NMDA and non-NMDA receptors are involved in supraspinally administered KA-induced pyramidal cell death in CA3 region of hippocampus in the mouse and the p-ERK and the dephosphorylation of CREB protein may play an important role in CA3 region cell death of the hippocampus induced by KA administered supraspinally. Furthermore, c-Fos and c-Jun proteins may serve as third messengers responsible for CA3 pyramidal cell death induced by supraspinally administered KA.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Apoptosis; Blotting, Northern; Blotting, Western; Cyclic AMP Response Element-Binding Protein; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Immunoenzyme Techniques; Injections, Intraventricular; Kainic Acid; Lethal Dose 50; Male; Memory Disorders; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Neurons; Phosphorylation; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; RNA Probes; Survival Rate

We examined the effects of a histidine-deficient diet on brain histamine contents as well as on learning and memory using the eight-arm radial maze in rats. A significant decrease in histamine content in the hippocampus was observed after long-term feeding of rats with a histidine-deficient diet. At the same time, significant enhancement of the acquisition process in radial maze performance was also observed. Pyrilamine did not show a significant effect on radial maze performance in histidine-deficient rats. On the other hand, pyrilamine caused a significant spatial memory deficit in control rats. Scopolamine was effective in inhibiting spatial memory in both histidine-deficient and control rats. MK-801 caused spatial memory deficits more potently in histidine-deficient rats than in controls. Brain glycine contents showed a significant increase in the hippocampus in histidine-deficient rats. These results indicated that the spatial memory deficits induced by MK-801 in histidine-deficient rats are closely related to increased glycine levels and activation of NMDA receptors.

Topics: Amino Acids; Animals; Brain; Diet; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Histamine H1 Antagonists; Histidine; Male; Maze Learning; Memory Disorders; Pyrilamine; Rats; Rats, Wistar; Scopolamine

The objective of this study was to investigate whether hypothermia would suppress secondary damage in the chronic postischemic stage, in terms of glutamate excitotoxicity.. Gerbils underwent 5 minutes of ischemia via bilateral common carotid artery occlusion. Seven groups were studied, as follows: 1) ischemia without treatment group; 2) intraischemic hypothermia group; 3) postischemic hypothermia group (32 degrees C for 4 h); 4) MK-801 treatment group (2 mg/kg, every other day for 1 mo); 5) postischemic hypothermia with MK-801 treatment for 1 week group (2 mg/kg, every other day); 6) postischemic hypothermia with MK-801 treatment for 1 month group (2 mg/kg, every other day); and 7) sham-treated control group. One month after ischemia, histological changes in hippocampal CA1 neurons (assessed using hematoxylin and eosin staining) and memory function (assessed using an eight-arm radial maze) were studied. Extracellular glutamate concentrations were monitored by microdialysis during ischemia and hypothermia. Staining of microglia was performed 1 week and 1 month after ischemia.. MK-801 alone, postischemic hypothermia alone, and postischemic hypothermia with MK-801 treatment for 1 week failed to prevent ischemic neuronal damage and memory function decreases 1 month after the insult (P < 0.05 versus control). However, the postischemic hypothermia with MK-801 treatment for 1 month group exhibited significant protective effects (not significant [P > 0.05] compared with the control group). Extracellular glutamate levels for the intraischemic hypothermia group were significantly low, compared with the postischemic hypothermia group. There was no microglial activation in the postischemic hypothermia at 1 week and 1 month after ischemia groups.. Postischemic hypothermia and long-term intermittent administration of MK-801 demonstrated significant neuronal protection, indicating that long-term glutamatergic activation, with changes in N-methyl-D-aspartate receptors, plays a role in neuronal damage in the chronic postischemic stage.

