dizocilpine-maleate and Psychotic-Disorders

Phencyclidine (PCP), ketamine (Special K), and MK-801 are noncompetitive N-methyl-d-aspartate (NMDA) antagonists that produce acute psychosis in humans. The psychosis produced by these psychomimetic drugs is indistinguishable from schizophrenia and includes both positive and negative symptoms. This drug-induced psychosis occurs after puberty in humans. On the basis of the MK-801-induced spike-and-wave activity in rats and increased blood flow and metabolism in brain of patients with psychosis caused by these psychomimetics, this brief review argues that this psychosis is an atypical form of limbic epilepsy. Moreover, there is a specific limbic thalamcortical psychosis circuit that mediates cell injury in limbic cortex of rodents and may mediate this PCP-induced psychosis in humans. It is proposed that this thalamocortical psychosis circuit develops at puberty and can mediate PCP and ketamine-mediated psychosis and possibly the psychosis of schizophrenia, bipolar disease and other disorders that have their onset at puberty. Finally, based on this developmentally regulated psychosis/epilepsy-related thalamocortical circuitry, it is proposed that antiepileptic drugs that promote GABAergic mechanisms may decrease the probability of episodic psychosis from any cause.

Topics: Adolescent; Animals; Antipsychotic Agents; Dizocilpine Maleate; Epilepsy; Excitatory Amino Acid Antagonists; Hallucinogens; Humans; Ketamine; Limbic System; Neurons; Phencyclidine; Psychoses, Substance-Induced; Psychotic Disorders; Puberty; Rats; Regional Blood Flow; Sexual Maturation

Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia.

Topics: Animals; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Prohibitins; Prolyl Oligopeptidases; Psychotic Disorders; Rats; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Topics: Amphetamine; Animals; Antipsychotic Agents; Aripiprazole; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Psychotic Disorders; Quinolones; Rats; Receptors, Serotonin

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.

Topics: Animals; Dizocilpine Maleate; GABAergic Neurons; Mice; Mice, Knockout; N-Methylaspartate; Phencyclidine; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate

Males are more prone to psychosis, schizophrenia and substance abuse and addiction in adolescence and early adulthood than females. However, the role of androgens during this developmental period is poorly understood.. This study aimed to examine how androgens in adolescence influence psychosis-like behaviour in adulthood and whether brain-derived neurotrophic factor (BDNF) is a mediator of these developmental effects.. Wild-type and BDNF heterozygous male mice were castrated at pre-pubescence and implanted with testosterone or dihydrotestosterone (DHT). In adulthood, we assessed amphetamine- and MK-801-induced hyperlocomotion as a model of psychosis-like behaviour. Western blot analysis was used to quantify levels of the dopamine transporter (DAT) and N-methyl-d-aspartate (NMDA) receptor subunits.. While castration itself had little effect on behaviour, adolescent testosterone, but not DHT, significantly reduced amphetamine-induced hyperlocomotion, whereas both testosterone and DHT reduced the effect of MK-801. These effects were similar in mice of either genotype. In wildtype mice, both testosterone and DHT treatment reduced DAT expression in the medial prefrontal cortex (mPFC) but these effects were absent in BDNF heterozygous mice. There were no effects on NMDA receptor subunit levels.. The differential effect of adolescent testosterone and DHT on amphetamine-induced hyperlocomotion in adulthood suggests involvement of conversion of testosterone to estrogen and subsequent modulation of dopaminergic signalling. In contrast, the similar effect of testosterone and DHT treatment on NMDA receptor-mediated hyperlocomotion indicates it is mediated by androgen receptors. The involvement of BDNF in these hormone effects remains to be elucidated. These results demonstrate that, during adolescence, androgens significantly influence key pathways related to various mental illnesses prevalent in adolescence.

