dizocilpine-maleate and Cognition-Disorders

Schizophrenia affects about 1% of the world population and is a major socio-economical problem in ours societies. Cognitive symptoms are particularly resistant to current treatments and are believed to be closely related to an altered function of prefrontal cortex (PFC). Particularly, abnormalities in the plasticity processes in the PFC are a candidate mechanism underlying cognitive symptoms, and the recent evidences in patients are in line with this hypothesis. Animal pharmacological models of cognitive symptoms, notably with non-competitive NMDA receptor antagonists such as MK-801, are commonly used to investigate the underlying cellular and molecular mechanisms of schizophrenia. However, it is still unknown whether in these animal models, impairments in plasticity of PFC neurons are present. In this article, we briefly summarize the current knowledge on the effect of non-competitive NMDA receptor antagonist MK-801 on medial PFC (mPFC) neuronal activity and then introduce a form of plasticity found after acute exposure to MK-801, which was accompanied by cognitive deficits. These observations suggest a potential correlation between cognitive deficits and the aberrant plasticity in the mPFC in the animal model of schizophrenia.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Prefrontal Cortex; Rats; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase-3β (GSK3β) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies. AZD1080 inhibits tau phosphorylation in cells expressing human tau and in intact rat brain. Interestingly, subchronic but not acute administration with AZD1080 reverses MK-801-induced deficits, measured by long-term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3β signaling. The inhibitory pattern on tau phosphorylation reveals a prolonged pharmacodynamic effect predicting less frequent dosing in humans. Consistent with the preclinical data, in multiple ascending dose studies in healthy volunteers, a prolonged suppression of glycogen synthase activity was observed in blood mononuclear cells providing evidence of peripheral target engagement with a selective GSK3 inhibitor in humans.

Topics: Animals; Cell Line, Transformed; Cognition Disorders; Crystallography; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glycogen Synthase; Glycogen Synthase Kinase 3; Hippocampus; Humans; In Vitro Techniques; Indoles; Leukocytes, Mononuclear; Long-Term Potentiation; Male; Mice; Middle Aged; Phosphorylation; Protein Binding; Protein Kinases; Pyridines; Rats; Rats, Sprague-Dawley; tau Proteins

Cognitive deficits in schizophrenia, which include impairments in working memory and attention, represent some of the most disabling symptoms of this complex psychiatric condition, and lack effective treatments. NMDA receptor (NMDAr) hypofunction is a strong candidate mechanism underlying schizophrenia pathophysiology, and has been modeled preclinically using acute administration of NMDAr antagonists to rodents to investigate biological mechanisms underpinning cognitive dysfunction. However, whether and how NMDAr hypofunction specifically influences all affected cognitive domains is unclear. Here we studied the effects of the NMDAr antagonist MK-801 (dizocilpine) on tasks of attention and working memory in rats using automated touchscreen chambers. Adult male Wistar rats were trained to perform the trial-unique nonmatching to location (TUNL) task of spatial working memory, or the 5-choice serial reaction time task (5CSRTT) of attention. Once trained, rats received injection of vehicle (saline) or low-dose MK-801 (0.06 mg/kg sc) 10 min prior to commencing test sessions. MK-801 significantly impaired working memory, as evidenced by reduced performance accuracy on the TUNL task (p < .0001), compared with vehicle. However, we found no significant effects on attentional processing or perseveration on the 5CSRTT. Additional measures indicated that MK-801 impaired behavioral flexibility in the TUNL task, and decreased response inhibition in both tasks. Using the automated touchscreen system to measure different cognitive functions under the same testing environment, we demonstrate that spatial working memory, response inhibition, and behavioral flexibility are more vulnerable to NMDAr hypofunction than attentional processing. This may have implications for the NMDAr hypofunction hypothesis of schizophrenia. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Topics: Animals; Antipsychotic Agents; Attention; Cognition; Cognition Disorders; Cognitive Dysfunction; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Memory, Short-Term; N-Methylaspartate; Rats; Rats, Wistar; Reaction Time; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Schizophrenia treatment remains a major challenge, especially the associated cognitive impairments, as these are not consistently alleviated by conventional antipsychotics. Recent animal and clinical studies suggest that the nitric oxide (NO) donor sodium nitroprusside (SNP) reduces the psychiatric symptoms and cognitive deficits of schizophrenia. The present study was designed to investigate the efficacy of SNP against schizophrenia-like behavioral and cognitive deficits in the dizocilpine (MK-801) rat model. We used the rotarod and open field tests to identify the SNP dose which had no adverse effects on rat's exploratory and motor behavior, then established the schizophrenia model by injecting adult Sprague-Dawley rats intraperitoneally with MK-801 (0.4 mg/kg) with or without SNP pre-treatment. Behavioral changes were examined after 10 min. Prepulse inhibition (PPI) and the Y maze tests were conducted to assess cognitive deficits, and elevated plus maze and open field tests to assess anxiety-like behaviors. Preliminary rotarod and open field tests demonstrated that 2.5 mg/kg SNP had no effect on motor performance. Acute MK-801 treatment induced both cognitive deficits and anxiety. Co-administration of SNP (2.5 mg/kg) failed to improve these schizophrenia-like abnormalities. Sodium nitroprusside appears unable to improve schizophrenia-like symptoms and cognitive deficits induced by MK-801, inconsistent with the effectiveness of SNP as an adjunct therapy for anxiety disorders and working memory impairments in schizophrenia patients. Future studies are required to define an effective dose range for SNP monotherapy and adjunct therapy in different rodent models.

Topics: Animals; Antipsychotic Agents; Anxiety; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Male; Maze Learning; Memory, Short-Term; Motor Activity; Nitroprusside; Prepulse Inhibition; Rats; Rats, Sprague-Dawley; Schizophrenia

Schizophrenia is known to be a complex and disabling psychiatric disorder. Dopamine receptor antagonists have a significant therapeutic effect in improving the positive symptoms that are associated with the illness. Therefore, dopamine receptor antagonists are commonly used in the treatment of schizophrenia; however, they do not achieve satisfactory results in improving negative symptoms and cognitive impairment. Metformin, widely known as an antidiabetic drug, has been found to enhance spatial memory formation and improve anxiety-like behaviors in rodents. Metformin's neuroprotective effect has been well documented in several neurological disorders including Alzheimer's disease, Parkinson's disease, strokes, Huntington's disease, and seizures. In the present study, we used a rat model to explore the effect of metformin on schizophrenia-like behaviors induced by MK-801 (dizocilpine), an N-methyl-D-aspartate (NMDA) receptor antagonist. We found that the pre-pulse inhibition (PPI) deficit caused by MK-801 could be alleviated by metformin. The hyperlocomotion in the open field test induced by chronic treatment of MK-801 was reversed by administration of metformin. Metformin has no effect on the baseline level of anxiety in normal naive rats, while metformin could relieve the anxiety-like behaviors in MK-801-treatment rats, though this effect is not reaching a significant level. Additionally, metformin could significantly ameliorate working memory impairments induced by MK-801. Moreover, the increased level of phosphorylation of Akt and GSK3β in the frontal cortex induced by MK-801 was normalized by metformin. In conclusion, our results demonstrate that metformin improved schizophrenia-like symptoms in rats, and is therefore a potential agent for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Anxiety; Behavior, Animal; Cognition Disorders; Cognitive Dysfunction; Disease Models, Animal; Dizocilpine Maleate; Glycogen Synthase Kinase 3 beta; Male; Maze Learning; Memory, Short-Term; Metformin; Neuroprotective Agents; Prepulse Inhibition; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia

The aim of this study investigates whether β-asarone can improve cognition deficits in dizocilpine (MK-801) treated mice. Six-week-old male C57BL/6 mice were divided into four groups: control group (CON), MK-801-treated group (MK-801), MK-801 plus β-asarone group (MK-801+β-asa) and β-asarone group (β-asa). Behavioral tests, including sociability test, open field test (OPT) and Morris water-maze (MWM), were performed. Extracellular field excitatory postsynaptic potentials were recorded in the hippocampal dentate gyrus (DG) region. Western blot was employed to measure the expression of cognitive function-associated proteins and pro-inflammatory cytokines in the hippocampus. Immunofluorescence was performed to assess the microglial activation in the hippocampus DG region. The data show that social interactions and spatial learning and memory were impaired by MK-801. However, β-asarone significantly mitigated the impairments. Furthermore, it was found that MK-801 aggravated the hyperactivity and anxiety-like behavior, but β-asarone alleviated them. Moreover, β-asarone alleviated the impairments of hippocampal synaptic plasticity and enhanced the expression of hippocampal synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) in MK-801-treated mice. In addition, it suppressed the expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), inducible nitric oxide synthase (i-Nos) and cyclo-oxygenase-2 (COX-2) expression in MK-801-treated mice. The results suggest that β-asarone improved the impairment of cognition and synaptic plasticity possibly through modulating the excess release of pro-inflammatory cytokines and microglia activation in MK-801-treated mice.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anti-Inflammatory Agents; Brain; Cognition; Cognition Disorders; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Hippocampus; Interpersonal Relations; Male; Memory; Mice; Mice, Inbred C57BL; Microglia; Neuronal Plasticity; Neuroprotective Agents; Nitric Oxide Synthase Type II; Social Behavior; Synaptophysin

We previously reported that YQA31 is a dopamine D3 receptor antagonist with modest 5-HT1A receptor affinity and that it exhibits antipsychotic properties in animal models of schizophrenia. However, the contributions of D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31 are not clear. The current study evaluated the role of these two receptors in the effect of YQA31 on the hyperactivity and novel object recognition deficit in mice.. We used dopamine D3 receptor knockout mice and 5-HT1A receptor antagonist WAY100635 pretreatment, respectively, to investigate the involvement of these receptors in the effects of YQA31. The anti-psychotic effects were tested by inducing hyperlocomotion with methamphetamine or MK-801 and by inducing novel object recognition deficit with MK-801, which are the animal models to represent a positive symptom and a cognitive disorder.. YQA31 significantly inhibited MK-801-induced hyperlocomotion and novel object recognition deficit in WT mice, which was significantly inhibited by dopamine D3 receptor knockout. The 5-HT1A receptor antagonist, WAY100635, also blocked the effect of YQA31 in MK-801-induced novel object recognition deficit but not hyperlocomotion. The effect of YQA31 on methamphetamine-induced hyperlocomotion was not reversed by either dopamine D3 receptor knockout or WAY100635 pretreatment.. These results demonstrate the different roles of dopamine D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31. Both dopamine D3 and 5-HT1A receptors contributed to the effects of YQA31 on the inhibition of MK-801-induced novel object recognition deficit, and the dopamine D3 receptor mediated the inhibiting effect of YQA31 on hyperlocomotion induced by MK-801.

Topics: Animals; Antipsychotic Agents; Benzothiazoles; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Hyperkinesis; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperazines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D3; Recognition, Psychology

Cortical gray matter loss in schizophrenia remains a great therapeutic difficulty. Each psychotic episode causes irreversible cortical gray matter loss, that causes the patients to never regain their previous state of functioning. Microglial cells are part of the innate immune system and their functions, among others, include phagocytosis and release of neurotrophic factors. They have a key impact on developmental and plasticity-induced removal of neuronal precursors, live-but-stressed neurons and synapses, while also stimulating synaptic growth and development. We hypothesize that microglia are the culprit for the cortical gray matter loss in schizophrenia through abnormal synaptic pruning, phagocytosis of stressed neurons and lacking neurotrophic factor release. Furthermore, we propose a research that could validate the hypotheses using serum samples of first-episode early-onset patients. By measuring the serum levels of milk fat globule-EGF factor 8 (MFG-E8), subcomponent in the classical pathway of complement activation (C1q), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6) and interleukin-10 (IL-10), we could gain an insight into the state of microglial activation during various stages of the disease. If this hypothesis is valid, new targeted drugs could be developed in order to reduce the deterioration of cortical gray matter, thereby possibly improving negative symptoms and cognitive deficits.

Topics: Anti-Inflammatory Agents; Antigens, Surface; Brain-Derived Neurotrophic Factor; Clozapine; Cognition Disorders; Complement C1q; Dizocilpine Maleate; Gray Matter; Humans; Immunity, Innate; Interleukin-10; Interleukin-6; Microglia; Milk Proteins; Models, Theoretical; Neurons; Phagocytosis; Schizophrenia; Synapses

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

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ

Topics: Allosteric Site; Amphetamines; Animals; Attention; Calcium; Cerebral Cortex; Cognition; Cognition Disorders; Cyclic AMP; Dizocilpine Maleate; Electroconvulsive Therapy; HEK293 Cells; Humans; Indans; Male; Maze Learning; Memory; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxazoles; Phenotype; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Schizophrenia

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute's breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

Topics: Animals; Avoidance Learning; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Escape Reaction; Excitatory Amino Acid Antagonists; Male; Psychomotor Performance; Psychoses, Substance-Induced; Rats; Rats, Long-Evans; Reversal Learning

Cognitive impairment, including impaired social cognition, is largely responsible for the deterioration in social life suffered by patients with psychiatric disorders, such as schizophrenia and major depressive disorder (MDD). Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel serotonin-dopamine activity modulator, was developed to offer efficacious and tolerable therapy for different psychiatric disorders, including schizophrenia and adjunctive treatment of MDD. In this study, we investigated whether brexpiprazole could improve social recognition deficits (one of social cognition deficits) in mice, after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine). Dosing with dizocilpine (0.1mg/kg) induced significant impairment of social recognition in mice. Brexpiprazole (0.01, 0.03, 0.1mg/kg, p.o.) significantly ameliorated dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on social recognition in untreated control mice. By contrast, neither risperidone (0.03mg/kg, p.o.) nor olanzapine (0.03mg/kg, p.o.) altered dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced social recognition deficits via 5-HT1A receptor activation in mice. Therefore, brexpiprazole may confer a beneficial effect on social cognition deficits in patients with psychiatric disorders.

Topics: Analysis of Variance; Animals; Cognition Disorders; Dizocilpine Maleate; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred C57BL; Quinolones; Recognition, Psychology; Serotonin Agents; Social Behavior; Thiophenes

Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice].. We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered.. We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens.. These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.

Topics: Animals; Astrocytes; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Transporter 2; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glutamic Acid; Homeostasis; Kainic Acid; Locomotion; Mice; Mice, Inbred C57BL; Mice, Transgenic; Psychomotor Disorders; Pyrimidines; Receptor, Adenosine A2A; Receptors, N-Methyl-D-Aspartate; Synaptosomes; Time Factors; Triazoles

Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia.. The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL.. Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination.. While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model.. These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.

