dizocilpine-maleate and Learning-Disabilities

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

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

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.

Topics: Analysis of Variance; Animals; CA3 Region, Hippocampal; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fear; Freezing Reaction, Cataleptic; Gene Expression Regulation; Learning Disabilities; Male; Protein Binding; Rats; Receptors, N-Methyl-D-Aspartate; Social Behavior; Stress, Psychological; Tritium

The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze.

Topics: Analysis of Variance; Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Learning Disabilities; Locomotion; Male; Maze Learning; Rats; Rats, Long-Evans; Reaction Time

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

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

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

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

N-methyl-D-aspartate receptors (NMDARs) are essential for several kinds of synaptic plasticity and play a critical role in learning and memory. Deficits in NMDAR functioning may be partially responsible for the learning and memory deficits associated with aging and numerous diseases. Administration of MK-801, a noncompetitive NMDAR antagonist, is commonly used as a preclinical model of NMDAR dysfunction. The objective of this study was to assess the effects of α5GABAA receptor inhibition on learning deficits in the incremental repeated acquisition (IRA) task induced by acute MK-801 administration. The IRA task, commonly used to examine factors that affect learning, begins with a single response and increments to progressively longer chains throughout a single session as behavior meets preset criteria. MK-801 (0.03-0.5 mg/kg, intraperitoneally), administered 10 min pretesting, produced a significant dose-dependent decrease in measures of IRA performance at doses greater than or equal to 0.25 mg/kg. The MK-801-induced deficit was attenuated after treatment with an α5GABAA receptor inverse agonist, L-655,708 (1 mg/kg, intraperitoneally). The present study provides the focus for, and supports the feasibility of, further in-depth definitive studies examining α5GABAA receptor inhibition as a suitable candidate for the attenuation of NMDAR-related deficits.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; GABA-A Receptor Agonists; Imidazoles; Learning; Learning Disabilities; Male; Mice; Neuropsychological Tests; Receptors, GABA-A

Blockade of N-methyl-d-aspartate receptor (NMDA) by the noncompetitive NMDA receptor (NMDAR) antagonist MK-801 produces behavioral abnormalities and alterations in prefrontal cortex (PFC) functioning. Due to the critical role of the PFC in operant conditioning task learning, we evaluated the effects of acute, repeated postnatal injections of MK-801 (0.1mg/kg) on learning performance. We injected Long-Evans rats i.p. with MK-801 (0.1mg/kg) using three different administration schedules: injection 40 min before beginning the task (during) (n=12); injection twice daily for six consecutive days prior to beginning the experimental procedures (prior) (n=12); or twice daily subcutaneous injections from postnatal day 7 to 11 (postnatal) (n=12). Next, we orally administered risperidone (serotonin receptor 2A and dopamine receptor 2 antagonist, 1mg/kg) or buspirone (serotonin receptor 1A partial agonist, 10mg/kg) to animals treated with the MK-801 schedule described above. The postnatal and prior administration schedules produced severe learning deficits, whereas injection of MK-801 just before training sessions had only mild effects on acquisition of an operant conditioning. Risperidone was able to reverse the detrimental effect of MK-801 in the animals that were treated with MK-801 during and prior training sessions. In contrast, buspirone was only effective at mitigating the cognitive deficits induced by MK-801 when administered during the training procedures. The data demonstrates that NMDA antagonism disrupts basic mechanisms of learning in a simple PFC-mediated operant conditioning task, and that buspirone and risperidone failed to attenuate the learning deficits when NMDA neurotransmission was blocked in the early stages of the postnatal period.

