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Conditioned taste aversions induced by phencyclidine and other antagonists of N-methyl-D-aspartate.

Taste aversions can be conditioned in rats by a variety of psychoactive drugs, including those with reinforcing properties. Previous research, however, has not established clearly whether phencyclidine and related drugs are active in such procedures. The present study was carried out to investigate whether phencyclidine would induce a conditioned taste aversion and whether several other compounds (MK-801, the stereoisomers of NANM and ifenprodil) which, like phencyclidine, are known to antagonise the actions of N-methyl-D-aspartate (NMDA), would produce similar effects. When rats received injections of these compounds, after consuming a novel solution of saccharin, their subsequent consumption of the same solution decreased. The smallest doses of the different drugs which induced clear taste aversions were: phencyclidine 3 mg/kg, MK-801 0.3 mg/kg, (+)-NANM 10 mg/kg, (-)-NANM 3 mg/kg and ifenprodil 10 mg/kg. Thus, all the drugs were active. However, as neither the potencies nor the efficacies of the different compounds in inducing taste aversions correlated with their other behavioural effects or with their relative potencies in antagonising the effects of NMDA or in displacing phencyclidine from its binding sites, the mechanisms involved are unclear.

Adrenergic alpha-Antagonists↗

Phencyclidine prevents spatial navigation and passive avoidance deficits in ibotenate lesioned rats.

The potential neuroprotective effects of phencyclidine (5 mg/kg i.p.) were assessed in rats which had been treated with the excitotoxin, ibotenic acid (IBO) (0.015 M) to lesion the nucleus basalis magnocellularis. IBO treated rats showed a significant impairment in 13 of the 25 test trials in the spatial navigation Morris water maze task and deficits in passive avoidance learning. Phencyclidine was found to prevent the IBO-induced impairment in 4 of the 13 test trials in which the IBO Morris maze deficit was observed and also successfully prevented the passive avoidance learning deficits. Neurochemically, IBO was shown to reduce the levels of gamma amino-n-butyric acid (GABA) in the cortex. This effect of IBO on the inhibitory GABAergic system may contribute to the direct toxic effects of IBO which is mediated through excitatory amino acid receptors. Phencyclidine had no effect on the changes in GABA produced by IBO. The effect of phencyclidine treatment on IBO behavioural toxicity observed in this study demonstrates that antagonism of the phencyclidine receptor site on the N-methyl-D-aspartate receptor complex may be partially protective against the excitotoxic damage induced by IBO.

Animals↗

Phencyclidine in combination with pentobarbital: supra-additive effects on complex operant behavior in patas monkeys.

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When administered alone, phencyclidine and pentobarbital, at the higher doses, generally decreased the overall response rate and increased the percent errors in both components. The performance component tended to be less sensitive than the learning component to the drug effects. When phencyclidine was administered in combination with pentobarbital, the phencyclidine dose-effect curves for both rate and accuracy generally shifted progressively to the left as the dose of pentobarbital was increased. In two of three monkeys, combinations of phencyclidine with a high dose of pentobarbital consistently produced greater rate-decreasing and error-increasing effects than expected from simple addition of the effects of each drug given alone. In other words, the phencyclidine-pentobarbital combinations produced supra-additive effects on responding under the multiple schedule.

Animals↗

Cocaine potentiates the disruptive effects of phencyclidine on repeated acquisition in monkeys.

Patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms. The response chain was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. Each day there were four 15-min sessions, with a 10-min intersession interval. Cumulative dose-effect curves for phencyclidine were obtained by giving an IM injection before each of the four sessions; successive injections increased the cumulative dose by 1/4 log-unit steps. When phencyclidine was administered alone, overall response rate decreased and percent errors increased with increasing doses. When cocaine was injected IM before the first session at a dose that was ineffective when given alone, the phencyclidine dose-effect curves for both rate and accuracy tended to shift to the left. After pretreatment with the lowest effective dose of cocaine, which decreased rate without affecting accuracy when given alone, the rate-decreasing and error-increasing effects of phencyclidine were generally even more pronounced in two of three subjects. The results indicate that cocaine potentiates the disruptive effects of phencyclidine on complex operant behavior in monkeys.