Topics: Amphetamine; Animals; Antipsychotic Agents; Central Nervous System Stimulants; Cognition Disorders; Dizocilpine Maleate; Dopamine Agonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Paired-Associate Learning; Psychomotor Performance; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenic Psychology

Traumatic brain injury (TBI) is a major health problem in pediatric ages and also has major social, economic, and emotional outcomes, with diverse sequelae in many spheres of everyday life. We aimed to investigate the effect of MK-801, a competitive NMDA receptor antagonist, on hippocampal damage and behavioral deficits on 10-day-old rat pups subjected to contusion injury. The aims of the present study were to determine: (i) the short term effects of MK-801 on hippocampal BDNF, NGF and NMDA receptor immunoreactivity and neuron density in hippocampus (ii) long term effects of MK-801 on cognitive dysfunction following TBI in the immature rats. MK-801, was injected intraperitoneally at the doses of 1mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining, BDNF, NGF and NMDAR receptor immunohistochemistry on P10 day and behavioral alterations were evaluated using elevated plus maze and novel object recognition tests two months after the trauma. Histopathological and immunohistochemical evaluations showed that treatment with a single dose of 1mg/kg MK-801 (i.p.) significantly ameliorated the trauma induced hippocampal neuron loss and decreased BDNF, NGF and NMDAR expressions in CA1, CA3 and DG hippocampal brain regions. Additionally, treatment with MK-801 ameliorated anxiety and hippocampus dependent memory of animals subjected to trauma. These results show that acute treatment of MK-801 has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in immature rats.

Topics: Animals; Brain Injuries; Brain-Derived Neurotrophic Factor; Cognition Disorders; Dizocilpine Maleate; Hippocampus; Memory; N-Methylaspartate; Nerve Growth Factor; Neurons; Neuroprotective Agents; Rats, Wistar

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

Attentional set shifting, a measure of executive function, is impaired in schizophrenia patients. Current standard of care has little therapeutic benefit for treating cognitive dysfunction in schizophrenia; therefore, novel drugs and animal models for testing novel therapies are needed. The NMDA receptor antagonist, MK-801, produces deficits in a rat maze-based set-shifting paradigm, an effect which parallels deficits observed on tests of executive function in schizophrenia patients. Alpha7 nicotinic acetylcholine receptor (nAChR) agonists, currently under clinical development by several companies, show promise in treating cognitive symptoms in schizophrenia patients and can improve cognition in various animal models.. The objectives of the present study were to determine whether the MK-801 deficit in set shifting could be reproduced in a drug discovery setting and to determine whether cognitive improvement could be detected for the first time in this task with alpha7 nAChR agonists.. The data presented here replicate findings that a systemic injection of the NMDA receptor antagonist MK-801 can induce a deficit in set shifting in rats. Furthermore, the deficit could be reversed by the atypical antipsychotic clozapine as well as by several alpha7 nAch receptor agonists (SSR-180711, PNU-282987, GTS-21) with varying in vitro properties.. Results indicate that the MK-801 set-shift assay is a useful preclinical tool for measuring prefrontal cortical function in rodents and can be used to identify novel mechanisms for the potential treatment of cognitive deficits in schizophrenia.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Attention; Benzamides; Benzylidene Compounds; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Discovery; Male; Maze Learning; Neuropsychological Tests; Pyridines; Rats; Rats, Sprague-Dawley; Schizophrenia; Set, Psychology

Despite ample evidence supporting the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (D-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.).. The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test.. We found that systemic administration of CIQ (20 mg·kg⁻¹, i.p.) in mice reversed MK-801 (0.15 mg·kg⁻¹, i.p.)-induced, but not methamphetamine (3 mg·kg⁻¹, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze.. Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia.

Topics: Allosteric Regulation; Animals; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Hyperkinesis; Isoquinolines; Male; Maze Learning; Memory, Short-Term; Mice; Mice, Inbred C57BL; Motor Activity; Nerve Tissue Proteins; Neural Inhibition; Neuroprotective Agents; Nootropic Agents; Protein Subunits; Quinolines; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; False Positive Reactions; Inhibition, Psychological; Male; Memory; Mice; Nootropic Agents; Predictive Value of Tests; Psychotropic Drugs; Receptors, N-Methyl-D-Aspartate; Reproducibility of Results; Schizophrenia; Schizophrenic Psychology; Sodium Channel Blockers

Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.

Topics: Animals; Animals, Newborn; Avoidance Learning; Cognition Disorders; Complement C3; Disease Models, Animal; Dizocilpine Maleate; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Net; Neurons; Picrotoxin; Synapses; Ultrasonography; Valine

Cognitive deficits are the core symptoms of schizophrenia and major contributors to disability in schizophrenic patients, but effective treatments are still lacking. Previous studies have demonstrated that impaired BDNF/TrkB signaling is associated with the cognitive impairments of schizophrenia. 7,8-Dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The present study aimed to assess the effect of 7,8-DHF on the cognitive and synaptic impairments of schizophrenia. A brief disruption of NMDA receptors with MK-801 during early development serves as an animal model for cognitive deficits of schizophrenia. We found that MK-801-treated rats showed significant deficits in working learning ability and hippocampal synaptic plasticity, as well as reduction of BDNF, TrkB, and phosphorylated TrkB in the hippocampus. After intraperitoneal administration with 7,8-DHF (5 mg/kg) once daily for a consecutive 14days, we found that chronic 7,8-DHF treatment significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased the phosphorylation levels of TrkB downstream signal cascades including ERK1/2, CaMKII, CREB and GluR1, and promoted hippocampal synaptic plasticity, which in turn rescued performance in spatial working learning. Our results thus demonstrate that activation of TrkB signaling can reverse the cognitive deficits of schizophrenia and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in treating schizophrenia-related cognitive impairments.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Flavones; Hippocampus; Male; Neuronal Plasticity; Organ Culture Techniques; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, trkB; Schizophrenia

Previous studies have shown the beneficial effects of enriched environment (EE) in rescuing behavioral deficits such as pre-pulse inhibition and locomotor hyperactivity associated with N-methyl-D-aspartate (NMDA) receptor blockade; however, cognitive deficits remain unresponsive.. We designed experiments to determine the consequences of raising rat pups in an EE on several behavioral aberrations, mainly cognitive deficits, observed in rats postnatally exposed to MK-801 (NMDA receptor antagonist).. Male Wistar rats were injected with MK-801 (1 mg/kg) from postnatal day (P) 6-10. Rat pups were housed in an EE from birth up to the time of behavioral experiments at P28-34. The effects of EE in correcting MK-801-associated behaviors were assessed by rotarod, wire grip, open filed, and Morris water maze tests.. We found that EE not only has beneficial effects on cognitive performance of normal rats but also prevents spatial learning and memory deficits in Morris water maze induced by MK-801. Postnatal MK-801 treatment also led to motor deficits both in wire grip and accelerating rotarod tests. These deficits were not observed in MK-801-treated rats raised in EE. In the open field test, EE prevented increase in "frequency of grooming" and decrease in "time spent in the center" associated with MK-801.. Our results suggest that exposure to an EE would be strongly beneficial in correcting deficits, notably cognitive, associated with MK-801. Given that the postnatal MK-801 treatment represents an animal model of schizophrenia, we propose timely environmental interventions might be an effective strategy in the protection against schizophrenia.