Topics: Animals; Buspirone; Conditioning, Operant; Dizocilpine Maleate; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Learning Disabilities; Male; Rats; Rats, Long-Evans; Reaction Time; Risperidone; Serotonin Agents; Statistics, Nonparametric

Reasoning and problem solving deficits have been reported in schizophrenic patients. In the present study, we have tested rats in a two-lever reversal learning task in a Skinner box to model these deficits. In other studies using the Skinner box, atypical antipsychotics fully reversed phencyclidine (PCP)-induced impairments in reversal learning which is in contrast to clinical observations where antipsychotics lack the ability to fully reverse cognitive deficits in schizophrenia. Therefore, it can be argued that the outcome of these tests may lack predictive value. In the present study, after training on a spatial discrimination between two levers, rats were exposed to a reversal of the previously learned stimulus-response contingency during 5 days. We first investigated the effects of sub-chronic treatment with the non-competitive N-methyl-d-aspartate (NMDA) antagonists dizocilpine (MK-801) and PCP on reversal learning and extinction in male Sprague Dawley rats. Subsequently, we studied the effects of different PCP treatment regimes. Then, we investigated whether the atypical antipsychotics risperidone and clozapine and the 5-hydroxytryptamine6 (5-HT6) antagonist GSK-742457 could reverse the PCP-induced deficits. All drugs were administered subcutaneously (s.c.). MK-801 did not impair reversal learning, while PCP (1.0 and 2.0 mg/kg) induced a clear deficit in reversal learning. Both compounds, however, disrupted extinction at all tested doses. Risperidone and clozapine were both ineffective in significantly ameliorating the PCP-induced deficit in reversal learning which fits well with the clinical observations. The lowest dose of clozapine (1.25 mg/kg) had an intermediate effect in ameliorating the deficit in reversal learning induced by PCP (not different from control or PCP-treated rats). The lowest dose of GSK-742457 (0.63 mg/kg) fully reversed the PCP-induced deficits while the higher dose (5.0 mg/kg) had an intermediate effect.

Topics: Animals; Antipsychotic Agents; Clozapine; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Extinction, Psychological; Learning Disabilities; Male; Phencyclidine; Quinolines; Rats; Rats, Sprague-Dawley; Reversal Learning; Risperidone; Serotonin Antagonists; Sulfones

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

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

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

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

Cannabinoids acting on CB(1) receptors induce learning and memory impairments. However, the identification of novel non-CB(1) receptors which are insensitive to the psychoactive ingredient of marijuana, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) but sensitive to synthetic cannabinoids such as WIN55,212-2 (WIN-2) or endocannabinoids like anandamide lead us to question whether WIN-2 induced learning and memory deficits are indeed mediated by CB(1) receptor activation. Given the relative paucity of receptor subtype specific antagonists, a way forward would be to determine the transmitter systems, which are modulated by the respective cannabinoids. This study set out to evaluate this proposition by determination of the effects of WIN-2 on acquisition of spatial reference memory using the water maze in rats. Particular weight was given to performance in trial 1 of each daily session as an index of between-session long-term memory, and in trial 4 as an index of within-session short-term memory. Intraperitoneal (i.p.) administration of WIN-2 (1 mg/kg and 3 mg/kg) prior to training impaired long-term, but not short-term memory. This deficit was not reversed by the CB(1) antagonists/inverse agonists Rimonabant (3mg/kg i.p.) and AM281 (0.5 mg/kg i.p.), but recovered in the presence of the cholinesterase inhibitor rivastigmine (1 mg/kg). Reversal by rivastigmine was specific to WIN-2, as it failed to reverse MK801 (0.08 mg/kg) induced learning impairments. Collectively, these data suggest that in this spatial reference memory task WIN-2 causes a reduction in cholinergic activation, possibly through a non-CB(1)-like mechanism, which affects long-term but not short-term spatial memory.