Animals↗

Delta-9-tetrahydrocannabinol potentiates the disruptive effects of phencyclidine on repeated acquisition in monkeys.

Patas monkeys acquired a different four-response chain each session by responding sequentially on three keys or levers in the presence of four discriminative stimuli (geometric forms or numerals). The response chain was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. Each day there were four 15-min sessions, with a 10-min intersession interval. Cumulative dose-effect curves for phencyclidine were obtained by giving an IM injection before each of the four sessions; successive injections increased the cumulative dose by 1/4 log-unit steps. When phencyclidine was administered alone, overall response rate decreased and percent errors increased with increasing doses. When delta-9-tetrahydrocannabinol (THC) was administered PO before the first session at a dose that was ineffective when given alone, the phencyclidine dose-effect curves for both rate and accuracy tended to shift to the left. After pretreatment with a higher dose of THC, which decreased rate in one of three subjects without affecting accuracy when given alone, the rate-decreasing and error-increasing effects of phencyclidine were generally even more pronounced. The results indicate that THC potentiates the disruptive effects of phencyclidine on complex operant behavior in monkeys.

Animals↗

Sensitization to amphetamine and tolerance to cocaine and phencyclidine stimulation in mice.

Amphetamine (1.0-7.0 mg/kg), cocaine (5.0-40.0 mg/kg) and phencyclidine (1.0-7.0 mg/kg) increased acoustic startle responding in mice. These drugs, however, had varying effects on habituation of the startle response after repeated exposure to the auditory stimulus. The primary effect of phencyclidine was to disrupt the habituation process, whereas increased startle responding after cocaine developed without modification of the habituation curve. Amphetamine facilitated acoustic startle at all doses, and after administration of 3.0 mg/kg a significant response sensitization as a function of repeated stimulus presentation was evident. Consistent with previous reports the excitatory effects of cocaine and amphetamine on acoustic startle were blocked by pretreatment with haloperidol. Haloperidol, which decreased startle responding, attenuated the facilitating effects of PCP on acoustic startle as well. Chronic exposure to amphetamine, cocaine and phencyclidine had differential effects on startle responding. The facilitating effects of amphetamine on startle were further enhanced after long-term exposure to the drug and the sensitizing effect of repeated amphetamine exposure was observed only when animals were tested with amphetamine. In contrast, tolerance developed after chronic exposure to both cocaine and phencyclidine, and the response attenuation was evident when animals were tested for acoustic startle after cocaine, amphetamine and phencyclidine.

Animals↗

Effects of calcium antagonists on phencyclidine behaviors.

The calcium antagonists nifedipine and verapamil were evaluated for their potential behavioral interactions with phencyclidine induced changes in mouse rotarod performance and motor activity. Nifedipine (2 and 10 mg/kg) and verapamil (2 mg/kg) significantly potentiated impairment of rotarod performance produced by phencyclidine. These doses of nifedipine and verapamil did not by themselves affect rotarod performance. This action does not appear to be dependent on the hypotensive properties of these drugs, since hypotensive doses of prazosin did not alter the effect of phencyclidine on rotarod performance. Nifedipine, 4.0 mg/kg, antagonized increases in ambulatory motor activity, and potentiated decreases in vertical motor activity (rearing) induced by phencyclidine. The effects of calcium antagonists to alter the behavioral actions of phencyclidine in mice may occur through an interaction with the dihydropyridine calcium antagonist binding site present in the central nervous system.

Animals↗

Acylating phencyclidines irreversibly enhance brain calcium antagonist binding.