Topics: Animals; Behavior, Animal; Cognition Disorders; Dizocilpine Maleate; Environment; Excitatory Amino Acid Antagonists; Male; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Cognitive impairment associated with schizophrenia (CIAS) is an important etiological feature of this disorder with implications for symptom severity and quality of life. Acute N-methyl-d-aspartate receptor (NMDAR) blockade using MK-801, a non-competitive antagonist to NMDARs, is assumed to produce temporary cognitive impairments in mice similar to those seen in schizophrenia patients. Less is known, however, about the effects of subchronic MK-801 administration on cognition. In the current study, twenty-eight male C57/BL6 mice received a daily dose of MK-801 (0.1mg/kg, i.p.) for seven days. Spatial memory was assessed using an object location task prior to MK-801 administration as well as at multiple time points after the treatment. Subchronic treatment with MK-801 caused lasting memory deficits, which were ameliorated by acute doses of an acetylcholinesterase inhibitor (donepezil) and an alpha-7 nicotinic agonist (PHA 568487), but were unaffected by acute administration of the atypical antipsychotic risperidone. Subchronic administration of MK-801 may lend this pharmaceutical model increased face validity, while its resemblance to prodromal schizophrenia makes it suitable for screening new CIAS treatments.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Aza Compounds; Cholinesterase Inhibitors; Cognition Disorders; Dioxins; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Indans; Male; Mice, Inbred C57BL; Nicotinic Agonists; Nootropic Agents; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Spatial Memory

Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Haloperidol; Hippocampus; Male; Memory, Short-Term; Neuronal Plasticity; Olanzapine; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Schizophrenia; Spatial Learning

Adolescence is a critical period for neurodevelopment. MK-801 treatment and social isolation are important animal models for various neurodevelopmental disorders. Dysfunctions in the central cholinergic system are involved in creating the cognitive deficits observed in neurological diseases. In the present study, we aimed to investigate whether the acetylcholinesterase inhibitor galanthamine could reverse pre-cognitive prepulse inhibition (PPI) deficits and spatial learning deficits of adult rats in the Morris water maze. We induced these effects using either adolescent MK-801 treatment or social isolation from postnatal day (PND) 38-51. Our results showed that both adolescent social isolation and MK-801 treatment impaired PPI in adult rats, but neither had an effect on spatial learning. Furthermore, galanthamine injections over 7 days significantly enhanced PPI of normal rats and improved PPI disruption induced by adolescent pharmacological and rearing interventions. The results suggest that acetylcholinesterase inhibitors, such as galanthamine, might have the potential to improve pre-cognition in neurodevelopmental diseases by improving auditory sensory gating.

Topics: Age Factors; Animals; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Galantamine; Male; Prepulse Inhibition; Rats; Rats, Wistar; Social Isolation; Spatial Learning

Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-D-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABA(A) receptors.. The present study used a rodent model to compare the inhibition of NMDA and GABA(A) receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing.. Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats.. Reducing GABA(A) receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC.. These data demonstrate that, while tonic stimulation of NMDA and GABA(A) receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.

Topics: 3-Mercaptopropionic Acid; Animals; Attention; Carbolines; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; GABA Antagonists; Glutamate Decarboxylase; Gyrus Cinguli; Male; Pyridazines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Topics: Age Factors; Amphetamine; Animals; Animals, Newborn; Body Weight; Central Nervous System Stimulants; Cognition Disorders; Cohort Studies; Disease Models, Animal; Dizocilpine Maleate; Drinking; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Food Deprivation; Male; Motor Activity; Polydipsia; Random Allocation; Rats; Rats, Sprague-Dawley

Microinfarctions are present in the aged and injured human brain. Their clinical relevance is controversial, with postulated sequelae ranging from cognitive sparing to vascular dementia. To address the consequences of microinfarcts, we used controlled optical methods to create occlusions of individual penetrating arterioles or venules in rat cortex. Single microinfarcts, targeted to encompass all or part of a cortical column, impaired performance in a macrovibrissa-based behavioral task. Furthermore, the targeting of multiple vessels resulted in tissue damage that coalesced across cortex, even though the intervening penetrating vessels were acutely patent. Post-occlusion administration of memantine, a glutamate receptor antagonist that reduces cognitive decline in Alzheimer's disease, ameliorated tissue damage and perceptual deficits. Collectively, these data imply that microinfarcts likely contribute to cognitive decline. Strategies that have received limited success in the treatment of ischemic injury, which include therapeutics against excitotoxicity, may be successful against the progressive nature of vascular dementia.

Topics: Animals; Brain Infarction; Brain Mapping; Calcium; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Glial Fibrillary Acidic Protein; Humans; Imaging, Three-Dimensional; Infarction, Middle Cerebral Artery; Male; Memantine; Microscopy, Confocal; Microvessels; Models, Biological; Neural Pathways; Neuroprotective Agents; Phosphopyruvate Hydratase; Psychomotor Performance; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Somatosensory Cortex; Vibrissae

Kami-ondam-tang (KODT) has been used to treat neuropsychiatric disorders, including neurosis and insomnia, in traditional herbal medicine. However, the mechanisms of this drug have not been well characterized in the treatment of schizophrenia-like behaviors.. We investigated whether schizophrenia-like behaviors induced by MK-801, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, could be attenuated by KODT.. Acute systemic administration of MK-801 was used to establish an animal model of schizophrenia. The effects of KODT on the MK-801-induced prepulse inhibition (PPI) deficits, hyperlocomotion, social withdrawal, and cognitive impairment were assessed. We also examined the changes in the expression levels of Akt and extracellular signal-regulated kinase (ERK) after the administration of KODT with MK-801 in the cortical and hippocampal tissues.. The acoustic startle response test showed that the acoustic startle enhancement and PPI deficits induced by MK-801 were attenuated by KODT. Moreover, KODT ameliorated social and objective recognition impairments that were induced by MK-801 in the social novelty preference test and the novel object recognition test. In addition, the upregulation of phosphorylated Akt or phosphorylated ERK expression induced by MK-801 was blocked by KODT in the cortex. However, MK-801-induced hyperlocomotion was not affected by KODT in the open field test.. These findings suggest that KODT attenuates MK-801-induced PPI disruption, social interaction deficits, and cognitive impairments, possibly, by regulating of cortical Akt and ERK signaling.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cognition Disorders; Dizocilpine Maleate; Drugs, Chinese Herbal; Extracellular Signal-Regulated MAP Kinases; Hippocampus; Male; Memory; Mice; Mice, Inbred ICR; Motor Activity; Phytotherapy; Proto-Oncogene Proteins c-akt; Reflex, Startle; Social Behavior

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

Schizophrenia is a complex and debilitating disorder, characterized by positive, negative, and cognitive symptoms. Among the cognitive deficits observed in patients with schizophrenia, recent work has indicated abnormalities in multisensory integration, a process that is important for the formation of comprehensive environmental percepts and for the appropriate guidance of behavior. Very little is known about the neural bases of such multisensory integration deficits, partly because of the lack of viable behavioral tasks to assess this process in animal models. In this study, we used our recently developed rodent cross-modal object recognition (CMOR) task to investigate multisensory integration functions in rats treated sub-chronically with one of two N-methyl-D-aspartate receptor (NMDAR) antagonists, MK-801, or ketamine; such treatment is known to produce schizophrenia-like symptoms. Rats treated with the NMDAR antagonists were impaired on the standard spontaneous object recognition (SOR) task, unimodal (tactile or visual only) versions of SOR, and the CMOR task with intermediate to long retention delays between acquisition and testing phases, but they displayed a selective CMOR task deficit when mnemonic demand was minimized. This selective impairment in multisensory information processing was dose-dependently reversed by acute systemic administration of nicotine. These findings suggest that persistent NMDAR hypofunction may contribute to the multisensory integration deficits observed in patients with schizophrenia and highlight the valuable potential of the CMOR task to facilitate further systematic investigation of the neural bases of, and potential treatments for, this hitherto overlooked aspect of cognitive dysfunction in schizophrenia.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Ketamine; Male; Nicotine; Nicotinic Agonists; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Schizophrenia

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

Neuroactive steroids modulate receptors for neurotransmitters in the brain and thus might be efficacious in the treatment of various diseases of the central nervous system such as schizophrenia. We have designed and synthetized a novel use-dependent NMDA receptor antagonist 3α5β-pregnanolone glutamate (3α5β-P-Glu). In this study, we evaluate procognitive properties of 3α5β-P-Glu in an animal model of schizophrenia induced by systemic application of MK-801. The procognitive properties were evaluated using active place avoidance on a rotating arena (Carousel maze). We evaluated effects of 3α5β-P-Glu on the avoidance, on locomotor activity, and anxiety. 3α5β-P-Glu alone altered neither spatial learning nor locomotor activity in control animals. In the model animals, 3α5β-P-Glu reversed the MK-801-induced cognitive deficit without reducing hyperlocomotion. The highest dose of 3α5β-P-Glu also showed anxiolytic properties. Taken together, 3α5β-P-Glu may participate in the restoration of normal brain functioning and these results may facilitate the development of new promising drugs improving cognitive functioning in schizophrenia.