Topics: Age Factors; Androgens; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Dihydrotestosterone; Dizocilpine Maleate; Dopamine; Dopamine Plasma Membrane Transport Proteins; Heterozygote; Male; Mice; Mice, Inbred C57BL; Orchiectomy; Psychotic Disorders; Receptors, Androgen; Receptors, N-Methyl-D-Aspartate; Sexual Maturation; Testosterone

Conceptual and computational models have been advanced that propose that perceptual disturbances in psychosis, such as hallucinations, may arise due to a disruption in the balance between bottom-up (ie sensory) and top-down (ie from higher brain areas) information streams in sensory cortex. However, the neural activity underlying this hypothesized alteration remains largely unexplored. Pharmacological N-methyl-d-aspartate receptor (NMDAR) antagonism presents an attractive model to examine potential changes as it acutely recapitulates many of the symptoms of schizophrenia including hallucinations, and NMDAR hypofunction is strongly implicated in the pathogenesis of schizophrenia as evidenced by large-scale genetic studies. Here we use in vivo 2-photon imaging to measure frontal top-down signals from the anterior cingulate cortex (ACC) and their influence on activity of the primary visual cortex (V1) in mice during pharmacologically induced NMDAR hypofunction. We find that global NMDAR hypofunction causes a significant increase in activation of top-down ACC axons, and that surprisingly this is associated with an ACC-dependent net suppression of spontaneous activity in V1 as well as a reduction in V1 sensory-evoked activity. These findings are consistent with a model in which perceptual disturbances in psychosis are caused in part by aberrant top-down frontal cortex activity that suppresses the transmission of sensory signals through early sensory areas.

Topics: Animals; Axons; Disease Models, Animal; Dizocilpine Maleate; Evoked Potentials, Visual; Excitatory Amino Acid Antagonists; Gyrus Cinguli; Hallucinations; Mice; Neural Inhibition; Neural Pathways; Optical Imaging; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Visual Cortex

Psychosis is a mental condition that is characterized by hallucinations, delusions, disordered thought, as well as socio-emotional and cognitive impairments. Once developed, it tends to progress into a chronic psychotic illness. Here, the duration of untreated psychosis plays a crucial role: the earlier the treatment begins, relative to the first episode of the disease, the better the patient's functional prognosis. To what extent the success of early interventions relate to progressive changes at the neurotransmitter receptor level is as yet unclear. In fact, very little is known as to how molecular changes develop, transform, and become established following the first psychotic event. One neurotransmitter receptor for which a specific role in psychosis has been discussed is the N-methyl-d-aspartate receptor (NMDAR). This receptor is especially important for information encoding in the hippocampus. The hippocampus is one of the loci of functional change in psychosis, to which a role in the pathophysiology of psychosis has been ascribed. Here, we examined whether changes in NMDAR subunit expression occur along the dorsoventral axis of the hippocampus 1 week and 3 months after systemic treatment with an NMDAR antagonist (MK801) that initiates a psychosis-like state in adult rats. We found early (1 week) upregulation of the GluN2B levels in the dorso-intermediate hippocampus and late (3 month) downregulation of GluN2A expression across the entire CA1 region. The ventral hippocampus did not exhibit subunit expression changes. These data suggest that a differing vulnerability of the hippocampal longitudinal axis may occur in response to MK801-treatment and provide a time-resolved view of the putative development of pathological changes of NMDAR subunit expression in the hippocampus that initiate with an emulated first episode and progress through to the chronic stabilization of a psychosis-like state in rodents.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Psychoses, Substance-Induced; Psychotic Disorders; Rats; Receptors, N-Methyl-D-Aspartate; Time Factors; Up-Regulation

The NMDA receptor (NMDAr) hypofunction theory of schizophrenia suggests that aberrant signaling through NMDAr underlies the pathophysiology of this disease. This is commonly modeled in rodents via treatment with NMDAr antagonists, which causes a range of behavioral effects that represent endophenotypes related to schizophrenia. These drugs also disrupt high-frequency neural oscillations within the brain, also potentially relevant to disease. We studied the effect of localized NMDAr hypofunction on the generation of neural oscillations occurring both locally and in distant brain regions, and on behaviors routinely used as endophenotypes to model psychosis in rodents. Wistar rats were implanted with local field potential recording electrodes in the prefrontal cortex, dorsal hippocampus and nucleus accumbens, as well as cannulae in these regions to facilitate drug infusion. Rats received bilateral infusions of MK801 (0, 5μg, 20μg, 50μg) into one of the three target regions and their behavior measured in an open field. We also assessed the effects of systemic MK801 injection (0.16mg/kg sc). Electrophysiological signals were recorded continuously, allowing assessment of gamma oscillations (30-80Hz) and high-frequency oscillations (HFO: 130-180Hz) occurring as a result of infusions. Regardless of MK801 infusion location, gamma oscillations and HFOs significantly and consistently increased in all three regions studied, similar to that observed following systemic injection. Locomotor activity, stereotypies and ataxia were also observed following infusion into all regions. We conclude that localized regions exhibiting NMDAr hypofunction are sufficient to disrupt local as well as diffuse neural circuits and global brain function, and concomitantly cause psychosis-related behavioral effects.