Topics: Animals; Brain; Brain Ischemia; Carotid Stenosis; Dizocilpine Maleate; Extracellular Space; Gerbillinae; Glutamates; Hippocampus; Hypothermia; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Space Perception

The effects of fmol doses of nociceptin/orphanin FQ on scopolamine-induced impairment of learning and/or memory were examined using spontaneous alternation of Y-maze and step-down type passive avoidance tasks. While fmol doses of nociceptin alone had no effect on spontaneous alternation or passive avoidance behavior in normal mice, administration of nociceptin (10 and/or 100 fmol/mouse) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, significantly improved the scopolamine-induced impairment of spontaneous alternation and passive avoidance behavior. This ameliorating effect was not antagonized by nocistatin (0.5 and 5.0 nmol/mouse, i.c.v.), naloxone benzoylhydrazone (2.3, 11.2, and 56.1 micromol/kg, s.c.) or nor-binaltorphimine (4.9 nmol/mouse, i.c.v.). These results indicated that very low doses of nociceptin ameliorate impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that this peptide has bidirectional modulatory effects on learning and memory; impairment at high doses and amelioration at low doses.

Topics: Analgesics, Opioid; Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Nociceptin; Opioid Peptides; Psychomotor Performance; Rats; Scopolamine

Rolipram, a selective inhibitor of type 4 cyclic AMP phosphodiesterase (PDE4), completely reversed the amnesic effects of MK-801 on working and reference memory (F[4,64] = 11.10; p <.0001 and F[4,64] = 2.53; p <.05, respectively) at doses of 0.01-0.1 mg/kg in the radial-arm maze task. Similar antagonism by rolipram of the effects of MK-801 was observed on inhibitory avoidance behavior (F[3,35] = 190.8; p <.0001). In vitro evidence suggests that an increase in cAMP concentrations may mediate the observed behavioral effects of rolipram. In the absence of PDE4 inhibition, NMDA did not increase cAMP concentrations in primary cultures of rat cerebral cortical neurons. However, when PDE4 was inhibited with rolipram, NMDA markedly elevated cAMP. These observations suggest that PDE4 is an integral component of the NMDA receptor-mediated signal transduction pathway involved in memory processes. Inhibitors of PDE4 may act on this pathway to produce their effects on memory and may represent a new class of cognitive enhancers.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Avoidance Learning; Cells, Cultured; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory Disorders; N-Methylaspartate; Neurons; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Rolipram

Activation of N-methyl-d-aspartate (NMDA) receptors has been hypothesized to mediate certain forms of learning and memory. This hypothesis is based on the ability of competitive and uncompetitive NMDA receptor antagonists to disrupt learning. We investigated the effects of glycine site antagonists and partial agonists on deficits of acquisition (learning) and consolidation (memory) in a single trial inhibitory avoidance learning paradigm. Posttraining administration of either hypoxia (exposure to 7% oxygen) or the convulsant drug pentylenetetrazole (PTZ) (45 mg/kg) to mice impaired consolidation without producing neuronal cell death. Pretreatment with the competitive glycine antagonist 7-chlorokynurenic acid (7KYN) and the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+)HA-966 prevented memory deficits induced by hypoxia and PTZ, but did not affect scopolamine-induced learning impairment. In addition, ACPC prevented consolidation deficits evoked by a nonexcitotoxic concentration of l-trans-pyrrolidine-2, 4-dicarboxylate, a competitive inhibitor of glutamate transport that increases extracellular levels of glutamate. Moreover, (+)HA-966, 7KYN, and ACPC facilitated both acquisition and consolidation of inhibitory avoidance training, an effect that was dose-dependent and reversed by glycine. These results indicate that memory deficits induced by both hypoxia and PTZ involve NMDA receptor activation. Furthermore, the present findings demonstrate that glycine site antagonists and partial agonists prevent memory deficits of inhibitory avoidance learning by affecting consolidation, but not acquisition processes.