Phencyclidine was previously shown to allosterically increase the apparent affinity of the dihydropyridine ( [3H]nitrendipine) calcium antagonist binding site in a lysed synaptosomal membrane preparation of rat forebrain. Treatment of a similar preparation of mouse forebrain with 4-isothiocyanato-1-(1-phenylcyclohexyl) piperidine (FOURPHIT), an acylating phencyclidine derivative, resulted in a concentration dependent (0.1-10 microM), irreversible, increase in the apparent affinity of [3H]nitrendipine in contrast to the effects of phencyclidine which were reversible. The FOURPHIT isomer, 1-[1-(3-isothiocyanatophenyl) cyclohexyl] piperidine (METAPHIT), (10 microM) also irreversibly increased the apparent affinity of [3H]nitrendipine, but was much less efficacious than FOURPHIT. Phencyclidine blocked the irreversible increase in the apparent affinity of [3H]nitrendipine produced by FOURPHIT. The interactions of multivalent cations and the calcium antagonist diltiazem with the [3H]nitrendipine binding site were altered following treatment of membranes with FOURPHIT. These studies suggest that FOURPHIT irreversibly interacts with the same sites as PCP, and thus may be a useful tool with which to further probe both the behavioral and biochemical interactions between phencyclidine and the dihydropyridine calcium antagonist binding site.

Animals↗

Enhancement of brain calcium antagonist binding by phencyclidine and related compounds.

The abilities of compounds structurally or pharmacologically related to phencyclidine to increase the apparent affinity of the [3H]dihydropyridine calcium channel antagonist [3H]nitrendipine were examined in lysed synaptosomal membrane preparations of rat brain. The p-bromo analog of phencyclidine (1-(1-(4-bromophenyl)cyclohexyl)piperidine) was the most efficacious compound tested in enhancing the apparent affinity of [3H]nitrendipine. The efficacy of this compound was approximately two-fold greater than PCP. The stereoisomers of PCMP (1-(1-phenylcyclohexyl-3-methylpiperidine) were also more efficacious than phencyclidine, although only a small degree of stereoselectivity was observed. Levoxadrol, dexoxadrol and the enantiomers of ketamine did not potentiate [3H]nitrendipine binding. The enantiomers of SKF 10047 (n-allylormetazocine), dextrorphan, levorphanol and the ion channel toxins histrionicotoxin and pumiliotoxin-B also increased the apparent affinity of [3H]nitrendipine, while several local anesthetics and mu-opiate receptor ligands were without effect. These studies suggest that the ability of phencyclidine and structurally related compounds to increase the apparent affinity of [3H]nitrendipine is not mediated through an interaction with phencyclidine receptors, but may represent a unique site for allosteric modulation of neuronal dihydropyridine calcium channel antagonist binding sites.

Anesthetics, Local↗

Effects of phencyclidine, ketamine and MDMA on complex operant behavior in monkeys.

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three levers in the presence of four numerals (acquisition). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. After IM administration, phencyclidine, ketamine, and MDMA (3,4-methylenedioxymethamphetamine or "ecstasy") each produced dose-related decreases in overall response rate in both schedule components, though ketamine and MDMA were less potent (on a mg/kg basis) than phencyclidine. At high doses of each drug, the marked decrease in overall response rate was due primarily to a long initial pause. Ketamine was similar to phencyclidine in producing dose-related increases in percent errors in both schedule components, but the maximal error-increasing effect was considerably smaller with ketamine. This quantitative difference appeared to be related to the shorter duration of ketamine's effects on accuracy. Unlike phencyclidine and ketamine, MDMA had no effect on accuracy in either acquisition or performance. The results indicate that MDMA disrupts complex operant behavior to a lesser extent than phencyclidine-type drugs.

3,4-Methylenedioxyamphetamine↗

Phencyclidine-induced behavioral sensitization.

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.

Animals↗

Phencyclidine-induced expression of c-Fos-like immunoreactivity in mouse brain regions.

For the purpose of studying a role of immediate early genes in psychotomimetic-induced behavioral excitation, we experimentally enhanced the locomotor activity of mice by acute administration of phencyclidine and examined the expression and localization of the c-Fos-like and c-Jun-like immunoreactivities in brain regions. A single injection of phencyclidine (5.0 mg/kg, i.p.) significantly increased not only the locomotor activity but also the expression of c-Fos-like immunoreactivity in several brain regions, particularly in the parietal cortex, hippocampal dentate gyrus, piriform cortex and hypothalamus. Interestingly, the c-Fos-like immunoreactivity in the parietal cortex continued to increase for 1 week after the phencyclidine injection. These results indicate that phencyclidine, even injected only once, can induce the persistent expression of c-Fos or c-Fos-related protein(s) in the mouse brain, and also suggest the possibility that such a c-Fos expression may underlie the behavioral and/or psychotomimetic effects of phencyclidine.

