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Neuroscience Nov 2009The mechanism underlying phencyclidine (PCP)-induced apoptosis in perinatal rats and the development of schizophrenia-like behaviors is incompletely understood. We used...
The mechanism underlying phencyclidine (PCP)-induced apoptosis in perinatal rats and the development of schizophrenia-like behaviors is incompletely understood. We used antagonists for N-methyl-D-aspartate (NMDA) receptor subunit NR2A- and NR2B-containing NMDA receptor to test the hypothesis that the behavioral and apoptotic effects of PCP are mediated by blockade of NR1/NR2A-containing receptors, rather than NR1/NR2B-containing receptors. Sprague-Dawley rats were treated on PN7, PN9, and PN11 with PCP (10 mg/kg), PEAQX (NR2A-preferring antagonist; 10, 20, or 40 mg/kg), or ifenprodil (selective NR2B antagonist; 1, 5, or 10 mg/kg) and sacrificed for measurement of caspase-3 activity (an index of apoptosis) or allowed to age and tested for locomotor sensitization to PCP challenge on PN28-PN35. PCP or PEAQX on PN7, PN9, and PN11 markedly elevated caspase-3 activity in the cortex; ifenprodil showed no effect. Striatal apoptosis was evident only after subchronic treatment with a high dose of PEAQX (20 mg/kg). Animals treated with PCP or PEAQX on PN7, PN9, and PN11 showed a sensitized locomotor response to PCP challenge on PN28-PN35. Ifenprodil treatment had no effect on either measure. Therefore, PCP blockade of cortical NR1/NR2A, rather than NR1/NR2B, appears to be responsible for PCP-induced apoptosis and the development of long-lasting behavioral deficits.
Topics: Animals; Animals, Newborn; Apoptosis; Caspase 3; Corpus Striatum; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; In Vitro Techniques; Locomotion; Male; Neurons; Phencyclidine; Piperidines; Quinoxalines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Time Factors
PubMed: 19654040
DOI: 10.1016/j.neuroscience.2009.07.058 -
Biological Psychiatry Jul 2010Schizophrenia patients suffer from cognitive impairments that are not satisfactorily treated by currently available medications. Cognitive dysfunction in schizophrenia... (Review)
Review
Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia.
Schizophrenia patients suffer from cognitive impairments that are not satisfactorily treated by currently available medications. Cognitive dysfunction in schizophrenia encompasses deficits in several cognitive modalities that can be differentially responsive to different medications and are likely to be mediated by different neurobiological substrates. Translational animal models of cognitive deficits with relevance to schizophrenia are critical for gaining insights into the mechanisms underlying these impairments and developing more effective treatments. The five-choice serial reaction time task (5-CSRTT) is a cognitive task used in rodents that allows simultaneous assessment of several cognitive modalities, including attention, response inhibition, cognitive flexibility, and processing speed. Administration of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists disrupts multiple 5-CSRTT performance measures in a way that mirrors various cognitive deficits exhibited by schizophrenia patients. Some of these disruptions are partially attenuated by antipsychotic medications that exhibit partial effectiveness on cognitive dysfunction in schizophrenia, suggesting that the model has predictive validity. Examination of the effects of pharmacological manipulations on 5-CSRTT performance disruptions induced by NMDA antagonists have implicated a range of brain regions, neurotransmitter systems, and specific receptor subtypes in schizophrenia-like impairment of different cognitive modalities. Thus, disruption of 5-CSRTT performance by NMDA antagonists represents a valuable tool for exploring the neurobiological bases of cognitive dysfunction in schizophrenia.
Topics: Animals; Choice Behavior; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Antagonists; Humans; Neuropsychological Tests; Phencyclidine; Reaction Time; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 20488434
DOI: 10.1016/j.biopsych.2010.03.004 -
Psychopharmacology Aug 2015Tobacco use is a serious health problem in the USA, and this problem is potentiated in patients with schizophrenia. The reward system is implicated in schizophrenia and...
RATIONALE
Tobacco use is a serious health problem in the USA, and this problem is potentiated in patients with schizophrenia. The reward system is implicated in schizophrenia and may contribute to the high comorbidity between nicotine use and schizophrenia, but very little research has been done on the topic. The reward-enhancement effect of nicotine has been shown to be important in nicotine use, but there have been no studies on this effect in animal models of schizophrenia.
OBJECTIVES
This study was designed to determine the effects of phencyclidine, used to model negative symptoms of schizophrenia, on self-administration of nicotine with or without a co-occurring sensory reinforcer [i.e., visual stimulus (VS)] in rats.
METHODS
Phencyclidine (2.0 mg/kg) was administered before each of seven nicotine self-administration sessions (0.01 mg/kg/inf) after which rats (n = 8-9 per group) were given 7 days of extinction without phencyclidine pretreatment. Reinstatement using phencyclidine (2.0 mg/kg), nicotine (0.2 mg/kg), and yohimbine (1.25 mg/kg, a pharmacological stressor) was tested after extinction to determine if previous exposure to phencyclidine would alter reinstatement of active lever pressing.
RESULTS
Phencyclidine initially decreased nicotine self-administration but only in the groups with a concurrent VS. This decrease in self-administration dissipated after 5 days. During reinstatement, rats that had previously received phencyclidine during self-administration with a VS were more sensitive to stress-induced reinstatement than any other group.
CONCLUSIONS
These results show a transitory effect of phencyclidine on nicotine self-administration. Phencyclidine may induce a potential sensitivity to pharmacological stressors contributing to reinstatement of nicotine.
Topics: Animals; Behavior, Animal; Cues; Excitatory Amino Acid Antagonists; Extinction, Psychological; Male; Nicotine; Phencyclidine; Photic Stimulation; Rats; Rats, Sprague-Dawley; Reward; Self Administration; Yohimbine
PubMed: 25845436
DOI: 10.1007/s00213-015-3923-0 -
Neuropharmacology Dec 2013Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and...
Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms--two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2-3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles.
Topics: Analysis of Variance; Animals; Antipsychotic Agents; Avoidance Learning; Benzodiazepines; Clozapine; Dibenzocycloheptenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Heterocyclic Compounds, 4 or More Rings; Hyperkinesis; Male; Motor Activity; Olanzapine; Phencyclidine; Rats; Rats, Sprague-Dawley
PubMed: 23954676
DOI: 10.1016/j.neuropharm.2013.05.031 -
The Journal of Physiology Jan 19911. Stable N-methyl-D-aspartic acid (NMDA) receptor-mediated currents in cultured mouse hippocampal neurons were evoked by 20 ms pressure pulse applications of...
1. Stable N-methyl-D-aspartic acid (NMDA) receptor-mediated currents in cultured mouse hippocampal neurons were evoked by 20 ms pressure pulse applications of L-aspartate, repeatedly applied at 30 or 40 s intervals, to the cell body region of the neurone. We have characterized the voltage- and use-dependent blockade of the currents by three dissociative anaesthetics: ketamine, phencyclidine (PCP) and MK-801 in mouse hippocampal neurones grown in dissociated tissue culture. 2. We have used a simple model of the blockade, based on the 'guarded receptor hypothesis' to interpret our data. The model assumes that receptors are maximally activated at the peak of the response with an open probability (Po) approaching 1, that there is no desensitization and that the blocking drug only associates with, or dissociates from, receptor channels which have been activated by agonist (e.g. open channels). 3. The model allows us to estimate forward and reverse rate constants for binding of the blockers to open channels from measurements of the steady-state level of blockade and the rate of change of the current amplitude per pulse during onset and offset of blockade. As predicted by the model, the estimated reverse rate was independent of blocker concentration while the forward rate increased with concentration. Changing the level of positively charged ketamine (pKa 7.5) tenfold by changing pH from 6.5 to 8.5 caused a corresponding change in the forward rate while having no effect on the reverse rate. Most of the voltage dependence of the blockade could be accounted for by reduction of the reverse rate by depolarization. 4. Estimated forward rate constants for ketamine, PCP and MK-801 were similar to one another when measured under similar conditions and were 3 x 10(4) - 3 x 10(5) M-1 S-1. Most of the differences in potency of the three blockers could be accounted for by differences in the reverse rate constants which were approximately 0.2, 0.03 and 0.003 s-1 for ketamine, PCP and MK-801, respectively. The estimated rate constants actually are the product of the rate constants and 1/Po. Suggestions that maximum Po is much less than 1 for NMDA channels imply that both forward and reverse rate constants of blockade may in fact be larger than we have calculated. However, their magnitudes, relative to one another, are unaffected by this consideration. 5. The reverse rate constant of blockade increased at positive potentials. This increase was prevented when the neurone was loaded with N-methyl-D-glucamine, an impermeant cation which prevented outward currents.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Aspartic Acid; Culture Techniques; Dizocilpine Maleate; Hippocampus; Ion Channel Gating; Ketamine; Mice; Mice, Inbred Strains; Neurons; Phencyclidine; Receptors, N-Methyl-D-Aspartate
PubMed: 1832184
DOI: 10.1113/jphysiol.1991.sp018396 -
Pharmacology, Biochemistry, and Behavior Oct 2007Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the...
Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of psilocybin was observed following treatment with the 5-HT(2A) receptor antagonist, M100907. In contrast, no significant antagonism was observed following treatment with the 5-HT(1A/7) receptor antagonist, WAY-100635, or the DA D(2) antagonist, remoxipride. Psilocybin generalized fully to DOM, LSD, psilocin, and, in the presence of WAY-100635, DMT while partial generalization was seen to 2C-T-7 and mescaline. LSD and MDMA partially generalized to psilocybin and these effects were completely blocked by M-100907; no generalization of PCP to psilocybin was seen. The present data suggest that psilocybin induces a compound stimulus in which activity at the 5-HT(2A) receptor plays a prominent but incomplete role. In addition, psilocybin differs from closely related hallucinogens such as 5-MeO-DMT in that agonism at 5-HT(1A) receptors appears to play no role in psilocybin-induced stimulus control.
Topics: Animals; Conditioning, Operant; Data Interpretation, Statistical; Discrimination, Psychological; Dose-Response Relationship, Drug; Generalization, Stimulus; Hallucinogens; Lysergic Acid Diethylamide; Male; N-Methyl-3,4-methylenedioxyamphetamine; Phencyclidine; Psilocybin; Rats; Rats, Inbred F344; Reinforcement Schedule
PubMed: 17688928
DOI: 10.1016/j.pbb.2007.06.003 -
Neuropsychopharmacology : Official... Feb 2012The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)-used as a pharmacological model of schizophrenia-disrupts prefrontal cortex (PFC) activity. PCP...
The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)-used as a pharmacological model of schizophrenia-disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15-4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT(2A) and 5-HT(1A) receptors (5-HT(2A)R and 5-HT(1A)R, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT(2A)R and behaves as partial agonist in vivo at 5-HT(1A)R. We used wild-type (WT) mice and 5-HT(1A)R and 5-HT(2A)R knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n=23, 13, 11, respectively; p<0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT(1A)R antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT(1A)R activation without the need to block 5-HT(2A)R, as observed with clozapine-induced cortical dopamine release.
Topics: Animals; Clozapine; Excitatory Amino Acid Antagonists; Mice; Mice, Knockout; Neurons; Phencyclidine; Piperazines; Prefrontal Cortex; Pyridines; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists
PubMed: 22012474
DOI: 10.1038/npp.2011.249 -
Neuropsychopharmacology : Official... Mar 2024One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved.... (Comparative Study)
Comparative Study
Activation of prefrontal parvalbumin interneurons ameliorates working memory deficit even under clinically comparable antipsychotic treatment in a mouse model of schizophrenia.
One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2-3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60-80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.
Topics: Animals; Humans; Mice; Antipsychotic Agents; Calcium; Chromatography, Liquid; Disease Models, Animal; Interneurons; Memory Disorders; Olanzapine; Parvalbumins; Phencyclidine; Prefrontal Cortex; Receptors, Dopamine D2; Schizophrenia; Tandem Mass Spectrometry
PubMed: 38049583
DOI: 10.1038/s41386-023-01769-z -
The Israel Medical Association Journal... Aug 2005
Topics: Adult; Electrocardiography; Fatal Outcome; Female; Humans; Multiple Organ Failure; Phencyclidine
PubMed: 16106785
DOI: No ID Found -
Brain Research Apr 2009Exposure to methamphetamine (METH) and phencyclidine (PCP) during early development is thought to produce later behavioral deficits. We postulated that exposure to METH...
Exposure to methamphetamine (METH) and phencyclidine (PCP) during early development is thought to produce later behavioral deficits. We postulated that exposure to METH and PCP during later development would produce similar behavioral deficits, particularly learning deficits in adulthood. Wistar rats were treated with METH (9 mg/kg), PCP (9 mg/kg), or saline during later development, postnatal days (PD) 50-51, and subsequent behavioral changes were examined including: locomotor activity during the acute drug state (PD 50-51) and the post-drug phase (PD 50-80); social interaction on PD 54-80; and spatial discrimination and reversal in adulthood (after PD 90). METH and PCP differentially affected locomotion during the acute state, but not during the post-drug phase. METH decreased social interaction throughout tests two weeks after drug treatment, whereas PCP decreased social interaction only during the first 8 min of tests. Neither METH nor PCP impaired initial acquisition of spatial discrimination. However, reversal was significantly impaired by PCP, whereas METH produced a mild deficit, compared to controls. Our data provide evidence that exposure to PCP and METH during later development lead to enduring cognitive deficits in adulthood. Selective impairment of reversal may reflect neurological damage in the prefrontal cortex due to early exposure to drugs.
Topics: Aging; Analysis of Variance; Animals; Conditioning, Operant; Learning; Learning Disabilities; Male; Methamphetamine; Motor Activity; Phencyclidine; Rats; Rats, Wistar; Social Behavior; Spatial Behavior
PubMed: 19245799
DOI: 10.1016/j.brainres.2009.02.024