Topics: Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Inhibition, Psychological; Kynurenic Acid; Male; Memory Disorders; Mice; Muscarinic Antagonists; Pyrrolidinones; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Retention, Psychology; Scopolamine

Alterations in N-methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity, characteristic of aged rodents, may contribute to impaired memory with advanced age. The purpose of the current research was to examine whether NMDARs contribute to rapid forgetting on a spatial memory task. Aged (22-24 months) and adult (3-6 months) male Fischer 344 rats received 18 training trials, over a period of 3 to 4 h, on the spatial version of the Morris water maze. Immediately after training, a standard free-swim probe trial was administered to assess the acquisition of spatial bias, which was determined by the percent of time spent in the goal quadrant and the number of platform crossings. Rats then received injections of the noncompetitive NMDAR antagonist, (+)-10, 11-dihydro-5methyl-5H-dibenzo(a,b)cycloheptene-5,10 imine (MK-801, 0. 05 mg/kg, i.p.), or a vehicle injection of equal volume. Approximately 24 h later, rats were administered a second free-swim probe trial to assess retention of spatial bias. All age/drug groups exhibited a spatial bias on the acquisition probe, with adults generally outperforming the aged rats. On the retention probe, this spatial bias continued to be shown by adult rats, regardless of treatment. For the aged group, in contrast, only MK-801-injected rats maintained a spatial bias on the retention probe, suggesting that NMDAR activity may be involved in rapid forgetting during aging. Because blockade of NMDARs also may impair new learning, which may, in turn, protect previously stored information from retroactive interference, rats in a second experiment received post-training injections of scopolamine (0.05 mg/kg), a compound known to inhibit learning. However, scopolamine did not enhance retention in the aged group, consistent with the hypothesis that MK-801 influenced memory in aged rats through its actions on NMDAR-dependent synaptic plasticity.

Topics: Aging; Animals; Behavior, Animal; Dizocilpine Maleate; Male; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Rats; Retention, Psychology; Space Perception; Spatial Behavior; Synapses

The effects of histamine on the spatial memory deficits induced by MK-801 were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (i.c.v.) injection of histamine or thioperamide, and intraperitoneal (i.p.) injection of histidine improved the spatial memory deficits induced by MK-801. Similar results were obtained with 2-thiazolylethylamine. In contrast, 4-methylhistamine showed no significant effect. Based on these observations, it seems likely that the protective effect of histamine on MK-801-induced spatial memory deficit is mediated by H(1)-receptors.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Histamine; Injections, Intraperitoneal; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Psychomotor Performance; Rats; Rats, Wistar

The effects of a novel vasopressin fragment analog NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate) were studied on learning and/or memory impairment in passive avoidance task and on cell damage of cultured cerebro-cortical neurocytes induced by glutamic acid. A small dose of NC-1900 (1 ng/kg, s.c.) ameliorated impairments of learning and/or memory induced by intracisternal injection of 467.6 micrograms of 10 microliters glutamic acid. NC-1900 also ameliorated the impairments induced by intracisternal NMDA, AMPA-antagonist CNQX and by metabotropic receptor (mGluR1) agonist 3,5-dihydroxyphenylglycine but not by kainate agonist domoic acid nor MK-801 in mice. NC-1900 (100 pM, 1nM) ameliorated the cell damage of cultured rat cerebro-cortical neurocytes induced by 100 and 1000 microM of glutamic acid. These results suggest that NC-1900 may serve as a remedies in various patients with certain brain disorders induced by excess glutamic acid.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Arginine Vasopressin; Avoidance Learning; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Kainic Acid; Learning Disabilities; Male; Memory Disorders; Mice; Mice, Inbred Strains; N-Methylaspartate; Neuromuscular Depolarizing Agents; Oligopeptides; Pyrrolidonecarboxylic Acid; Rats; Rats, Sprague-Dawley; Resorcinols

The role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 mumol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 mumol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 mumol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 mumol/kg) and mecamylamine (12 mumol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1-13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylamine via the kappa receptor-mediated opioid neuronal system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetylcholine; Animals; Dizocilpine Maleate; Dynorphins; Learning Disabilities; Male; Mecamylamine; Memory Disorders; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Scopolamine

This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.