Topics: Acetylcholine; Animals; Benzoxazines; Cannabinoid Receptor Agonists; Cholinergic Antagonists; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Learning Disabilities; Male; Maze Learning; Memory; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Rimonabant; Scopolamine; Spatial Behavior

Several executive functions rely on the medial prefrontal cortex (mPFC) in the rat. Aspiration and neurotoxic lesions of the mPFC impair reversal learning in adult rats. Systemic administration of MK-801, an NMDA-receptor antagonist, impairs T-maze reversal learning in weanling rats but the role of mPFC NMDA-receptor antagonism in this effect is not known in either adult or young animals. This set of studies showed that mPFC NMDA receptors are specifically involved in T-maze discrimination reversal in weanling rats. In Experiment 1, 26-day-old rats (P26) demonstrated a dose-dependent impairment following bilateral mPFC administration of either 2.5 or 5.0microg MK-801 or saline (vehicle) during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but four groups of rats received bilateral mPFC infusions during acquisition only (MK-SAL), reversal only (SAL-MK), both phases (MK-MK), or neither phase (SAL-SAL). MK-801 impaired performance only when infused during reversal. This suggests that NMDA-receptor antagonism in the mPFC is selectively involved in reversal learning during development and this may account for the previously reported effects of systemic MK-801 on T-maze discrimination reversal in weanling rats.

Topics: Aging; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Learning Disabilities; Male; Maze Learning; Prefrontal Cortex; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Reversal Learning; Time Factors

Rg1, as a ginsenoside extracted from Panax ginseng, could ameliorate spatial learning impairment. Previous studies have demonstrated that Rg1 might be a useful agent for the prevention and treatment of the adverse effects of morphine. The aim of this study was to investigate the effect of Rg1 on learning impairment by chronic morphine administration and the mechanism responsible for this effect. Male rats were subcutaneously injected with morphine (10 mg/kg) twice a day at 12 hour intervals for 10 days, and Rg1 (30 mg/kg) was intraperitoneally injected 2 hours after the second injection of morphine once a day for 10 days. Spatial learning capacity was assessed in the Morris water maze. The results showed that rats treated with Morphine/Rg1 decreased escape latency and increased the time spent in platform quadrant and entering frequency. By implantation of electrodes and electrophysiological recording in vivo, the results showed that Rg1 restored the long-term potentiation (LTP) impaired by morphine in both freely moving and anaesthetised rats. The electrophysiological recording in vitro showed that Rg1 restored the LTP in slices from the rats treated with morphine, but not changed LTP in the slices from normal saline- or morphine/Rg1-treated rats; this restoration could be inhibited by N-methyl-D-aspartate (NMDA) receptor antagonist MK801. We conclude that Rg1 may significantly improve the spatial learning capacity impaired by chonic morphine administration and restore the morphine-inhibited LTP. This effect is NMDA receptor dependent.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Central Nervous System Agents; Dizocilpine Maleate; Electric Stimulation; Electrodes; Ginsenosides; Hippocampus; Injections, Subcutaneous; Learning Disabilities; Long-Term Potentiation; Male; Maze Learning; Medicine, Chinese Traditional; Morphine; Panax; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

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

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

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

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

Recent studies have indicated that learning-induced activation of extracellular signal-regulated kinase (ERK) signaling via N-methyl-D-aspartate (NMDA) receptors is required for consolidation of the resultant learning. These findings raise an idea that control of ERK signaling may be a potential target for treatment of cognitive dysfunction. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from Citrus depressa, enhances cAMP/protein kinase A/ERK signaling in cultured rat hippocampal neurons and PC12D cells. Here, we, for the first time, present the evidence that this natural compound reverses learning impairment associated with NMDA receptor antagonism by activation of ERK in the hippocampus. Treatment with 50 mg/kg nobiletin reversed the NMDA receptor antagonist MK-801 (dizocilpine maleate)-induced learning impairment in mice. Western blot analysis also showed that nobiletin reversed MK-801-induced inhibition of learning-associated ERK activation in the hippocampus of the animals. Furthermore, consistent with these results, in cultured rat hippocampal neurons, nobiletin restored MK-801-induced impairment of NMDA-stimulated phosphorylation of ERK in a concentration-dependent manner. Taken together, the present study suggests that compounds that activate ERK signaling improve cognitive deficits associated with NMDA receptor hypofunction and that nobiletin may give us a new insight into therapeutic drug development for neurological disorders exhibiting cognitive impairment accompanied by a hypofunction of NMDA receptor-ERK signaling.