Topics: Animals; Anxiety; Avoidance Learning; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Male; Motor Activity; Pregnanolone; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; Vocalization, Animal

In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5 mg/kg dose of the NMDA antagonist,MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline-supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25 days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline-supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia.

Topics: Animals; Choline; Choline Deficiency; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Eating; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Male; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Long-Evans; Schizophrenia; Schizophrenic Psychology; Stress, Physiological

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

Deficits in executive functions are key features of schizophrenia. Rodent behavioral paradigms used so far to find animal correlates of such deficits require extensive effort and time. The puzzle box is a problem-solving test in which mice are required to complete escape tasks of increasing difficulty within a limited amount of time. Previous data have indicated that it is a quick but highly reliable test of higher-order cognitive functioning. We evaluated the use of the puzzle box to explore executive functioning in five different mouse models of schizophrenia: mice with prefrontal cortex and hippocampus lesions, mice treated sub-chronically with the NMDA-receptor antagonist MK-801, mice constitutively lacking the GluA1 subunit of AMPA-receptors, and mice over-expressing dopamine D2 receptors in the striatum. All mice displayed altered executive functions in the puzzle box, although the nature and extent of the deficits varied between the different models. Deficits were strongest in hippocampus-lesioned and GluA1 knockout mice, while more subtle deficits but specific to problem solving were found in the medial prefrontal-lesioned mice, MK-801-treated mice, and in mice with striatal overexpression of D2 receptors. Data from this study demonstrate the utility of the puzzle box as an effective screening tool for executive functions in general and for schizophrenia mouse models in particular.

Topics: Animals; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Executive Function; Gene Expression Regulation; Hippocampus; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate; Prefrontal Cortex; Problem Solving; Reaction Time; Receptors, AMPA; Receptors, Dopamine D2; Schizophrenia

Cognitive impairments have been proposed as a core feature of schizophrenia. Studies have shown that chronic or subchronic treatment with N-methyl-d-aspartate (NMDA) antagonists could induce cognitive deficits that resemble the symptoms of schizophrenia, yet few studies have investigated the effects of repeated NMDA blockade during adolescence on cognition. In the current study, adolescent, male rats were treated with an intraperitoneal injection of MK-801 (0.05, 0.1, and 0.2mg/kg) once daily for 14days. They were then tested 24h and 14days after drug cessation, respectively, in a series of behavioural tasks, including the object recognition task, the object-in-context recognition task and the working memory task of the Morris water maze (MWM). Results showed that object-in-context recognition and spatial working memory in the MWM were significantly impaired by repeated MK-801 treatment when animals were tested 24h after drug cessation, but object recognition was left intact. In particular, such deficits were observed 14days after drug cessation in the 0.2mg/kg group. The cognition-impairing effect of MK-801 could not be attributed to malnutrition or alterations in motor functions. Taken together, this study may provide support for establishing an animal model of cognitive deficits of schizophrenia based on low-dose, repeated treatment of MK-801 during adolescence.

Topics: Animals; Cognition; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Maze Learning; Memory; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Schizophrenia; Time Factors

A major challenge in developing schizophrenia pharmacotherapy is treating the different symptoms of this disorder, typically divided into positive, negative and cognitive symptoms. M₁/M₄ muscarinic acetylcholine receptor (mAChR) agonists have emerged as a promising therapeutic target, particularly for positive and cognitive symptoms. Here, we examined the activity of the M₁/M₄ mAChR-preferring agonist xanomeline in four pharmacological latent inhibition (LI) models. LI is the poorer conditioning to a stimulus previously experienced as irrelevant during repeated non-reinforced pre-exposure to that stimulus. No-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak, but not strong, conditioning (2 vs. 5 tone-shock pairings). Amphetamine (1 mg/kg)- or scopolamine (0.15 mg/kg)-treated rats failed to show LI with weak conditioning, whereas MK801 (0.05 mg/kg)- or scopolamine (1.5 mg/kg)-treated rats persisted in displaying LI with strong conditioning. Xanomeline (5 mg/kg, 15 mg/kg) reversed amphetamine- and scopolamine-induced LI disruption, effects considered predictive of activity against positive symptoms of schizophrenia. In addition, xanomeline alleviated MK801-induced abnormally persistent LI. Activity of xanomeline on NMDA antagonist-induced behaviour was demonstrated here for the first time and suggests that the drug is effective against negative/cognitive symptoms. Finally, xanomeline alleviated abnormally persistent LI induced by scopolamine, which was suggested to model antipsychotic drug-resistant cognitive impairments, providing further evidence for the cognition-enhancing capacity of xanomeline. Although the use of xanomeline in schizophrenia was discontinued due to cholinergic-related side-effects, our findings suggest that M₁/M₄ mAChR agonism should be an important target in drug development in schizophrenia, potentially beneficial for treatment of positive, negative and cognitive symptoms.

Topics: Amphetamine; Animals; Antimanic Agents; Behavior, Animal; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Kinetics; Male; Molecular Targeted Therapy; Muscarinic Agonists; Neural Inhibition; Neurotransmitter Agents; Pyridines; Rats; Rats, Wistar; Receptor, Muscarinic M1; Receptor, Muscarinic M4; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Scopolamine; Tachyphylaxis; Thiadiazoles

Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Studies have demonstrated that these behavioral changes are, in some cases, sensitive to remediation by antipsychotic drugs. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs and to discover new pharmacological targets. In the current study we investigated the ability of antipsychotic drugs to reverse schizophrenia-like symptoms produced by the NMDA receptor antagonist MK-801. Results showed that MK-801 (5μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250μM) and olanzapine (50μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9μM) was ineffective to reverse those behavioral deficits. Therefore, MK-801-treated zebrafish showed some behavioral features observed in schizophrenia, such as cognitive and social interaction deficits, which were reverted by current available atypical drugs.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Interpersonal Relations; Male; Statistics, Nonparametric; Zebrafish

The manipulation of glutamate neurotransmission could represent a potential strategy for the pharmacotherapy of schizophrenic symptoms. Preclinical studies suggest that two subtypes of metabotropic glutamate (mGlu) receptors such as mGlu2/3 and mGlu5 receptors have the potential to ameliorate deficits in schizophrenia. In our study we evaluated the role of a non-specific mGlu receptor agonist ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; 1S,3R-ACPD), mGlu5 receptor agonist or positive modulators ((RS)-2-Chloro-5-hydroxyphenylglycine;CHPG; [(3-Fluoro-phenyl)methylene]hydrazone-3-fluorobenzaldehyde; DFB; 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; CDPPB) and a mGlu2/3 receptor agonist (2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyrdinylmethyl)ethanesulfonamide hydrochloride; LY-487379) on performance in a cognitive task (Active Allothetic Place Avoidance) after sub-chronic administration of 5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imine; MK-801 . The Active Allothetic Place Avoidance task is suitable for assessing the executive function and attention of animals and was previously validated for testing the effect of anti-psychotics. Application of the mGlu2/3 receptor agonist had no effect on cognitive impairment induced by MK-801. However, the mGlu5 receptor agonists ameliorated cognitive impairment induced by MK-801 without affecting locomotion. In conclusion, the mGlu5 receptor agonists could be effective in the treatment of cognitive deficits in patients with schizophrenia. However, the pro-cognitive effect of the agonist of mGlu2/3 receptors was not demonstrated in the present study.