Topics: Animals; Ataxia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Eating; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory Disorders; Nootropic Agents; Phenazocine; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

Both nicotinic cholinergic and NMDA glutaminergic systems are important for memory function. Nicotine has been found repeatedly to significantly improve working memory performance in the radial-arm maze. The NMDA antagonist dizocilpine has been found to impair working memory performance. There is neuropharmacological evidence that these two systems are functionally related. Nicotine is potent at releasing many transmitters including glutamate. The current study was conducted to examine the interaction of nicotinic and NMDA systems with regard to working and reference memory. Rats were trained on a working/reference procedure on a 16-arm radial maze. After acquisition, they were administered nicotine (0, 0.2, and 0.4 mg/kg) and dizocilpine (0, 100, and 200 microg/kg) alone or in combination in a repeated measures, counterbalanced design. As seen previously, nicotine at a dose of 0.2 mg/kg caused a significant improvement in working but not reference memory performance in the radial-arm maze. The 200 microg/kg dose of dizocilpine made the rats nonresponsive on the maze so that choice accuracy could not be assessed. The 100 microg/kg dose of dizocilpine caused significant impairments in both working and reference memory. The 0.4 mg/kg dose of nicotine significantly attenuated the dizocilpine-induced deficit in both working and reference memory. NMDA blockade impairs working and reference memory and blocks the expression of the working memory improvement caused by 0.2 mg/kg of nicotine. However, a higher dose of 0.4 mg/kg of nicotine is effective at attenuating the dizocilpine-induced deficit, even though this dose alone is not effective in improving performance. A second study examined the effects of a lower dose range of dizocilpine. Comensurately smaller memory impairments were seen with lower doses of dizocilpine down to 12.5 microg/kg, which did not produce any significant effects on memory performance or response latency. Nicotine had a more modest effect in attenuating the smaller deficits caused by these lower doses of dizocilpine. These studies provide evidence for important interactions between nicotinic and NMDA systems with regard to memory function.

Topics: Animals; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Maze Learning; Memory; Memory Disorders; Nicotine; Nicotinic Agonists; Psychomotor Performance; Rats; Rats, Sprague-Dawley

In order to investigate whether strychnine-insensitive glycine sites coupled with hippocampal NMDA (N-methyl-d-aspartate) receptors are involved in spatial memory in rats, we examined the effects of intrahippocampal treatment of d-cycloserine (DCS), a glycine-site agonist, on spatial-memory deficits which were produced by an NMDA antagonist MK-801 (dizocilpine) on the radial-arm maze task. After the acquisition of this task, the radial-maze performance was tested under the combined treatments of intraperitoneal MK-801 or saline (SAL) and intrahippocampal DCS or SAL. The results showed that MK-801 impaired the performance, and that DCS improved the MK-801-induced performance impairment. These results suggest that glycine sites are involved in spatial memory through their modulatory action on hippocampal NMDA receptors.

Topics: Analysis of Variance; Animals; Cycloserine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Memory Disorders; Rats; Rats, Wistar; Stereoisomerism

Intrahippocampal administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.18 microg/side) significantly increased the number of errors in the working memory task with a three-panel runway setup. The increase in working memory errors by intrahippocampal MK-801 was significantly attenuated by concurrent infusion of D-cycloserine (1.0 microg/side) or spermidine (10 microg/side), agonists of the glycine and polyamine modulatory sites on the NMDA receptor/channel complex, respectively. Combined injection of the behaviorally ineffective doses of 0.1 microg/side D-cycloserine and 0.32 microg/side spermidine synergistically reduced intrahippocampal MK-801-induced increase in working memory errors. The combination of D-cycloserine and spermidine also synergistically attenuated the increase in working memory errors resulting from intrahippocampal injection of the muscarinic acetylcholine receptor antagonist scopolamine (3.2 microg/side). These results suggest that positive modulation of the NMDA receptor/channel through activation of the glycine and polyamine sites can synergistically compensate deficiency of hippocampal NMDA and muscarinic receptor-mediated neurotransmission involved in working memory function.