Analysis of Variance↗

The effects of phencyclidine on spontaneous aggressive behavior in the rat.

Phencyclidine induced dose-related alterations in the pattern of spontaneous aggressive behavior in pairs of rats, in which only one animal of each pair was drug-treated. At the lowest dose tested (0.25 mg/kg, sc), phencyclidine produced attacks by the drug-treated animal and a corresponding increase in submissive behavior by the untreated partner, as well as an increase in boxing behavior by both animals. In contrast, the highest dose of phencyclidine tested (1.0 mg/kg, sc) elicited attacks and allogrooming by the untreated animal. The low dose effect is interpreted as the result of phencyclidine-induced distortion in perception of social cues, while the high dose effect may be due to a general disruption in social communication by ataxia in the phencyclidine-treated animal.

Aggression↗

Actions of phencyclidine on rat locus coeruleus neurones in vitro.

Intracellular recordings were made from neurones in the rat locus coeruleus in a brain slice maintained in vitro. Phencyclidine and related psychotomimetic drugs, applied in known concentrations in the fluid bathing the slice, depressed responses to N-methyl-D-aspartic acid noradrenaline (in the presence of the uptake inhibitor desmethylimipramine) and [D-Ala2,MePhe4,Gly-ol5]enkephalin and also prolonged the action potential. The sensitivities of these responses to depression by phencyclidine was N-methyl-D-aspartic acid (IC50 0.4 microM) greater than noradrenaline (IC50 3.9 microM) greater than [D-Ala2,MePhe4,Gly-ol5]enkephalin (IC50 8.5 microM) greater than prolongation of the action potential (41% increase by 30 microM). Stereoselectivity was observed only in the depression of responses to N-methyl-D-aspartic acid where (+)-1-(1-phenylcyclohexyl)-3-methyl piperidine was 3.3-fold more potent in suppressing N-methyl-D-aspartic acid depolarizations than its (-) isomer. The responses to N-methyl-D-aspartic acid were also depressed by the structurally unrelated psychotomimetic (+/-)-N-allyl-N-normetazocine (IC50 0.9 microM). All of the effects of the psychotomimetic drugs examined were slow in onset and difficult to reverse following washout. No effect of phencyclidine (0.03-100 microM) or related drugs was observed on membrane potential, input resistance or spontaneous action potential firing rate of locus coeruleus neurones. The depression of responses to N-methyl-D-aspartic acid by phencyclidine was the most potent and the only stereoselective effect of those studied. The importance of this effect and of those not showing stereoselectivity in relation to the phencyclidine behavioural syndrome is discussed.

Action Potentials↗

Tolerance following the repeated administration of high doses of phencyclidine: no relation to central catecholamine depletion.

The tolerance which develops following the repeated administration of phencyclidine has been attributed to both pharmacological and behavioral adaptations. In the present study, the possibility that neurochemical alterations induced by the repeated administration of phencyclidine might account for some portion of the observed tolerance was examined. Specifically, it was postulated that the repeated administration of high doses of phencyclidine might result in long lasting depletion of central catecholamine stores and that this neurochemical perturbation might result in tolerance to the drug's effects. It was observed that phencyclidine disrupted the performance of rats on a fixed-interval schedule maintained by water presentation. The repeated administration of high doses of phencyclidine (but not of a comparable volume of saline) during a period when subjects were not engaged in the fixed-interval task resulted in the development of a long lasting tolerance, but this tolerance could not be accounted for in terms of a depletion of central catecholamine stores.

Animals↗

Phencyclidine-induced changes in rat cortical gene expression identified by microarray analysis: implications for schizophrenia.

Acute phencyclidine induces schizophrenia-like symptoms in healthy humans and psychotic episodes in schizophrenics. Although phencyclidine is known as a N-methyl d-aspartate receptor antagonist (NMDA-R), the molecular events underlying the behavioral symptoms remain largely unknown. Statistical analysis of oligonucleotide microarray data was used to identify phencyclidine-induced alterations in rat cortical gene expression. Acute phencyclidine produced a statistically significant change in 477 genes in rat prefrontal cortex (PFC), a brain area associated with cognitive dysfunction in schizophrenics. Real-time quantitative PCR (RTQ-PCR) confirmed a subset of these changes ranging from -59% to 255% (smallest confirmation: -19%). Subsequent time-course and dose-response studies using RTQ-PCR confirmed and extended the original microarray results. At the molecular level, genes altered by phencyclidine are related to diverse biological processes including stress, inflammatory response, growth and development, neural plasticity and signal transduction. Further analysis, aimed at assessing the relevance of our results to schizophrenia, revealed dysregulation of genes related to: (i) thalamocortical projections, (ii) neurotransmission and neuromodulation, (iii) thyroid hormone activity, (iv) oligodendrocyte linage, (v) brain lipid metabolism, (vi) sleep architecture and (viii) the velocardiofacial syndrome.

Animals↗

Involvement of serotonin 2A receptors in phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats.

BACKGROUND: The disruption of prepulse inhibition of acoustic startle (PPI) is an animal model for some aspects of schizophrenia. Phencyclidine causes psychotomimetic symptoms in human and disrupts PPI in animals, however, the mechanism underlying this disruption remains unclear. The present experiment tested the hypothesis that serotonin 2A receptor blocking property of drugs reverses the phencyclidine-induced PPI disruption. METHODS: The ED50 value of spiperone, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, seroquel, pipamperone, mianserin, or desipramine to reverse the phencyclidine- or apomorphine-induced PPI disruption in rats was determined. Then the correlation between the ED50 value and the affinity for the serotonin 2A, 2C, dopamine D2, or alpha-1 receptor of each drug was examined. RESULTS: The ED50 value of the drugs to reverse the phencyclidine-induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D2, serotonin 2C, or alpha-1 receptor of each drug. In contrast, the ED50 value of the drugs to reverse the apomorphine-induced PPI disruption was significantly correlated with the affinity for the dopamine D2 receptor, but not for the serotonin 2A receptor. CONCLUSIONS: An activation of serotonin 2A receptors would mediate the phencyclidine-induced PPI disruption.

Animals↗

Effects of scopolamine in comparison with apomorphine and phencyclidine on prepulse inhibition in rats.

The potential involvement of the muscarinic cholinergic system in the underlying mechanisms of prepulse inhibition of the acoustic startle reflex was evaluated in male Sprague-Dawley rats under conditions of varying dose, prepulse intensity, and interstimulus interval. The effects of scopolamine on prepulse inhibition were also directly compared with the effects observed using apomorphine and phencyclidine under the same test parameters. Scopolamine (0. 03-1.0 mg/kg) produced a significant dose-dependent decrease in prepulse inhibition, but had no effect on startle amplitude over the dose range tested. Apomorphine (0.03-1.0 mg/kg) and phencyclidine (0. 1-5.6 mg/kg) produced significant dose-dependent decreases in prepulse inhibition and changes in startle amplitude. The scopolamine-induced decrease in prepulse inhibition varied with prepulse intensity in that the changes produced by scopolamine became smaller in magnitude as the prepulse intensity was increased from 9 to 30 dB above background. On the other hand, apomorphine and phencyclidine decreased prepulse inhibition to approximately the same magnitude across all prepulse intensities tested. The observed decreases in prepulse inhibition produced by scopolamine, apomorphine, and phencyclidine were also dependent on interstimulus interval duration. Scopolamine produced marked decreases in prepulse inhibition at the 100- and 300-ms interstimulus interval durations, but had little or no effect on prepulse inhibition at the 30- and 1000-ms interstimulus interval durations. In contrast, apomorphine decreased prepulse inhibition across all interstimulus interval durations while phencyclidine decreased prepulse inhibition across the 30- to 300-ms interstimulus interval durations. The present findings support the hypothesis that the muscarinic cholinergic system, like the dopaminergic and glutamatergic systems, is directly involved in the mechanisms of prepulse inhibition. However, these three neurotransmitter systems appear to modulate different aspects of prepulse inhibition.

Acoustic Stimulation↗