Topics: Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Dizocilpine Maleate; Extracellular Signal-Regulated MAP Kinases; Flavones; Hippocampus; Learning Disabilities; Male; MAP Kinase Signaling System; Mice; Phosphorylation; Receptors, N-Methyl-D-Aspartate

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

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

The neuromodulator adenosine fulfills a unique role in the brain affecting glutamatergic neurotransmission and dopaminergic signaling via activation of adenosine A1 and A2A receptors, respectively. The adenosine system is thus ideally positioned to integrate glutamatergic and dopaminergic neurotransmission, which in turn could affect behavior and cognition. In the adult brain, adenosine levels are largely regulated by its key metabolic enzyme adenosine kinase (ADK), which may assume the role of an 'upstream regulator' of these two neurotransmitter pathways. To test this hypothesis, transgenic mice with an overexpression of ADK in brain (Adk-tg), and therefore reduced brain adenosine levels, were evaluated in a panel of behavioral and psychopharmacological assays to assess possible glutamatergic and dopaminergic dysfunction. In comparison to non-transgenic control mice, Adk-tg mice are characterized by severe learning deficits in the Morris water maze task and in Pavlovian conditioning. The Adk-tg mice also exhibited reduced locomotor reaction to systemic amphetamine, whereas their reaction to the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 was enhanced. Our results confirmed that ADK overexpression could lead to functional concomitant alterations in dopaminergic and glutamatergic functions, which is in keeping with the hypothesized role of ADK in the balance and integration between glutamatergic and dopaminergic neurotransmission. The present findings are of relevance to current pathophysiological hypotheses of schizophrenia and its pharmacotherapy.

Topics: Adenosine Kinase; Amphetamine; Animals; Behavior, Animal; Brain; Central Nervous System Stimulants; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Freezing Reaction, Cataleptic; Learning Disabilities; Maze Learning; Memory; Mice; Mice, Transgenic; Psychomotor Performance; Spatial Behavior

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

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

Alcohol exposure during development can produce severe and long-lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor-mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK-801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK-801's ability to mitigate ethanol's teratogenic effects.. Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge-like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty-one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK-801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18-19, activity level was monitored, and on PD 40-42, serial spatial discrimination reversal learning was assessed.. Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol-induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05-0.5 mg/kg) of MK-801 during withdrawal. The performance of ethanol-exposed subjects treated with the high dose of MK-801 (1.0 mg/kg) did not differ from that of the Ethanol Only group.. These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Brain; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Female; Learning Disabilities; Male; Motor Activity; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Teratogens

The sigma1 (sigma1) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma1 receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma1 receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[3H]SKF-10,047 binding to sigma1 sites showed that Bmax values were significantly decreased in the hippocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum, of aODN treated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippocampus and cortex but not in the cerebellum. The anti-amnesic effects of the selective sigma1 agonists PRE-084 or SA4503 were evaluated against the learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The anti-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-treatment, were blocked after aODN administration. These observations bring a molecular basis to the modulatory role of sigma1 receptors in memory processes.

Topics: Amnesia; Animals; Brain; Dizocilpine Maleate; Excitatory Amino Acid Agonists; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Mice; Morpholines; Nootropic Agents; Oligonucleotides, Antisense; Phenazocine; Piperazines; Receptors, sigma

The aim of the study was to assess the contribution of central dopaminergic and glutamatergic systems to the age-dependent loss of motor functions in rats. Rats of three age groups were compared: young (3-5-month-old), middle-aged (20-21-month-old) and old (29-31-month-old). The obtained results showed an age-dependent decline in the electromyographic (EMG) resting and reflex activities in the gastrocnemius and tibialis anterior muscles, as well as in the T-maze performance. Although these disturbances were accompanied with significant age-dependent decreases in the binding to NMDA, AMPA and dopamine D2 receptors, and a decline in the number of nigral dopamine neurons, they were significantly correlated with the loss of the binding to NMDA receptors only. The reduction in T-maze performance with aging was additionally correlated with a decrease in motor functions (EMG activity). The study suggests a crucial role of the loss of NMDA receptors in age-dependent motor disabilities, as well as in disturbances measured in the T-maze.