Topics: Animals; Antimetabolites; Cycloserine; Dizocilpine Maleate; Drug Synergism; Glycine; Hippocampus; Injections, Intraventricular; Male; Memory Disorders; Polyamines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spermidine

We previously reported that high-affinity sigma type 1 (sigma 1) ligands attenuate the learning impairment induced in mice by dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist. Neurosteroids, such as pregnenolone sulfate, progesterone and dehydroepiandrosterone sulfate (DHEAS), modulate NMDA-evoked responses in the central nervous system. Furthermore, some of them were reported to interact with sigma-receptors. This study was carried out to investigate whether DHEAS, a neurosteroid with memory-enhancing effects, attenuates the dizocilpine-induced learning impairment in mice, and, if so, by a mechanism involving sigma 1-receptors. Learning was evaluated using spontaneous alternation in the Y-maze for spatial working memory and step-down type of passive avoidance for long-term memory. At doses about 10-20 mg/kg s.c., DHEAS significantly attenuated dizocilpine (0.15 mg/kg i.p.)-induced impairment of learning on both tests. The enhancing effect of DHEAS (20 mg/kg s.c.) was antagonized by co-administration of the sigma-antagonist BMY-14802 (5 mg/kg i.p.) and suppressed by a subchronic treatment with haloperidol (4 mg/kg/day s.c. for 7 days). These results indicate that DHEAS attenuates dizocilpine-induced learning impairment via an interaction with sigma 1-receptors.

Topics: Animals; Anti-Anxiety Agents; Avoidance Learning; Dehydroepiandrosterone Sulfate; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Haloperidol; Injections, Subcutaneous; Learning Disabilities; Ligands; Male; Memory Disorders; Mice; Pyrimidines; Receptors, sigma

The purpose of the present research was to study the interaction between the non-competitive NMDA receptor antagonist MK-801 and morphine in memory consolidation. The involvement of dopamine (DA) mechanisms in this interaction was also studied. Four sets of experiments were carried out with CD1 mice in a one-trial inhibitory avoidance task with post-training injections of drugs. In a first series of experiments post-training administration of morphine or of the non-competitive NMDA receptor antagonist MK-801 impaired memory consolidation. In the second set of experiments the memory consolidation impairment exerted by MK-801 was potentiated by the administration of the D1 dopamine (DA) receptor antagonist SCH 23390 and by that of the D2 DA receptor antagonist (-)-sulpiride. In the third set of experiments, administration of a dose of MK-801 ineffective by itself potentiated the memory impairment exerted by morphine. In the fourth series of experiments, similar ineffective doses of the D1 DA receptor agonist SKF 38393 or of the D2 DA receptor agonist LY 171555 antagonized the impairment of memory consolidation produced by MK-801 and morphine in combination, suggesting the involvement of dopaminergic mechanisms.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analgesics, Opioid; Animals; Dizocilpine Maleate; Dopamine Agonists; Drug Synergism; Excitatory Amino Acid Antagonists; Learning; Male; Memory Disorders; Mice; Morphine; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate

Both N-methyl-D-aspartate (NMDA) and cholinergic receptors are thought to participate in processes of learning and memory. The effects of the noncompetitive NMDA antagonist ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) MK-801 on recognition memory in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample DNMS were compared to those of the cholinergic compounds physostigmine and scopolamine. In the sample phase of the test, 20 symbols were presented sequentially every 30 sec on a color monitor fitted with a touch-sensitive screen. These symbols were then presented again in the same order as before, but each symbol was now paired with a different novel symbol. A monkey was rewarded with a food pellet if it touched the symbol in the sample phase and the previously unseen symbol in the choice phase. Physostigmine (3.2, 10 and 32 micrograms/kg), scopolamine (3.2, 10, 17.8 and 32 micrograms/kg) or MK-801 (3.2, 10 and 32 micrograms/kg) was injected i.m. 20, 20 and 30 min before testing, respectively. The highest doses of both MK-801 and scopolamine significantly impaired performance. In addition, scopolamine, but not MK-801, prolonged response latency, whereas MK-801, but not scopolamine, increased response bias. Physostigmine produced a small but significant increase in correct responses at the intermediate dose, but not at the highest dose. These results suggest that both the glutamatergic and the cholinergic systems participate in visual recognition memory in monkeys, though probably by different mechanisms.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Learning; Learning Disabilities; Macaca mulatta; Male; Memory; Memory Disorders; Physostigmine; Scopolamine