Topics: Animals; Ataxia; Brain; Brain Waves; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Excitatory Amino Acid Antagonists; Gamma Rhythm; Locomotion; Male; Psychotic Disorders; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2AR) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2AR knockout (KO) mice with complete and specific inactivation of A2AR, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2AR KO animals. Hyperlocomotion induced by d-amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2AR KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Dextroamphetamine; Disease Models, Animal; Dizocilpine Maleate; Female; Inhibition, Psychological; Male; Mice, Knockout; Motor Activity; Neurotransmitter Agents; Psychotic Disorders; Receptor, Adenosine A2A; Schizophrenia; Sensory Gating; Social Behavior

NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms.

Topics: Animals; Antipsychotic Agents; Brain; Calcium-Binding Proteins; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microfilament Proteins; Neuroglia; Phosphopyruvate Hydratase; Psychotic Disorders; Recognition, Psychology

The etiology of schizophrenia is unknown. However, some of the neuropathological changes in schizophrenia may be the result of increased free radical-mediated or reactive oxygen species (ROS) mediated neurotoxicity. Melatonin is a hormone produced especially at night in the pineal gland; additionally is a highly important antioxidant. The aim of this study is to indicate the contribution effect of the neuropathophysiology of schizophrenia and protective effects of melatonin against this oxidative damaged. MK-801 induced selective neurotoxicity has been proposed as an animal model for psychosis.. 21 healthy adult and male Wistar albino rats were divided into three groups. MK-801 was given intraperitoneally for 5 days in experimental psychosis group. Melatonin was given to the treatment group for 6 days by intraperitoneally. In control group, saline was given in the same way. At the 7th day of the experiments, rats were killed by decapitation. Brains were removed and prefrontal part of the brain was divided for biochemical analyses.. Some antioxidant enzymes, malondialdehyde and protein carbonyl analyses were made by spectrophotometric methods. SOD, GSH-Px, XO activities and malondialdehyde, protein carbonyl and NO levels were found to be increased significantly in prefrontal cortex of MK-801 group (p < 0.0001) compared to the control group. In melatonin treated rats, prefrontal tissue malondialdehyde and protein carbonyl levels were decreased significantly in comparison with MK-801 group (p < 0.0001).. MK-801 may induce oxidative stress in prefrontal cortex of rats. This experimental study provides some evidences for the protective effects of melatonin on MK-801-induced changes in prefrontal rat cortex.

Topics: Animals; Antioxidants; Disease Models, Animal; Dizocilpine Maleate; Glutathione Peroxidase; Male; Malondialdehyde; Melatonin; Oxidants; Oxidative Stress; Prefrontal Cortex; Psychotic Disorders; Rats; Rats, Wistar; Reactive Oxygen Species; Schizophrenia; Superoxide Dismutase

Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia.. Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations.. LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used.. Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminobutyrates; Amphetamines; Animals; Antipsychotic Agents; Cyclohexanes; Dextroamphetamine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Phosphinic Acids; Piperazines; Psychotic Disorders; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Metabotropic Glutamate; Signal Transduction

Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate-dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (Arc, c-fos, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-fos in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-fos, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects.

Topics: Animals; Antipsychotic Agents; Carrier Proteins; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Drug Delivery Systems; Excitatory Amino Acid Antagonists; Homer Scaffolding Proteins; Intracellular Signaling Peptides and Proteins; Ketamine; Male; Memantine; Membrane Proteins; Nootropic Agents; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction

The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; Drug Evaluation, Preclinical; Enzyme Activation; Female; Half-Life; Imidazoles; Molecular Docking Simulation; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles

To study the effects of sertraline on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior, and amphetamine or MK-801-induced locomotor activities in female Swiss albino mice weighing 30-35 g.. This study was performed in the Department of Pharmacology, Eskisehir Osmangazi University, Eskisehir, Turkey between April 2008 and January 2010. Catalepsy was induced by haloperidol (1 mg/kg intraperitoneally [ip]). Apomorphine (1.5 mg/kg subcutaneously [sc]) was used for studying climbing behavior, and d-amphetamine (30 mg/kg ip) or MK-801 (0.3 mg/kg ip) was used for testing locomotor activities. Eight animals were used in each group. Sertraline (10 mg/kg ip) was injected either acutely, or over 5 days of repeated treatment.. Sertraline inhibited catalepsy and climbing behavior when it was used for 5 days in repeated doses, while it augmented amphetamine-induced locomotor activity. It reduced MK-801-induced stereotypic movements, but did not significantly affect amphetamine-induced stereotypic movements when used in a single dose or repeated doses.. These results suggest that sertraline, a selective serotonin reuptake inhibitor may be a beneficial adjuvant drug during psychosis therapy.

Topics: Animals; Antidepressive Agents; Apomorphine; Catalepsy; Dextroamphetamine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Haloperidol; Mice; Motor Activity; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors; Sertraline; Time Factors

Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl-D-aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP.

Topics: Animals; Antipsychotic Agents; Cyclic AMP; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; Injections, Intraventricular; Injections, Subcutaneous; Long-Term Potentiation; Male; Mental Recall; Neuronal Plasticity; Neuroprotective Agents; Pattern Recognition, Visual; Phosphodiesterase 4 Inhibitors; Psychotic Disorders; Rats; Rats, Wistar; Rolipram; Synapses; Synaptic Transmission

Vitamin A regulates the development and maintenance of the central nervous system. Studies of vitamin A depletion (VAD) and mutations of retinoid receptors in rodents have revealed a dysfunction of motor and cognitive abilities. However, the molecular mechanisms underlying these behavioral changes are not well understood. In this study, VAD mice were examined and abnormal motor behavior related to psychosis symptoms was found. With the use of two-dimensional gel electrophoresis (2-DE), two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mass spectrometric (MS) technologies, 44 and 23 altered protein spots were identified in the cortex and hippocampus, respectively, in VAD mice. By Western blot, the up-regulation of mitogen-activated protein kinase 1 (MAPK1) and proteasome subunit beta type 2 (PSMB2) in the cortex and that of dihydropyrimidinase-related protein 2 (DPYSL2) and PSMB2 in the hippocampus were observed in VAD mice. Bioinformatic analysis using DAVID revealed that altered proteins induced by VAD showed significant enrichment of (i) glycolysis, cytoskeleton, mitochondrion and glutamate metabolism in the cortex; and (ii) actin binding, dopamine receptor signaling and transmission of nerve impulse in the hippocampus. The up-regulations of DPYSL2, MAPK1 and PSMB2 may indicate the activated neuronal defensive mechanism in VAD brain regions, which may underlie the VAD-related psychosis behavior.

Topics: Actins; Animals; Cerebral Cortex; Dizocilpine Maleate; Electrophoresis, Gel, Two-Dimensional; Female; Glutamic Acid; Hippocampus; Intercellular Signaling Peptides and Proteins; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Nerve Tissue Proteins; Proteasome Endopeptidase Complex; Proteome; Psychoses, Substance-Induced; Psychotic Disorders; Receptors, Dopamine; Signal Transduction; Two-Dimensional Difference Gel Electrophoresis; Vitamin A Deficiency

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Cyclopentanes; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Routes; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Frontal Lobe; Hyperkinesis; In Vitro Techniques; Male; Mice; Motor Activity; Psychotic Disorders; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate; Tricarboxylic Acids

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

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

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

Some behavioral symptoms and neuropathological features of schizophrenia, like alterations of local GABAergic interneurons, could be emulated in an animal model of psychosis based on prolonged low-dose exposure to N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. MK-801. Employing this model, we examined distinct subpopulations of GABAergic interneurons within the hippocampus and prefrontal cortex. Compared to saline control, animals receiving MK-801 exhibited a decreased density of hippocampal parvalbumin-positive interneurons. A co-administration of the antipsychotic drug haloperidol ameliorated this effect of MK-801 on PV(+) interneurons in the hippocampus, but led to a marked reduction of PV immunoreactivity in the prefrontal cortex, when comparing with saline, MK-801 or haloperidol treatment alone. Neither calretinin immunoreactivity nor nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining, representing neuronal nitric oxide synthase activity mostly detectable in interneurons, was altered by either treatment. With special reference to the hippocampus, these data show that a prolonged application of low-dose NMDA receptor antagonist could, in part, mimic some neuropathologic findings in human schizophrenia, thus strengthening the idea that (sub-) chronic NMDA receptor antagonism in animals is a viable approach in mimicking aspects of schizophrenia. Moreover, this study provides further evidence for regional differences in the response of GABAergic interneurons to NMDA receptor antagonism and antipsychotic treatment.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; gamma-Aminobutyric Acid; Haloperidol; Hippocampus; Interneurons; Male; Neural Inhibition; Neurons; Prefrontal Cortex; Psychotic Disorders; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Brain; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Inhibition, Psychological; Interpersonal Relations; Maze Learning; Methylazoxymethanol Acetate; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Psychotic Disorders; Rats; Recognition, Psychology; Reflex, Startle; Time Factors

Cinnarizine, a drug known as a calcium channel blocker, is currently used for the treatment of migraine and vertigo. Induction of extrapyramidal signs by cinnarizine has been reported in the elderly, which is related to its moderate antagonistic properties at dopamine D2 receptors, resembling the mechanism of action of most antipsychotic drugs. Despite this effect, cinnarizine has never been tested as a putative antipsychotic drug. Here we evaluate the potential effect of cinnarizine in two pharmacological models of psychosis, namely amphetamine- and MK-801-induced hyperlocomotion, as well as its ability to induce catalepsy. Cinnarizine significantly counteracted MK-801 (0.25 mg/kg) and amphetamine (5mg/kg) locomotor effects at doses as low as 20mg/kg, having no incremental effect at 60 or 180 mg/kg. Regarding side-effects, cinnarizine induced no catalepsy in mice at the effective dose of 20 mg/kg, inducing only mild catalepsy at the doses of 60 and 180 mg/kg. Based on these results and on the antagonist effect of cinnarizine on dopamine D2 receptors, we suggest that it has a potential antipsychotic effect with an atypical profile that should be evaluated clinically.

Topics: Amphetamine; Animals; Antipsychotic Agents; Calcium Channel Blockers; Catalepsy; Central Nervous System Stimulants; Cinnarizine; Dizocilpine Maleate; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Haloperidol; Hyperkinesis; Male; Mice; Motor Activity; Psychotic Disorders

Administration of a non-competitive NMDA antagonist dizocilpine (MK-801) was proposed to be an animal model of psychosis. NMDA-receptor blockade is accompanied by increased locomotion, behavioral deficits, and other changes resembling psychotic symptoms. However, the role of NMDA-receptors in organizing brain representations is not understood yet. We tested the effect of NMDA-receptor blockade by systemic administration of dizocilpine at two different doses (0.1 or 0.2 mg/kg) in a recently designed Active Allothetic Place Avoidance (AAPA), a task which requires rats to separate spatial stimuli from two continuously dissociated subsets. The effect of dizocilpine on learning in the AAPA task was compared with its effect on acquisition of the reference memory version of the Morris Water Maze task. Both doses impaired performance in the Morris Water Maze task, whereas only the higher dose impaired performance in the AAPA task. The Morris Water Maze appears to be more sensitive to dizocilpine-induced behavioral deficit than the AAPA task. These findings support the notion that these two tasks are differentially dependent on the NMDA-receptor function.

Topics: Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Maze Learning; Psychotic Disorders; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate

The non-competitive NMDA receptor antagonists, including PCP (phencyclidine), ketamine, and MK-801 (dizocilpine) produce psychosis in humans and injure neurons in retrosplenial cortex in adult rodent brain. This study examined the effects of the metabotropic mGlu2/3 agonist LY379268 and antagonist LY341495 on cortical injury produced by systemic MK-801 (1 mg/kg i.p.) in adult female rats. Systemic injections of mGlu2/3 agonist LY379268, but not mGlu2/3 antagonist LY341495, decreased the injury in the retrosplenial cortex produced by systemic MK-801 as assessed by Hsp70 induction. Bilateral injections of LY379268, but not vehicle, into retrosplenial cortex or bilateral injections of LY379268 into anterior thalamus also decreased the injury in retrosplenial cortex produced by systemic MK-801. The data show that bilateral activation of mGlu2/3 glutamate receptors in cortex or anterior thalamus decreases the neuronal injury in retrosplenial cortex produced by systemic MK-801. Because antipsychotic medications decrease cortical injury produced by NMDA antagonists in rodents and decrease psychosis in humans, mGlu2/3 agonists that decrease cortical injury produced by NMDA antagonists in rodents might be evaluated for decreasing psychosis in people.

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Dizocilpine Maleate; Female; HSP70 Heat-Shock Proteins; Neurons; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Thalamus

Psychosis frequently occurs in Alzheimer's disease (AD), being associated with more severe cognitive decline, but the underlying mechanisms are unknown.. To investigate the effect of centrally administered beta-amyloid peptide, a model for AD, in the locomotor response to amphetamine, caffeine and MK-801, which are psychoactive drugs related to neurochemical changes occurring in psychosis.. Mice were intracerebroventricularly injected with beta-amyloid (25-35), and after 1 week they were tested in the passive avoidance, spontaneous alternation and locomotor tasks.. Besides impaired performance in inhibitory avoidance and spontaneous alternation tasks, beta-amyloid-treated mice showed increased spontaneous locomotion, augmented response to amphetamine (1.5 mg/kg), blunted response to caffeine (30 mg/kg) and no difference in MK-801 (0.25 mg/kg)-induced locomotor activation when compared to its respective control.. These results are compatible with the hypothesis that beta-amyloid peptide may predispose to psychotic symptoms of AD by increasing sensitivity of the dopaminergic system, possibly related to a decreased adenosinergic inhibitory tone.

Topics: Adenosine; Adrenergic Agents; Alzheimer Disease; Amphetamine; Amyloid beta-Peptides; Animals; Avoidance Learning; Brain; Caffeine; Central Nervous System Stimulants; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Glutamine; Injections, Intraventricular; Male; Mice; Motor Activity; Psychotic Disorders

The present study has shown that a subthreshold dose of the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801, combined with a subthreshold dose of LSD, produces marked locomotor stimulation in monoamine-depleted mice. Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the alpha-adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT2 receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT2A receptor antagonist MDL 100,907. On the other hand, MDL 100,907 did not antagonize the hyperactivity response produced by clonidine given in combination with MK-801 or atropine in monoamine-depleted mice, nor the response produced by the mixed DA receptor agonist apomorphine, underlining the selectivity in the antagonistic action of MDL 100,907. Furthermore, MDL 100,907 attenuated the hyperactivity produced in intact mice by such disparate agents as MK-801, atropine or the DA uptake inhibitor GBR 12,909. A putative "permissive" role of the 5-HT2 receptor in the context of psychomotor activation is discussed, as well as its possible importance as target for antipsychotic therapy.

Topics: Animals; Biogenic Monoamines; Disease Models, Animal; Dizocilpine Maleate; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Fluorobenzenes; Glutamic Acid; Hallucinogens; Lysergic Acid Diethylamide; Male; Mice; Mice, Inbred Strains; Neurotransmitter Agents; Piperazines; Piperidines; Psychomotor Performance; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Muscarinic; Receptors, Serotonin; Serotonin; Serotonin Antagonists

We studied the effects of desipramine, alprazolam, muscimol and dizocilpine (MK-801) (alone or associated with desipramine) in the forced swimming test in rats after long-lasting termination of chronic exposure to vehicle and pentylenetetrazol. Sensitisation with pentylenetetrazol was ineffective in changing immobility time in the forced swimming test compared to vehicle treatment; pentylenetetrazol enhanced the anti-immobility effect of desipramine, abolished the anti-immobility effect of alprazolam and did not affect the anti-immobility effect of muscimol. MK-801 at the dose that did not modify immobility time in vehicle-treated rats and in pentylenetetrazol-treated animals strongly potentiated the anti-immobility effect of desipramine in pentylenetetrazol-treated rats. MK-801 in association with desipramine induced a marked hyperlocomotion and hyperexcitability, with swaying movements and oral stereotypies in pentylenetetrazol-sensitised rats. Results are considered the experimental representation of a 'gating mechanism' toward psychotic-like symptoms.

Topics: Alprazolam; Animals; Behavior, Animal; Desipramine; Disease Models, Animal; Dizocilpine Maleate; gamma-Aminobutyric Acid; Kindling, Neurologic; Male; Motivation; Motor Activity; Muscimol; N-Methylaspartate; Pentylenetetrazole; Psychotic Disorders; Rats; Rats, Wistar; Swimming