Topics: Aging; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Ankle Joint; Biomarkers; Biomechanical Phenomena; Brain Mapping; Cell Count; Dizocilpine Maleate; Dopamine; Electromyography; Female; Glutamic Acid; Learning Disabilities; Maze Learning; Movement Disorders; Muscle, Skeletal; Nerve Tissue Proteins; Pliability; Psychomotor Performance; Raclopride; Rats; Rats, Wistar; Reaction Time; Receptors, AMPA; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Substantia Nigra; Tyrosine 3-Monooxygenase

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Binding Sites; Blotting, Western; Brain; Cerebral Cortex; Dehydroepiandrosterone; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Memory; Mice; Morpholines; Oligonucleotides, Antisense; Phenazocine; Pregnenolone; Receptors, sigma; Sigma-1 Receptor

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

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

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

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

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

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

The ability of the nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-induced learning impairment, was tested in mice using two different behavioral models of long-term memory. The performance of aged mice (16 months old) in step-down type of passive-avoidance and elevated plus-maze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly improved the passive-avoidance and plus-maze performances in aged mice. Neurosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly attenuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without producing any promnestic effects alone in adult mice. In both cognitive tasks, the effects exhibited by the neurosteroids tested had a bell-shaped curve. Preadministration of L-NAME (10 and 20 mg/kg, i.p.), at doses that did not disrupt cognition alone in either young or aged mice, significantly blocked the beneficial and antiamnesic effects of neurosteroids PS (5 mg/kg) and DHEAS (10 mg/kg). A selective action of L-NAME on the effects of neurosteroids was indicated, since the effects of L-NAME were completely reversed by L-arginine (300 mg/kg, i.p.), a competitive substrate for NO synthase. Neither L-NAME nor L-arginine alone affected the antinociception, locomotor activity or rota-rod performance of young or aged mice. These observations suggest that a NO-dependent mechanism may be involved in the beneficial and antiamnesic effects of neurosteroids PS and DHEAS on the aging- and dizocilpine-induced impairment of learning and memory processes.

Topics: Aging; Amnesia; Animals; Avoidance Learning; Dehydroepiandrosterone Sulfate; Dizocilpine Maleate; Enzyme Inhibitors; Learning Disabilities; Male; Maze Learning; Memory; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nootropic Agents; Pregnenolone

1. This study investigated the effects of dizocilpine (MK-801) on learning ability in a non-human primate. Acquisition and reversal learning of visual discrimination tasks and acquisition of visuo-spatial discrimination tasks were assessed in marmosets using the Wisconsin General Test Apparatus. Dizocilpine impaired acquisition of visuo-spatial (conditional) tasks requiring spatial responses to coloured objects, and perceptually difficult visual discrimination tasks in which stimulus objects are painted black. Dizocilpine did not, however, impair either acquisition or reversal of a simple visual discrimination task using easily discriminated, coloured objects. 2. Motor effects of dizocilpine treatment, which have been seen in other primates, were examined by observation of the marmosets in their home cages, using both an automated locomotor activity monitor and 'blind', subjective counting of the number of abnormal movements in a given time period. Locomotor activity, assessed using the automated monitor, was not significantly affected at any of the doses tested. Incoordination, assessed by human observation of abnormal movements, was significantly increased only at a dose of 30 microg kg(-1) i.m., which was twice the highest dose used to assess the effects of dizocilpine on cognition. 3. We have, therefore, found an effect of dizocilpine on acquisition and reversal of some types of cognitive task, at a dose which does not cause significant motor effects. This demonstration of a cognitive deficit associated with glutamatergic blockade in a primate may be useful in understanding the contribution of glutamatergic dysfunction to cognitive decline in neurodegenerative disease, especially Alzheimer's disease.

Topics: Animals; Callithrix; Discrimination, Psychological; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamates; Humans; Learning; Learning Disabilities; Male; Motor Activity; Visual Perception

Harmaline is known to produce tremors and retard acquisition of the rabbit's nictitating membrane response. These actions have been demonstrated to depend on the ability of harmaline to activate the inferior olive which gives rise to climbing fibers that project directly onto Purkinje cells in cerebellar cortex. However, the precise receptor systems involved in harmaline's actions remains unknown. This study examined the role of the NMDA receptor in harmaline's actions. Harmaline (10 mg/kg, s.c.) produced intense tremors and impaired the acquisition of conditioned responses. Both of these effects of harmaline were significantly blocked by the prior administration of the noncompetitive NMDA channel blocker, dizocilpine (0.01 mg/kg, s.c. given 20 min prior to the administration of harmaline). This dose od dizocilpine had no effect on acquisition of conditioned responses when given alone. A higher dose of dizocilpine (0.1 mg/kg s.c.) completely blocked the tremorogenic effects of harmaline (10 mg/kg, s.c.). Dizocilpine had no effect on motor behavior when given alone. It was suggested that the blockade of harmaline's actions by dizocilpine may be occurring at NMDA channels within the inferior olive. Regardless of the site of action, these data demonstrate that harmaline's ability to activate the interior olivary nucleus depends on the normal activity of the NMDA receptor.

Topics: Animals; Conditioning, Classical; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Harmaline; Learning Disabilities; Male; Motor Activity; Nictitating Membrane; Olivary Nucleus; Rabbits; Receptors, N-Methyl-D-Aspartate; Tremor

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

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

The effects of N-methyl-D-aspartate NMDA receptor antagonists on scopolamine-induced amnesia and on delay-interposed short-term memory performance were investigated using an 8-arm radial maze in rats. Scopolamine, a muscarinic antagonist, deteriorated the radial maze performance, while MK-801, an NMDA receptor channel blocker and CGS-19755, a competitive NMDA receptor antagonist, showed no obstruction to the spatial cognition in the non-delayed maze task. MK-801 (0.01-0.03 mg/kg, i.v.) and CGS-19755 (1-10 mg/kg, i.v.) significantly augmented scopolamine-induced deficit in the non-delayed maze task and impaired the short-term memory in the 5-min delay-interposed task. These results suggest that NMDA antagonists have a negative action on short-term memory and that the interaction between the NMDA and the central muscarinic system plays a role in modulating the cognitive function.

Topics: Amnesia; Animals; Cholinergic Antagonists; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Learning Disabilities; Male; Maze Learning; Memory, Short-Term; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Wistar; Scopolamine

It has been shown recently that low doses of sigma (sigma) receptor ligands like 1,3-di-(2-tolyl)guanidine (DTG), (+)N-allylnormetazocine [(+)SKF 10,047] and (+)pentazocine can antagonize learning impairments induced by dizocilpine (MK-801), a non-competitive antagonist at the NMDA receptor channel. This antagonism has been proposed to involve sigma receptor sites since it is blocked by the administration of purported sigma antagonists such as NE-100 and BMY-14802. It has also been demonstrated that peptides of the neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) families modulate, in vivo, sigma labelling and electrophysiological effects in the hippocampal formation. Accordingly, we investigated if NPY- and CGRP-related peptides modulate cognitive processes by interacting with sigma sites in mice. In order to test this hypothesis, a step-down passive avoidance task was used. Interestingly, similarly to various sigma agonists, NPY, peptide YY (PYY) and the Y1 agonist [Leu31Pro34]NPY (but not NPY[13-36], a purported Y2 agonist), as well as hCGRPalpha and the purported CGRP2 agonist [Cys(ACM)2-7]hCGRPalpha (but not CGRP[8-37], a CGRP1 receptor antagonist), significantly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu31Pro34]NPY, hCGRPalpha and [Cys(ACM)2-7]hCGRPalpha were blocked by the administration of the sigma antagonist, BMY-14802. The present data suggest that NPY- and CGRP-related peptides can indirectly interact in vivo with sigma receptors to modulate cognitive processes associated with NMDA receptor function.

Topics: Animals; Avoidance Learning; Calcitonin Gene-Related Peptide; Cognition; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroshock; Humans; Learning Disabilities; Male; Memory; Mice; Neuropeptide Y; Peptide Fragments; Receptors, sigma

The NMDA receptor agonist quinolinic acid (9 mM) was infused i.c.v. via ALZET osmotic minipumps for 2 weeks. This treatment produced a persistent, short-term memory deficit in the T-maze. Autoradiography revealed a decrease in the density of choline uptake sites in the hippocampus. Parallel s.c. infusion by another minipump of the uncompetitive NMDA receptor antagonist memantine (1-amino-3,5-dimethyladamantane, 20 mg/kg per day) or (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, 0.31 mg/kg day) prevented the learning deterioration induced by quinolinic acid. The treatment with memantine resulted in steady-state serum levels of 1.2 mu M which, based on in vitro data, should assure inhibition of NMDA receptors and are similar to levels seen in the serum of demented patients treated with this agent. In naive animals this treatment had no effect on either learning or on ex vivo induction of long-term potentiation, indicating that under chronic conditions it is possible to obtain neuroprotective effects with NMDA receptor antagonists without negative effects on memory processes. This contrasts to some acute insults (e.g. ischaemia) where high doses of NMDA receptor antagonists that produce side effects are required.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dopamine Agents; Hippocampus; Injections, Intraventricular; Learning Disabilities; Male; Maze Learning; Memantine; Memory, Short-Term; Neuroprotective Agents; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

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

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

About 20 min prior to training in a shock-motivated 14-unit T-maze, young (3-4 months) and aged (24-25 months) male Fischer-344 rats were given s.c. injections of either saline or dizocilpine (MK-801, 0.02 or 0.04 mg/kg), a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. The aged rats showed a dose-dependent impairment in maze performance. Deficiencies were manifested as increases in errors, in runtime from start to goal, and in the number and duration of shocks received. In contrast, young rats exhibited no detrimental effects of dizocilpine on maze performance. Analysis of [3H]glutamate binding in these rats revealed a marked age-related decline in NMDA receptor binding in hippocampus. A significant correlation was observed between errors in the maze and hippocampal [3H]-glutamate binding, but the correlation was positive, i.e., rats that made the most errors had the highest level of NMDA receptor binding. Thus, compared to young rats, aged rats were more sensitive to the behavioral effects of NMDA receptor antagonism and they showed a hippocampal loss of [3H]glutamate in binding, which may be related to the increased sensitivity to dizocilpine. The positive correlation between poor maze performance and NMDA receptor binding suggests that the behaviors assessed involve complex interactions between NMDA receptors and other neuronal systems in the hippocampus.

Topics: Aging; Animals; Dizocilpine Maleate; Hippocampus; Learning Disabilities; Male; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate

The effect of Pb2+ on glutamate receptor activity in rat hippocampal neurons was investigated with a view of explaining the cognitive and learning deficits produced by this heavy metal. Pb2+ (2.5-50 microM) selectively inhibited N-methyl-D-aspartate (NMDA)-induced whole-cell and single-channel currents in a concentration-dependent but voltage-independent manner, without significantly altering currents induced by either quisqualate or kainate. The frequency of NMDA-induced channel activation was decreased by Pb2+. Neither glycine (10-100 microM), nor Ca2+ (10 mM) reversed the effect of Pb2+. Pb2+ also inhibited the [3H]MK-801 binding to rat hippocampal membranes in vitro. The elucidation of the actions of Pb2+ on the NMDA receptor ion channel complex provides important insights into the clinical and toxic effects of this cation.

Topics: Animals; Aspartic Acid; Calcium; Dibenzocycloheptenes; Dizocilpine Maleate; Electric Conductivity; Glycine; Hippocampus; Ion Channels; Kainic Acid; Lead; Learning Disabilities; Male; N-Methylaspartate; Oxadiazoles; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter