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Pharmacology, Biochemistry, and Behavior Mar 1994Chronic administration of a psychomotor stimulant has been shown to produce progressively enhanced effects, a phenomenon called "reverse tolerance" or sensitization. The...
Chronic administration of a psychomotor stimulant has been shown to produce progressively enhanced effects, a phenomenon called "reverse tolerance" or sensitization. The present study reexamined the effects of the daily injection of phencyclidine on locomotor activity and stereotypy in rats, and investigated whether drug-environment conditioning was necessary for the development of behavioral sensitization and whether (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,1 0-imine hydrogen maleate (MK-801, dizocilpine) blocked behavioral sensitization to phencyclidine. Female Sprague-Dawley rats were used. Locomotor activity and stereotypy were measured automatically with the Digiscan system. The results confirmed an earlier finding that four daily injections of phencyclidine induced sensitization to both locomotor activity and stereotypy. The development of behavioral sensitization did not require drug-environment conditioning. Moreover, MK-801 did not block behavioral sensitization to phencyclidine. The results of the present study suggest that the neuronal mechanisms underlying sensitization to phencyclidine are different from those underlying sensitization to amphetamine and cocaine.
Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Female; Motor Activity; Phencyclidine; Rats; Rats, Sprague-Dawley; Stereotyped Behavior
PubMed: 8208780
DOI: 10.1016/0091-3057(94)90165-1 -
The International Journal of... May 2022Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R...
Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.
Topics: Animals; Antipsychotic Agents; Brain; Hippocampus; Nucleus Accumbens; Phencyclidine; Prefrontal Cortex; Quinolines; Rats; Receptors, Serotonin; Serotonin Antagonists
PubMed: 35022720
DOI: 10.1093/ijnp/pyac003 -
The Israel Journal of Psychiatry and... 2010Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic... (Review)
Review
Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 20 years, however, limitations of the dopamine model have become increasingly apparent, necessitating development of alternative models. Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate NMDA receptor-mediated neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Encouraging results have been observed as well with agents such as metabotropic 2/3 agonists that decrease resting glutamate levels, reversing potential disruption in firing patterns within prefrontal cortex and possibly other brain regions. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.
Topics: Animals; Brain; Dopamine; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Ketamine; Nerve Net; Phencyclidine; Prefrontal Cortex; Psychological Theory; Receptors, Dopamine D2; Receptors, Glutamate; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission
PubMed: 20686195
DOI: No ID Found -
The International Journal of... May 2021Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant...
BACKGROUND
Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the development of effective therapeutics. One assay of reward learning characterized by orderly behavioral and pharmacological findings in both humans and rats is the probabilistic reward task. In this computerized task, subjects make discriminations across numerous trials in which correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy control subjects reliably develop a response bias to the rich alternative. However, participants with major depressive disorder as well as rats exposed to chronic stress typically exhibit a blunted response bias.
METHODS
The present studies validated a touchscreen-based probabilistic reward task for the marmoset, a small nonhuman primate with considerable translational value. First, probabilistic reinforcement contingencies were parametrically examined. Next, the effects of ketamine (1.0-10.0 mg/kg), a US Food and Drug Administration-approved rapid-acting antidepressant, and phencyclidine (0.01-0.1 mg/kg), a pharmacologically similar N-methyl-D-aspartate receptor antagonist with no known antidepressant efficacy, were evaluated.
RESULTS
Increases in the asymmetry of rich:lean probabilistic contingencies produced orderly increases in response bias. Consistent with their respective clinical profiles, ketamine but not phencyclidine produced dose-related increases in response bias at doses that did not reduce task discriminability.
CONCLUSIONS
Collectively, these findings confirm task and pharmacological sensitivity in the marmoset, which may be useful in developing medications to counter anhedonia across neuropsychiatric disorders.
Topics: Anhedonia; Animals; Antidepressive Agents; Behavior, Animal; Callithrix; Excitatory Amino Acid Antagonists; Ketamine; Male; Neuropsychological Tests; Phencyclidine; Probability Learning; Reward; Translational Research, Biomedical
PubMed: 33280005
DOI: 10.1093/ijnp/pyaa090 -
Neuroscience Bulletin Apr 2015The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In... (Review)
Review
The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In addition to the features typical of schizophrenia, patients also present with aspects of cognitive disorders. Based on these relationships, a monkey model mimicking the cognitive symptoms of schizophrenia has been made using treatment with the non-specific competitive N-methyl-D-aspartate receptor antagonist, phencyclidine. The symptoms are ameliorated by atypical antipsychotic drugs such as clozapine. The beneficial effects of clozapine on behavioral impairment might be a specific indicator of schizophrenia-related cognitive impairment.
Topics: Animals; Antipsychotic Agents; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Antagonists; Haplorhini; Phencyclidine; Prefrontal Cortex; Psychomotor Performance; Schizophrenia
PubMed: 25822218
DOI: 10.1007/s12264-014-1506-4 -
Progress in Neuro-psychopharmacology &... Apr 2012Mescaline and phencyclidine (PCP) are potent hallucinogenic agents affecting human and animal behavior. As their psychotropic effects remain poorly understood, further... (Comparative Study)
Comparative Study
Mescaline and phencyclidine (PCP) are potent hallucinogenic agents affecting human and animal behavior. As their psychotropic effects remain poorly understood, further research is necessary to characterize phenotypes they evoke in various animal models. Zebrafish (Danio rerio) are rapidly emerging as a new model organism for neuroscience research. Here, we examine the effects of mescaline (5-20mg/l) and PCP (0.5-3mg/l) in several zebrafish paradigms, including the novel tank, open field and shoaling tests. Mescaline and PCP dose-dependently increased top activity in the novel tank test, also reducing immobility and disrupting the patterning of zebrafish swimming, as assessed by ethograms. PCP, but not mescaline, evoked circling behavior in the open field test. At the highest doses tested, mescaline markedly increased, while PCP did not affect, zebrafish shoaling behavior. Finally, 20mg/l mescaline did not alter, and 3mg/l PCP elevated, whole-body cortisol levels. Overall, our studies indicate high sensitivity of zebrafish models to hallucinogenic compounds with complex behavioral and physiological effects.
Topics: Animals; Behavior, Animal; Hallucinogens; Mescaline; Models, Animal; Motor Activity; Phencyclidine; Zebrafish
PubMed: 22251567
DOI: 10.1016/j.pnpbp.2012.01.003 -
Methods and Findings in Experimental... Sep 1998Place conditioning paradigms are widely used for determining the motivational properties of drugs. Phencyclidine (PCP) has been a common drug of abuse during the past... (Review)
Review
Place conditioning paradigms are widely used for determining the motivational properties of drugs. Phencyclidine (PCP) has been a common drug of abuse during the past two decades and has a rewarding effect in animals. However, PCP produces place aversion in the conditioned place preference (CPP) task in animals. Here, we report the possible neuronal mechanisms of PCP-induced place aversion and preference in the CPP task in rodents. In naive rats and mice, PCP dose-dependently produced place aversion and PCP had a significant effect at the doses of 4 and 8 mg/kg in rats and mice, respectively. The aversive effect of PCP (4 mg/kg) in rats was significantly attenuated by ritanserin (3 and 10 mg/kg), a serotonin 15-HT2) receptor antagonist whereas the lesion of serotonergic (5-HTergic) neurons by 5,7-dihydroxytryptamine (100 micrograms i.c.v.) and alpha-methyl-rho-tyrosine (AMPT; 100 mg/kg), a tyrosine hydroxylase inhibitor, did not affect the aversive effect of PCP. In rats pretreated with PCP (10 mg/kg/day) for 14 days, tolerance was developed to PCP (4 mg/kg)-induced place aversion. In rats and mice pretreated with PCP (10 mg/kg/day) for 28 days, however, PCP dose-dependently produced place preference but not aversion. The preferred effect of PCP (8 mg/kg) in mice preteated with PCP (10 mg/kg/day for 28 days) was significantly attenuated by AMPT (100 mg/kg) and 6-hydroxydopamine (100 micrograms i.c.v.) a dopaminergic (DAergic) neurotoxin, but not by DSP-4 (30 mg/kg), a noradrenergic neurotoxin and ritanserin. In mice pretreated with methamphetamine (1 mg/kg/day) for 14 days, PCP (8 mg/kg) produced place preference. These findings suggest that 5-HTergic and DAergic systems are involved in the PCP-induced place aversion and preference, respectively, and some changes in the neuronal systems including DAergic systems, induced by repeated PCP treatment play a critical role in the addiction of PCP.
Topics: Animals; Avoidance Learning; Conditioning, Operant; Excitatory Amino Acid Antagonists; Humans; Mice; Nervous System; Nervous System Physiological Phenomena; Phencyclidine; Rats
PubMed: 9819806
DOI: 10.1358/mf.1998.20.7.485726 -
Pharmacology, Biochemistry, and Behavior May 2017The present study investigated the potential sex differences in repeated aripiprazole (ARI) treatment-induced behavioral sensitization from adolescence to adulthood, and...
The present study investigated the potential sex differences in repeated aripiprazole (ARI) treatment-induced behavioral sensitization from adolescence to adulthood, and to determine whether ARI sensitization can be transferred to olanzapine (OLZ) and/or clozapine (CLZ) using the conditioned avoidance response (CAR) and phencyclidine-induced (PCP) hyperlocomotion tests of antipsychotic activity. Male and female Sprague-Dawley adolescence rats (P46) were first treated with ARI (10mg/kg) for 5 consecutive days (P46-50) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion. After they became adults (>P68), rats were challenged with ARI (1.5mg/kg, sc) (P70), OLZ (0.5mg/kg, sc; P73), CLZ (5mg/kg, sc; P76) and again with ARI (1.5mg/kg, sc; P84) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion again. During the drug treatment period in adolescence, repeated ARI treatment suppressed avoidance response, inhibited the PCP-induced hyperlocomotion, and these effects were progressively increased across the 5-day period in both males and females, confirming the induction of ARI sensitization. On the challenge days, rats previously treated with ARI in adolescence also had significantly lower avoidance and lower PCP-induced hyperlocomotion than the previous vehicle rats, confirming the expression of ARI sensitization and its persistence into adulthood. More importantly, female rats made significantly more avoidances than males in both ARI and vehicle groups, indicating higher sensitivity to the acute and long-term effects of ARI. Further, on the OLZ and CLZ challenge days, prior ARI treatment seemed to increase sensitivity to OLZ exposure, however, this increase was not significant. Similarly, rats also showed an ARI sensitization to OLZ and CLZ on challenge days. Collectively, results from this experiment demonstrated a sex difference in response to ARI and enhanced inhibition of PCP-induced hyperlocomotion in animals that were pretreated with ARI as compared to controls.
Topics: Age Factors; Animals; Antipsychotic Agents; Aripiprazole; Avoidance Learning; Female; Locomotion; Male; Phencyclidine; Rats; Rats, Sprague-Dawley; Sex Factors
PubMed: 28389140
DOI: 10.1016/j.pbb.2017.04.001 -
Neuropharmacology May 2018Methoxetamine (MXE) is a novel drug of abuse that is structurally similar to phencyclidine (PCP). In the present study, rats were trained to discriminate PCP from saline...
Methoxetamine (MXE) is a novel drug of abuse that is structurally similar to phencyclidine (PCP). In the present study, rats were trained to discriminate PCP from saline and substitution tests were performed with arylcyclohexylamines PCP, eticyclidine (PCE), tenocyclidine (TCP), and MXE. PCP and PCE engendered PCP-lever selection in all subjects, whereas MXE and TCP produced PCP-lever selection in animals that did not display behavioral disruption. Last, the substituted tryptamine dipropyltryptamine (DPT) produced moderate PCP-lever selection and elicited behavioral disruption in all subjects at the highest dose tested. Immediately following the final substitution test in the drug discrimination experiment, the same rats and a separate group of experimentally-naïve rats were implanted with osmotic mini-pumps delivering continuous PCP infusions for 11 days. Consistent with PCP withdrawal, disruption of food-maintained operant responding was observed when the pumps were removed, but cumulative MXE administration dose-dependently reversed this effect. A third group of rats self-administered several unit doses of PCP and MXE. Results of the self-administration tests revealed that MXE was a less effective reinforcer than PCP. Lastly, mice were implanted with radiotelemetry probes to simultaneously monitor thermoregulatory and locomotor responses following injections of PCP, PCE, or MXE. All three arylcyclohexylamines elicited dose-dependent hypothermic effects, but only PCP produced increases in locomotor activity. Together, these findings indicate that MXE elicits PCP-like interoceptive effects, but reduced reinforcing and locomotor stimulant effects in vivo. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
Topics: Animals; Body Temperature; Cyclohexanones; Cyclohexylamines; Discrimination, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Illicit Drugs; Locomotion; Male; Mice; Phencyclidine; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome; Telemetry
PubMed: 28830759
DOI: 10.1016/j.neuropharm.2017.08.028 -
Epilepsy & Behavior : E&B Jun 2007Phencyclidine (PCP), ketamine (Special K), and MK-801 are noncompetitive N-methyl-d-aspartate (NMDA) antagonists that produce acute psychosis in humans. The psychosis... (Review)
Review
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
PubMed: 17416210
DOI: 10.1016/j.yebeh.2007.02.014