Topics: Animals; Cognition; Cognition Disorders; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Locomotion; Male; Rats; Rats, Long-Evans; Receptors, Metabotropic Glutamate; Schizophrenia

Metabotropic glutamate (mGlu) receptors provide a mechanism by which the function of NMDA glutamate receptors can be modulated. As NMDA receptor hypofunction is implicated in the etiology of psychiatric disorders, including schizophrenia, the pharmacological regulation of mGlu receptor activity represents a promising therapeutic approach. We examined the effects of the positive allosteric mGlu(5) receptor modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), alone and in combination with the NMDA receptor antagonist MK-801, on a task measuring cognitive set-shifting ability. This task measures NMDA receptor-dependent cognitive abilities analogous to those impaired in schizophrenia. Systemic administration of CDPPB (10 and 30 mg/kg i.p) blocked MK-801 (0.1mg/kg, i.p.)-induced impairments in set-shifting ability. The effect on learning was dose-dependent, with the 30 mg/kg dose having a greater effect than the 10mg/kg dose across all trials. This ameliorative effect of CDPPB reflected a reduction in MK-801-induced perseverative responding. These results add to the evidence that mGlu(5) receptors interact functionally with NMDA receptors to regulate behavior, and suggest that positive modulators of mGlu(5) receptors may have therapeutic potential in the treatment of disorders, like schizophrenia, characterized by impairments in cognitive flexibility and memory.

Topics: Allosteric Regulation; Animals; Benzamides; Cognition; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Learning; Male; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Cognitive deficits are a core feature of schizophrenia that may be linked to abnormalities in GABA and nitric oxide (NO). Subchronic treatment with glutamate receptor antagonists produces similar deficits, providing a useful model to examine potential therapeutics. The present study investigated the effects of subchronic MK-801 (intraperitoneally; 0.5 mg/kg twice daily for 7 days) on amphetamine-induced locomotor activity and reversal learning in the water maze in rats, and the ability of the novel compound GT 1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), containing dual pharmacophores producing NO- and GABA-mimetic activity, to ameliorate these effects. MK-801 enhanced locomotor responses to amphetamine. GT 1061 (0.1; not 0.0001, 0.001, 0.01, 1.0 mg/kg) further enhanced locomotion; the pro-GABA drug chlormethiazole (0.1, 1.0 mg/kg) had no significant effect. In saline-pretreated rats GT 1061 (0.1; not 0.0001, 0.001 mg/kg) increased amphetamine-induced locomotion; chlormethiazole (0.1, 1.0 mg/kg) had no effect. In the water maze, MK-801 impaired reversal learning after platform relocation. GT 1061 (0.001, 0.01, 0.1; not 0.0001 or 1.0 mg/kg) attenuated this impairment; chlormethiazole had no significant effect. These ameliorative effects of GT 1061 may be linked to the activation of NO- and GABA-dependent signaling and suggests a new direction for treating cognitive dysfunction in schizophrenia.

Topics: Amphetamine; Animals; Behavior, Animal; Central Nervous System Stimulants; Chlormethiazole; Cognition Disorders; Data Interpretation, Statistical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hypnotics and Sedatives; Male; Maze Learning; Motor Activity; Nitrates; Rats; Rats, Sprague-Dawley; Reversal Learning

Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of alpha7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective alpha7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with alpha7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

Topics: Acoustic Stimulation; alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Cognition Disorders; Conditioning, Psychological; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Male; Neural Inhibition; Neuroprotective Agents; Nicotinic Agonists; Nitroarginine; Rats; Rats, Wistar; Receptors, Nicotinic; Reinforcement, Psychology; Schizophrenia

The beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.. The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.. Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.. These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia.

Topics: Animals; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Drug Administration Schedule; Drug Therapy, Combination; Galantamine; Male; Maze Learning; Motor Activity; Rats; Rats, Wistar; Receptors, Serotonin; Scopolamine; Serotonin Antagonists; Sulfonamides; Thiophenes; Yawning

Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Clozapine; Cognition; Cognition Disorders; Dizocilpine Maleate; Exploratory Behavior; Glycine Plasma Membrane Transport Proteins; Haloperidol; Male; Nootropic Agents; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Sarcosine; Serine; Statistics, Nonparametric

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotinic Agonists; Phencyclidine; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Recognition, Psychology; Schizophrenia

Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission has been implicated in schizophrenia. We studied whether transient inhibition of NMDA receptor activity during early postnatal development would produce a behavioral phenotype resembling that of individuals who are susceptible to develop schizophrenia.. Rat pups were given injections of the NMDA channel blocker MK801 on postnatal days 7 through 10. This period is akin to the prenatal second trimester of primate development. Cognitive function was tested in adulthood.. Treatment with MK801 impaired cognitive flexibility and working memory. The impairment in cognitive flexibility was due to increased perseverative behavior. Treatment did not affect locomotor activity or recognition memory.. These results suggest that a brief disruption of NMDA receptors during a sensitive period of cortical development is sufficient to produce selective cognitive deficits that are relevant to schizophrenia.

Topics: Age Factors; Animals; Animals, Newborn; Behavior, Animal; Cognition Disorders; Discrimination, Psychological; Dizocilpine Maleate; Exploratory Behavior; Locomotion; Male; Memory, Short-Term; Neuropsychological Tests; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Spatial cognition appears to be compromised in elderly and in patients suffering from dementia. These deficits are believed to be modelled, at least partly, by the administration of scopolamine or MK-801 in normal adult animals. In order to establish an animal model suited for the evaluation of putative cognition enhancers, we assessed the effects of scopolamine (0.3, 0.5, 0.7 mg kg(-1), i.p.) and MK-801 (0.07, 0.08, 0.09 mg kg(-1), s.c.) in rats trained in the cone field. This task allows the simultaneous investigation of working memory (WM), reference memory (RM) and search strategies. Scopolamine and MK-801 reliably induced spatial cognition deficits in the cone field without inducing behavioural side effects. This task appears to be suited for assessing the effects of putative cognition-enhancing compounds on spatial cognition.

Topics: Animals; Cognition Disorders; Discrimination Learning; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Memory; Muscarinic Antagonists; Orientation; Psychomotor Performance; Rats; Rats, Wistar; Reproducibility of Results; Scopolamine; Space Perception

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Topics: Adrenergic alpha-Antagonists; Animals; Behavior, Animal; Cerebral Cortex; Clozapine; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Idazoxan; In Vitro Techniques; Male; Maze Learning; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Synaptic Transmission

Hippocalcin is a member of the neuronal calcium sensor (NCS) protein family that is highly expressed in hippocampal pyramidal cells and moderately expressed in the neurons of cerebral cortex, cerebellum and striatum. Here we examined the physiological roles of hippocalcin using targeted gene disruption. Hippocalcin-deficient (-/-) mice displayed no obvious structural abnormalities in the brain including hippocampal formation at the light microscopic level. Deletion of hippocalcin did not result in up-regulation of the hippocalcin-related proteins; neural visinin-like Ca(2+)-binding proteins (NVP) 1, 2, and 3. The synaptic excitability of hippocampal CA1 neurons appeared to be normal, as estimated by the shape of field excitatory postsynaptic potentials elicited by single- and paired-pulse stimuli, and by tetanic stimulation. However, N-methyl-d-aspartate stimulation- and depolarization-induced phosphorylation of cAMP-response element-binding protein (CREB) was significantly attenuated in -/- hippocampal neurons, suggesting an impairment in an activity-dependent gene expression cascade. In the Morris water maze test, the performance of -/- mice was comparable to that of wild-type littermates except in the probe test, where -/- mice crossed the previous location of the platform significantly less often than +/+ mice. Hippocalcin-deficient mice were also impaired on a discrimination learning task in which they needed to respond to a lamp illuminated on the left or right side to obtain food reinforcement. No abnormalities were observed in motor activity, anxiety behavior, or fear learning. These results suggest that hippocalcin plays a crucial role in the Ca(2+)-signaling pathway that underlies long-lasting neural plasticity and that leads to spatial and associative memory.

Topics: Animals; Association Learning; Avoidance Learning; Behavior, Animal; Blotting, Western; Brain; Cadmium Chloride; Calcium Channel Blockers; Calcium-Binding Proteins; Choice Behavior; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Discrimination Learning; Dizocilpine Maleate; Drug Interactions; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Flavonoids; Hippocalcin; Hippocampus; Immunohistochemistry; In Vitro Techniques; Male; Maze Learning; Mice; Mice, Knockout; Motor Activity; N-Methylaspartate; Nerve Tissue Proteins; Nimodipine; Phosphorylation; Potassium Chloride; Psychomotor Performance; Reaction Time; Rotarod Performance Test; Spatial Behavior; Valine

Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (> or =7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (> or =24 h) time window easily attainable for treatment of human accidental head injury.

Topics: Animals; Autoradiography; Brain; Cognition Disorders; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Head Injuries, Closed; Male; Mice; Receptors, N-Methyl-D-Aspartate

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.

Topics: Amphetamine; Animals; Brain-Derived Neurotrophic Factor; Cognition; Cognition Disorders; Dizocilpine Maleate; Enzyme-Linked Immunosorbent Assay; Glatiramer Acetate; Male; Maze Learning; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peptides; Reflex, Startle; Schizophrenia; T-Lymphocytes; Vaccination

With clinical data suggesting a role for excitatory amino acid neurotransmission in the pathogenesis of cardiopulmonary bypass (CPB)-associated brain injury, the current study was designed to determine whether xenon, an N-methyl-D-aspartate receptor antagonist, would attenuate CPB-induced neurologic and neurocognitive dysfunction in the rat.. Following surgical preparation, rats were randomly divided into four groups: (1) sham rats were cannulated but did not undergo CPB; (2) CPB rats were subjected to 60 min of CPB using a membrane oxygenator receiving a gas mixture of 30% O2, 65% N2, and 5% CO2; (3) CPB + MK801 rats received MK801 (0.15 mg/kg intravenous) 15 min prior to 60 min of CPB with the same gas mixture; and (4) CPB + xenon rats underwent 60 min of CPB using an oxygenator receiving 30% O2, 60% xenon, 5% N2, and 5% CO2. Following CPB, the rats recovered for 12 days, during which they underwent standardized neurologic and neurocognitive testing (Morris water maze).. The sham and CPB + xenon groups had significantly better neurologic outcome compared to both the CPB and CPB + MK801 groups on postoperative days 1 and 3 (P < 0.05). Compared to the CPB group, the sham, CPB + MK801, and CPB + xenon groups had better neurocognitive outcome on postoperative days 3 and 4 (P < 0.001). By the 12th day, the neurocognitive outcome remained significantly better in the CPB + xenon group compared to the CPB group (P < 0.01).. These data indicate that CPB-induced neurologic and neurocognitive dysfunction can be attenuated by the administration of xenon, potentially related to its neuroprotective effect via N-methyl-D-aspartate receptor antagonism.

Topics: Animals; Cardiopulmonary Bypass; Cognition Disorders; Dizocilpine Maleate; Male; Maze Learning; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Xenon

Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months and then withdrawn from alcohol. During the first 4 weeks of the withdrawal period, animals were intraperitoneally injected with either memantine (20 mg/kg bolus followed by 1 mg/kg every 12 h) or dizocilpine (MK-801; 0.1 mg/kg every 12 h), both of which are antagonists of N-methyl-D-aspartate receptors. Ten weeks after initiation of the withdrawal procedure, cognitive status of animals was assessed using the Morris water maze. Withdrawal from alcohol produced robust deficits in the performance of rats on the acquisition task and on the probe trial. Treatment with memantine resulted in a complete reversal of these behavioral impairments. In contrast, treatment with MK-801 was found to be ineffective in preventing cognitive alterations associated with chronic alcohol consumption and withdrawal.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Brain; Cognition Disorders; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memantine; Neurons; Neurotoxins; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups.These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.

Topics: Animals; Benzopyrans; Body Temperature; Brain; Brain Injuries; Cognition; Cognition Disorders; Dizocilpine Maleate; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Nerve Degeneration; Neurons; Neuroprotective Agents; Postural Balance; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Thiazoles; Vestibular Nuclei

Central glutamate neurotransmission is modulated by an upregulatory cholinergic influence and an inhibitory serotonergic influence. In Alzheimer's disease, cognitive decline is associated with loss of both glutamatergic and cholinergic neurones (Francis et al., 1992, Progress in Neurobiology 39, 517-545). While therapeutic strategies for alleviating this cognitive decline have concentrated on restoring cholinergic tone, we suggest that 5-HT1A antagonists also have the potential to alleviate the cognitive symptoms of Alzheimer's disease. Previous studies have shown that dizocilpine (MK-801), a glutamatergic antagonist acting at the NMDA receptor, produces learning impairments in the common marmoset, a non-human primate. Specifically, it impairs the acquisition of shape discrimination and visuospatial conditional tasks, at doses that do not affect locomotor behaviour or coordination (Harder et al., 1998, Society for Neuroscience Abstracts 23(1), 219). In the present study we investigated the effects of WAY 100 635, a 5-HT1A antagonist, on the cognitive deficits induced by dizocilpine. The number of trials required to learn each type of task under combined treatment with dizocilpine and WAY 100 635 was significantly lower than under dizocilpine treatment alone, and did not differ significantly from the number of trials required under saline, demonstrating that the cognitive effects of glutamatergic blockade can be overcome by treatment with a 5-HT1A antagonist.

Topics: Animals; Callithrix; Cognition Disorders; Conditioning, Psychological; Discrimination Learning; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Piperazines; Pyridines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Space Perception; Visual Perception

Glutamatergic hypofunction occurs in Alzheimer's disease (AD). MK801, a noncompetitive blocker of glutamate N-methyl-D-aspartate receptors, was used to disrupt the cognitive performance of rats trained on a delayed nonmatching to sample radial maze task. Drugs which act by blocking serotonin (5-HT) receptors were evaluated for their ability to reduce the cognitive impairment produced by MK801. Specifically, WAY-100635, a selective 5-HT1A receptor antagonist, buspirone, a 5-HT1A partial agonist, ritanserin, a 5-HT2 antagonist, and ondansetron, a 5-HT3 antagonist, were assessed. In addition, the muscarinic agonist arecoline was evaluated for its potential cognitive benefit in this model. It was found that WAY-100635 significantly reduced the cognitive impairment induced by MK801. Treatment with single doses of ritanserin, ondansetron, or arecoline in combination with MK801 did not result in a cognitive impairment, indicating that these drugs attenuated the MK801 impairment. The combination of buspirone and MK801 resulted in an inability of the animals to complete the task. These results suggest that interactions between 5-HT and glutamate may mediate the beneficial effects of reducing cognitive impairment and that 5-HT antagonists, especially selective 5-HT1A antagonists, may be useful in treating AD. Further, it is indicated that the MK801 model of cognitive impairment may add to the armamentarium of tools available to predict treatment efficacy in AD.

Topics: Alzheimer Disease; Animals; Arecoline; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Glutamates; Male; Maze Learning; Muscarinic Agonists; Neuroprotective Agents; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin Antagonists

The neuroprotective activity of the novel glycine receptor antagonist (E)-3[(phenylcarbamoil)ethenil]-4,6-dichloroindole-2-c arboxylic acid sodium salt) (GV150526) was recently reported in a model of focal ischemia in the rat. Here it was investigated whether GV150526 treatment results in any of the adverse side effects commonly detected after injection of NMDA (N-methyl-D-aspartate) receptor antagonists. First, it was found that neuronal vacuolization in the posterior cingulate/retrosplenial area of the cortex was not induced by GV150526 (200 mg/kg, i.v.), but was evident after injection of the NMDA receptor antagonist dizocilpine (MK801) (1 mg/kg, s.c.). In a second set of experiments, the effects of GV150526 were examined on perforant path-dentate gyrus long-term potentiation in rats. GV150526 (3 mg/kg, i.v.) injected 30 min or 150 min prior to tetanization did not block potentiation of the e.p.s.p. slope and population spike amplitude. In contrast, in animals treated with MK801 (1 mg/kg, i.p.) 150 min before tetanization there was a clear block of long-term potentiation of the e.p.s.p. slope and population spike amplitude. The effects of GV150526 were also examined in the Morris Water Maze. Rats injected with GV150526 (10 mg/kg or 60 mg/kg, p.o.) did not show any impairment in learning when compared to control. MK801 (0.08 mg/kg, i.p.), on the other hand, significantly affected the ability to locate the escape platform in the Water Maze. These findings show that GV150526 is devoid of adverse side effects even at doses well above those producing a neuroprotective effect. This, drug has therapeutic potential with a much greater margin of safety than NMDA channel blockers or competitive NMDA receptor antagonists.

Topics: Action Potentials; Animals; Brain; Cerebral Cortex; Cognition Disorders; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Indoles; Male; Maze Learning; N-Methylaspartate; Neurons; Neuroprotective Agents; Perforant Pathway; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Time Factors; Vacuoles

The effect of NMDA and AMPA receptor antagonists on a scopolamine-induced spatial cognitive deficit was investigated in rats using an 8-arm radial maze. The NMDA antagonists, MK801 and CGS19755, robustly augmented scopolamine-induced deficits but had no effect on spatial cognition when administered alone. In contrast, augmentation of the scopolamine-induced deficits was not observed when the selective AMPA antagonist, YM90K, was administered with scopolamine. These results suggest that the NMDA but not AMPA subtypes of the ionotropic glutamate receptors play important roles in regulation of the central cholinergic function related to the spatial learning and memory processes.

Topics: Animals; Cognition Disorders; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Male; Maze Learning; Pipecolic Acids; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Scopolamine

In rats trained to retain a passive avoidance response or to retrieve a learned task in the radial and water maze tests, a pretreatment with 2-hexyl-3-indoleacetamide (FGIN-1-27) (IC50 57 mumol/kg p.o.) or 4' chlorodiazepam (4'CD) (15 mumol/kg i.p.), two steroidogenic ligands at the mitochondria diazepam-binding inhibitor receptor complex (MDRC), antagonized the performance deficit elicited by dizocilpine (0.3 mumol/kg i.p.), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The 1-(2-chlorophenyl)-N-methyl-N-(-1-methyl-propyl)-3-isoquinoline carboxamide (PK-11195), an antagonist at MDRC in vivo, failed to modify the disruptive effect of dizocilpine in the passive avoidance response but reversed the FGIN-1-27- or 4' CD-induced antagonism of dizocilpine behavioral actions. Pretreatment with pregnenolone sulfate (48 mumol/kg i.p.), 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one (THDOC) (15 mumol/kg i.v.) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) (15 mumol/kg i.v.) also reduced the passive avoidance retention deficit elicited by dizocilpine. The (17-beta)-17-[[bis(1-methylethyl)amino[carbonyl]androstane-3,5-diene-3- carboxylic acid (SKF-105111), a 5 alpha-reductase inhibitor, blocked the antagonism of dizocilpine behavioral actions by pregnenolone sulfate or by FGIN-1-27 but not those caused by THDOC or allopregnanolone either in normal or adrenalectomized-castrated rats. Thus, it is inferred that the amnesic effect of dizocilpine is counteracted by FGIN-1-27, 4'CD and pregnenolone sulfate because of their ability to increase brain accumulation of allopregnanolone.

Topics: Amnesia; Animals; Avoidance Learning; Cognition; Cognition Disorders; Dizocilpine Maleate; Indoleacetic Acids; Male; Mitochondria; Pregnanolone; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Scopolamine; Steroids; Tritium

In order to examine the effectiveness of pre- and post-injury administration of muscarinic cholinergic and NMDA antagonists in reducing cognitive deficits following traumatic brain injury (TBI), rats were injected with either scopolamine (1 mg/kg) or MK-801 (0.3 mg/kg) 15 min prior to or 15 min after fluid percussion TBI. Cognitive performance was assessed with the Morris water maze procedure on days 11-15 after TBI or sham injury. When scopolamine and MK-801 were injected 15 min before injury, Morris water maze deficits were significantly reduced (P < 0.01 and P < 0.05, respectively). When scopolamine and MK-801 were injected 15 min after TBI, neither drug was effective in attenuating Morris water maze deficits. Consistent with other research, these results suggest that the cognitive deficits produced by TBI are the consequence of a brief period of excessive excitation of cholinergic and NMDA receptor systems. The results of this experiment also suggest that the temporal therapeutic window for the treatment of cognitive dysfunction with receptor antagonist intervention appears to be quite brief (< 15 min) in the rat.

Topics: Animals; Brain Injuries; Cognition Disorders; Dizocilpine Maleate; Learning; Male; Muscarinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Scopolamine; Space Perception

The overstimulation of receptors for L-glutamate, particularly those of the N-methyl-D-aspartate (NMDA) type, has been suggested to play a role in mediating damage in a variety of neurodegenerative conditions or disorders ranging from ischemia/hypoxia to senile dementia of the Alzheimer's type (SDAT). We report here that the functional deficits and histological damage mediated by the overactivation of NMDA receptors in the Fischer 344 rat hippocampus can be blocked effectively by systemic administration of the noncompetitive NMDA antagonist, MK-801. These results suggest that MK-801 may be effective clinically in attenuating memory loss and hippocampal damage in disorders associated with the overstimulation of NMDA receptors.

Topics: Animals; Aspartic Acid; Behavior, Animal; Cognition Disorders; Dibenzocycloheptenes; Dizocilpine Maleate; Hippocampus; Male; N-Methylaspartate; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter