Doses Of PCP Research Articles

Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats

Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled–unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP.

Potentiation of DOM-induced stimulus control by non-competitive NMDA antagonists: A link between the glutamatergic and serotonergic hypotheses of schizophrenia

The present investigation examined the interaction between 2,5-dimethoxy-4-methylamphetamine [DOM] and non-competitive NMDA antagonists in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with phencyclidine [PCP] at a dose of 3 mg/kg shifted the DOM dose-response relationship to the left. When a fixed dose of DOM [0.1 mg/kg] which by itself yielded 32% DOM-appropriate responding was combined with a range of doses of PCP, dizocilpine, and ketamine, DOM-appropriate percentages increased to maxima of 73%, 84%, and 79%, respectively. When given alone, PCP, dizocilpine, and ketamine were followed by maxima of 36%, 15%, and 13%, respectively. It is concluded that the effects of DOM as a discriminative stimulus are potentiated by pretreatment with non-competitive antagonists of glutamate receptors of the NMDA subtype. These data suggest that the application of the technique of drug-induced stimulus control may prove useful in the reconciliation and integration of current hypotheses as to the etiology of psychotic disorders.

Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5‐HT2A sites for PCP‐induced locomotion in the rat

In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

We have characterized excitatory effects of non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine in the rat entorhinal cortex and in cultured primary entorhinal cortical neurons using expression of immediate early gene c-fos as an indicator. NMDA receptor antagonists produced a strong and dose-dependent increase in c-fos mRNA and protein expression confined to neurons in the layer III of the caudal entorhinal cortex. Induction of c-fos mRNA is delayed and it is inhibited by antipsychotic drugs. Cultured entorhinal neurons are killed by high doses of MK-801 and PCP but c-fos expression is not induced in these neurons indicating that this in vitro model does not fully replicate the in vivo effects of PCP-like drugs in the entorhinal cortex. Excitatory effects of the NMDA receptor antagonists may be connected with the psychotropic side effects of these drugs and might become a useful model system to investigate neurobiology of psychosis.

In Vitro and In Vivo Inhibition of Rat Brain Nitric Oxide Synthase Activity by Phencyclidine

Phencyclidine (PCP) is a widely abused psychoactive drug that perturbs many neurotransmitter systems studied to date. Nitric oxide (NO) has been established as a neuronal messenger and its rapid diffusibility across cell membranes makes NO an extensive and versatile messenger in brain development and functioning. The present study was initiated to investigate the effect of PCP on rat brain nitric oxide synthase (NOS) activity both in vitro and in vivo. Brain cytosolic fractions from normal rats were used for in vitro and in vivo studies. The rats were treated with a single dose of PCP (10 mg/kg, intraperitoneally); the brains were removed at 0, 1, 2, 6, and 12 hours after PCP treatment and the cytosolic fractions were prepared by homogenization and centrifugation. NOS activity was assessed by quantifying the release of [3H]-citrulline from [3H]-arginine. PCP significantly inhibited rat brain NOS in vitro in a concentration (0.05–2 mM)-dependent manner. The kinetic evaluation of arginine, NADPH, and Ca2+ activation of NOS revealed that PCP (0.5 mM) inhibited NOS activity competitively with respect to arginine and NADPH and noncompetitively inhibited with respect to Ca2+. PCP also caused a time-dependent reduction of brain NOS activity in vivo as early as 1 hour after treatment. Even after 12 hours of PCP treatment, NOS activity did not reverse to its normal level as compared to the control group, suggesting sequestration and persistence of the drug in the central nervous system. These results suggest that inhibition of brain NOS by PCP might be one of the mechanisms through which PCP causes neurotoxicity.

Inhibition of calcium ATPase by phencyclidine in rat brain.

Phencyclidine (PCP) is a potent psychotomimetic drug of abuse and has profound effect on the functioning of the central nervous system (CNS). Many of the CNS functions are known to be mediated by calcium (Ca2+). In the present study we have investigated the effects of PCP on Ca2+ ATPase activity in rat brain both in vitro and in vivo. For in vitro studies, synaptic membrane fractions prepared from normal rat brain were incubated with PCP at different concentrations (25-100 microM) before the addition of substrate. For in vivo studies, rats were treated with a single moderate dose of PCP (10 mg/kg, i.p.) and animals were sacrificed at 1,2, 6 and 12 h after treatment. Ca2+ ATPase activity in synaptic membrane fractions was assayed by estimation of inorganic phosphate. PCP inhibited the Ca2+ ATPase in vitro in a concentration dependent manner with significant effect at 50 and 100 microM. A significant time-dependent reduction of the Ca2+ ATPase activity was evident in vivo. As early as 2 h after the treatment of rats with PCP the ATPase activity was significantly reduced. The reduction of Ca2+ ATPase observed even at 12 h after treatment suggesting a prolonged presence of the drug in the brain tissue. Further, kinetic studies in vitro indicated PCP to be a competitive inhibitor of Ca2+ ATPase with respect to the substrate, ATP. The present findings indicate that PCP inhibits synaptic membrane Ca2+ ATPase thus altering cellular Ca2+ homeostasis in CNS which may partially explain the pharmacological effects of the drug and/or its neurotoxicity.

Simulation of psychosis by continuous delivery of phencyclidine from controlled-release polymer implants

To simulate psychosis in rats we have developed a method for the continuous delivery of phencyclidine (PCP) using implantable controlled-release polymers. PCP polymer implants produced deficits in latent inhibition which do not occur after repeated bolus injections. PCP implanted rats were also devoid of any anxiogenic signs, motoric hyperactivity and learning acquisition which can be seen in rats receiving daily bolus injections of a comparable PCP dose. This behavioral double-dissociation of the two modes of PCP application was accompanied by respective neurochemical changes. PCP binding sites were reduced in both striatum and hippocampus, but in the hippocampus, loss of PCP binding sites was more severe following pulsatile PCP administration. Morphological assessment revealed a significant shrinkage of the CA3 region in hippocampus in both groups. Pharmacokinetic analysis showed that the maximum PCP concentration in the brain after bolus injections was 10-fold above the PCP implants.

The Delayed Effects of Phencyclidine (Pcp) Disrupt Latent Inhibition in a Conditioned Taste Aversion Paradigm

The acute effects of a low dose of phencyclidine (PCP) and the delayed effects of a high dose of PCP on latent inhibition (LI) were assessed in a series of experiments using conditioned taste aversion paradigms. Each paradigm involved a preexposure phase in which water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE), followed by a conditioning phase in which animals were allowed access to sucrose and subsequently injected with the negative reinforcer lithium chloride, and a test phase in which animals were allowed access to both sucrose and water. LI was assessed by comparing the %-sucrose consumed in PE and NPE groups on the test day. The effects of low-dose PCP (2.5 mg/kg) were assessed by comparing LI in animals treated with vehicle or PCP 15 min prior to the onset of the preexposure and conditioning phases. A 4-day paradigm involved 2 days of preexposure followed by a day of conditioning and a test day. This paradigm produced comparable levels of LI in vehicle and PCP-treated animals. A 5-day extinction paradigm involved 2 days of preexposure followed by 2 days of conditioning and a test day. This paradigm abolished LI in vehicle and PCP-treated animals. A 3-day paradigm involved 1 day of preexposure followed by a day of conditioning and a test day. One day of preexposure induced a modified LI effect in both in vehicle and PCP-treated animals. The delayed effects of high dose PCP (8.6 mg/kg) were assessed by comparing LI in animals treated with vehicle or PCP 20 h prior to the onset of the preexposure and conditioning phases in the 4-day paradigm. PCP disrupted latent inhibition in this paradigm. The results are discussed in the context of their relevance to the ability for PCP to model schizophrenic symptomatology.

Acquisition of oral phencyclidine (PCP) self-administration in rhesus monkeys: effects of dose and an alternative non-drug reinforcer.

The effects of drug dose and a non-drug alternative reinforcer on acquisition of oral PCP self-administration in rhesus monkeys were examined. Acquisition was studied using three groups of monkeys (seven subjects per group). One group received a low PCP dose (0.0375 mg/delivery) and the other two received a high PCP dose (0.15 mg/delivery). One of the high dose groups had concurrent access to a saccharin solution (0.03% w/v) and water during the intersession (17.5-h) period. Food non-restricted monkeys were initially given access to water under a fixed-ratio (FR) 1 schedule during daily 3-h sessions. Water was then replaced with PCP during the session. The monkeys were then reduced to 85% of their free-feeding body weights and fed before the session, and the FR value was increased from 1 to 2, 4 and 8. Subsequently, food was given post-session and water and PCP were available under concurrent FR 8 schedules. At this final step of the procedure, acquisition of PCP self-administration was considered to occur if PCP intake consistently exceeded water intake. When all three groups were given concurrent access to PCP and water, PCP intake was greater than water intake only in the group of monkeys receiving the high PCP dose. PCP intake increased when water replaced saccharin during intersession in the high PCP dose group. Within-group data revealed that 85.7% of monkeys acquired PCP reinforcement in the group given access to the high PCP dose while only 42.8% acquired in the other two groups. These data suggest that drug dose and presence of alternative non-drug reinforcers affect acquisition of drug self administration in non-human primates.

Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain.

The mRNA expression pattern for four different immediate early genes was examined dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6 mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1 and 48 hours. cfos mRNA was induced in cortical areas at early times after either dose of PCP or of MK801; the change was especially prominent in cingulate and auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed (24-48 hour) suppression after PCP and MK801 in neocortical areas. PCP also caused cjun and junB mRNA induction in cortical areas at early times, with a distribution and time course similar to its effects on cfos mRNA. No alterations in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any delayed time (>6 hours) after PCP treatment, whereas suppression of zif268 expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA antagonist, showed a similar pattern of effects on cfos and zif268 mRNA expression. These functional consequences of a PCP- or MK801-induced reduction in NMDA-sensitive glutamate transmission may be relevant to an understanding of animal NMDA pharmacology and/or to clinical psychotomimetic side effects of antiglutamatergic treatments.

Modulation of phencyclidine-induced changes in locomotor activity and patterns in rats by serotonin.

To test the hypothesis that serotonergic modulation of the effects of phencyclidine (PCP) are due to circuit- rather than receptor-based interactions between glutamatergic and serotonergic systems, multivariate profiles of rat behavior were assessed after treatments with the 5-hydroxytryptamine (5-HT) 5-HT2 receptor antagonist ketanserin (1.0 mg/kg), the 5-HT2 receptor agonist (1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (DOI; 0.27 mg/kg), various doses of PCP (0.75 to 10.125 mg/kg), or combinations thereof. Ketanserin blocked all effects of DOI, but reduced the effects of PCP only on locomotion. Depending on the dose, PCP was observed to increase or decrease locomotion and the roughness of the rats' patterns of locomotion. In any case, DOI always increased the activity and decreased the roughness of locomotor paths in PCP-treated rats. Thus, co-administration of DOI and PCP did not yield a shift in the dose-effect curve for either drug, but instead resulted in a new behavioral profile consistent with a circuit-based dynamic interaction.

A time-activity baseline to measure pharmacological and non-pharmacological manipulations of PCP-induced activity in mice.

At critical doses of PCP (10 mg/kg i.p. in the present studies), locomotor stimulation in mice is initially suppressed by short-lasting ataxia, albeit at higher levels of activity than controls. This provides a time-activity baseline of PCP-stimulated locomotion potentially sensitive to i) pharmacological antagonism indicated by a change in the time-activity relationship to that seen at lower PCP doses, ii) interaction with the ataxic phase resulting in further decreases in activity similar to that seen at higher PCP doses and iii) reductions in activity without a change in the time-activity relationship. This baseline was explored using three manipulations employed in the clinical management of PCP toxicity: treatment with a neuroleptic (haloperidol), a benzodiazepine (chlordiazepoxide) and modification in environmental stimulation (changing of lighting conditions). Both haloperidol (0.125-0.5 mg/ kg, i.p.) and chlordiazepoxide (5-20 mg/kg i.p.) further reduced activity during the ataxic phase of the PCP time-activity relationship qualitatively similar to the effects of pentobarbital (20-40 mg/kg i.p.). Changing of lighting conditions from red to white light resulted in significant reductions in levels of activity of PCP-treated animals but no change in the time-activity relationship. No manipulation resulted in true reversal of the PCP induced time-activity relationship. The results parallel the clinical findings that neuroleptic and benzodiazepine administration have no specific effects upon PCP-intoxication and that environmental manipulation may modify the degree of PCP stimulation. The time-activity baseline described may prove useful in the evaluation of the effects of pharmacological and non-pharmacological manipulations of PCP-induced activity in rodents.

Intrahippocampal Injections of Phencyclidine but not Naloxone Disrupt Acquisition of a Spatial Continuous Recognition Memory Task

Rats with 36 nM or 54 nM of phencyclidine (PCP), 36 nM of naloxone or saline injected into the dentate gyrus of the hippocampus were tested for acquisition of a spatial continuous recognition memory task. Results indicate that relative to controls and rats with 36 nM of PCP or 36 nM of naloxone injections, rats with 54 nM of PCP injections were impaired in acquisition of the task across all lags as measured by increases in latency for repeated items. Since it is assumed that successful learning of this continuous recognition memory task depends upon processes associated with consolidation of new learning into long term memory, it appears that high doses of PCP, but not naloxone are sufficient to impair this process.

Acute phencyclidine induces aversion, but repeated phencyclidine induces preference in the place conditioning test in rats

Phencyclidine (PCP) is a drug that has been widely abused in the past two decades. PCP produces place aversion, but not preference, in the place conditioning test. The present study examined PCP-induced place conditioning behavior in rats treated with PCP repeatedly. In naive rats, PCP (2–8 mg/kg i.p.) dose dependently produced place aversion, but did not produce any effect in rats treated with PCP (10 mg/kg i.p.) for 14 days, indicating that tolerance developed to PCP-induced place aversion on repeated PCP treatment. In rats treated with PCP (10 mg/kg i.p.) for 28 days, PCP (2–8 mg/kg i.p.) dose dependently produced place preference. These findings suggest that some changes in neuronal function induced by the repeated PCP treatment may play an important role in the addiction to this drug.

Effects of phencyclidine on immediate early gene expression in the brain.

The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) is a psychotomimetic drug which produces schizophrenia-like psychosis. In animal studies it is toxic to neurons in the posterior cingulate and retrosplenial cortex and to cerebellar Purkinje cells. To find clues about the mechanism and pathways of PCP action, we studied the effect of systemic PCP administration (10 and 50 mg/kg, intraperitoneal) on the expression of immediate-early genes (IEGs) (c-fos, c-jun, egr-2, egr-3, NGFI-A, NGFI-B, NGFI-C, and Nurr1) using in situ hybridization histochemistry. PCP, 50 mg/kg, produced a biphasic IEG induction: an early induction in the hippocampus, cerebral cortex, and cerebellar granule cell layer, and a delayed induction in the posterior cingulate cortex and cerebellar Purkinje cell layer. The early induction of all eight IEGs was observed 30 min after drug treatment in the cerebral cortex and in the hippocampus. c-fos, NGFI-A, and NGFI-B were also induced in thalamic nuclei, and c-fos was also induced in the cerebellar granule cell layer. In contrast, a delayed induction of c-fos, c-jun, NGFI-A, NGFI-B, NGFI-C, and Nurr1 in the posterior cingulate cortex was observed 2-6 hr after PCP, 50 mg/kg. egr-2 and egr-3 were not induced in the posterior cingulate cortex. c-fos induction in the cerebellar Purkinje cell layer peaked 2 hr after PCP, 50 mg/kg. In addition, PCP induced c-fos, egr-3, NGFI-A, NGFI-B, NGFI-C, and Nurr1 in the inferior olivary nucleus. PCP-induced IEG expression returned to baseline by 24 hr. A lower PCP dose, 10 mg/kg, induced lower levels of IEG expression, with similar anatomical and biphasic temporal pattern as with the higher PCP dose of 50 mg/kg. However, no IEG induction was observed in the hippocampus following 10 mg/kg PCP. These results demonstrate that PCP produces neural activation not only in the cingulate and retrosplenial cortex, but also in many other regions of forebrain and cerebellum. Moreover, prolonged IEG expression in the posterior cingulate cortex and cerebellar Purkinje cells, the sites of PCP toxicity, suggests that IEGs could mediate neurotoxic/neuroprotective effects in these brain regions.

FOS expression in the brainstem and cerebellum following phencyclidine and MK801.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine (PCP) and dizocilpine maleate (MK801) cause nystagmus, tremor, and cerebellar ataxia at toxic doses. We have shown that PCP but not MK801 is toxic to rat cerebellar Purkinje cells. To study the mechanism and pathways of PCP and MK801 action, Fos protein expression was examined in the cerebellum and functionally related nuclei of the brainstem. PCP, 1-50 mg/kg i.p., induced Fos immunostaining in neurons of the inferior olive, cerebellar granule cell layer, and deep cerebellar and vestibular nuclei. At higher doses, PCP, 25-50 mg/kg, induced dense Fos immunoreactivity throughout the inferior olive except for rostral parts of medial accessory olive and caudal parts of principal olive. At lower doses of PCP, 1-10 mg/kg, Fos positive cells in inferior olive were concentrated in the subnucleus beta. In the cerebellum Fos positive granule cells were arranged in patches distributed throughout the cerebellar cortex following PCP, 1-50 mg/kg. Rare Fos positive Purkinje cells were observed adjacent to these patches. At the highest dose of PCP tested (50 mg/kg), Fos was expressed in the fastigial, interpositus, and dentate nuclei, and in vestibular nuclei, most prominently in the medial vestibular nucleus. At lower doses, Fos was expressed mainly in medial cerebellar output nuclei and in vestibular nuclei. MK801, 0.2-10 mg/kg i.p., induced Fos expression in the same regions as PCP. However, MK801-induced Fos expression in inferior olive was localized primarily to subnucleus beta. No apparent differences in the number or distribution of Fos positive neurons were observed at MK801 doses of 0.2-10 mg/kg. MK801 also induced Fos expression in fastigial and vestibular nuclei, but not in lateral (interpositus and dentate) cerebellar nuclei. MK801, 0.2-10 mg/kg, induced patchy Fos expression in cerebellar granule cells that was similar to PCP. These results support our earlier observations that PCP and MK801 have different actions in the cerebellum, although they both cause ataxia and indistinguishable behavioral symptoms. That high doses of PCP induce substantially more Fos expression in inferior olive than MK801 suggests that its toxicity to Purkinje cells is at least partially the result of excessive activity of climbing fibers, the excitatory neural input that arises from the inferior olive and synapses on Purkinje cell dentrities.

Involvement of nitric oxide in phencyclidine-induced hyperlocomotion in mice

The present study was undertaken to investigate the involvement of nitric oxide (NO) in the behaviors induced by 1-(1-phenylcyclohexyl) piperidine (phencyclidine; PCP) in mice, using N G-nitro- l-arginine methyl ester (L-NAME), an inhibitor of NO synthase. PCP (1, 3, and 10 mg/kg s.c.) dose dependently induced hyperlocomotion and stereotyped behaviors, including sniffing, head movement, and ataxia, in mice. PCP also caused a marked deficit of motor coordination in mice, the effect being exerted in a dose-dependent manner. Although pretreatment with L-NAME (50 mg/kg i.p.) slightly enhanced the ataxia induced by PCP (3 mg/kg), it failed to modify other stereotyped behaviors and the lack of motor coordination induced by PCP (3 mg/kg). The hyperlocomotion induced by PCP (3 mg/kg) was significantly enhanced by L-NAME (5 and 50 mg/kg) and 7-nitro indazole (25 mg/kg), but not by D-NAME (50 mg/kg), a less active enantiomer of L-NAME. However, the behavioral changes induced by PCP, at the high dose, 10 mg/kg, were not enhanced by L-NAME and D-NAME. The enhancing effects of L-NAME on the PCP (3 mg/kg)-induced hyperlocomotion were significantly prevented by l-arginine (1 g/kg i.p.). However, d-arginine (1 g/kg i.p.) and l-lysine (1 g/kg i.p.) had no effect in this regard. These results suggested the involvement of central NO production in the mediation of PCP-induced behaviors, hyperlocomotion in particular, in mice.

Effect of repeated haloperidol administration on phencyclidine discrimination in rats

Wiley, Jenny L.: Effects of repeated haloperidol administration on phencyclidine discrimination in rats. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995, 19(4): 699–711. 1. 1. Previous research has shown that acute doses of haloperidol block many of themotor stimulatory effects of phencyclidine (PCP) and other PCP-like drugs. In addition, when given acutely, haloperidol produces partial attenuation of PCP's discriminative stimulus effects in rats. 2. 2. Haloperidol is often administered chronically in clinical situations; hence, it is important to investigate the effects of repeated, as well as acute, dosing with this drug. 3. 3. The purpose of the present study was to examine the effects of repeated administration of haloperidol on PCP discrimination in rats. Rats were trained to discriminate PCP (2.0 mg/kg) from saline in a two-lever drug discrimination procedure and were tested with cumulative doses of PCP before and after repeated administration of saline and of haloperidol (0.5 mg/kg/day). 4. 4. Discrimination training was suspended during the two 14–15-day repeated dosing regimens. Suspended training with repeated saline administration had little effect on the dose-effect curve for % PCP-lever responding. 5. 5. Repeated administration of haloperidol produced some diminution of PCP discrimination. After haloperidol, the ED 50 for % PCP-lever responding was 1.4 mg/kg, compared to the pre-haloperidol ED 50 of 0.7 mg/kg. 6. 6. These results are consistent with those of acute dosing studies with haloperidol in PCP-trained rats and suggest that repeated administration of haloperidol may disrupt PCP's discriminative stimulus effects, although most rats were still able to discriminate the higher doses of PCP.

Phencyclidine injections into the dorsal hippocampus disrupt long- but not short-term memory within a spatial learning task.

Since the hippocampus is likely to be a major site of phencyclidine (PCP) action, the effects of various doses of PCP (1.8, 18 or 36 nM) as well as 3.6 nM MK-801 or saline injected directly into the dentate gyrus of the hippocampus was tested for acquisition of a spatial navigation task (dry land version of a water maze) using a paradigm that assesses short term memory based on learning within a day and long term memory based on learning between days. Results indicated that relative to saline or 1.8 nM PCP injected rats, rats with 18 or 36 nM PCP or 3.6 nM MK-801 injections were impaired in acquisition of the task as measured by increased distances traveled to find the food location between days but not within days. In additional experiments 36 nM PCP or 3.6 nM MK-801 did not produce any deficits in the acquisition of an object discrimination task. It is suggested that PCP through its blocking action of the NMDA receptor in the dentate gyrus or CA1 region of the dorsal hippocampus mediates the consolidation of new spatial location information.

Response of extrapyramidal and limbic neurotensin systems to phencyclidine treatment

Although phencyclidine (PCP) has several neurochemical effects, the most pharmacologically relevant are thought to be its ability to antagonize the activity of N-methyl- d-aspartate (NMDA)-type glutamate receptors and to increase extracellular dopamine concentrations. In order to elucidate the nature and consequence of PCP actions on glutamatergic and dopaminergic pathways, this study examined the response of extrapyramidal and limbic neurotensin systems to this drug. Multiple, but not single, doses of PCP caused increases in striatal neurotensin-like immunoreactivity content of 150–200% of control. These effects were blocked by the dopamine D 1 receptor antagonist, SCH 23390, suggesting they were caused by PCP-mediated enhanced dopamine activity at dopamine D 1 receptors. In contrast, MK-801 (dizocilpine), a selective NMDA receptor antagonist that acts at the same site as PCP, had no effect on neurotensin-like immunoreactivity content when given alone. In addition, coadministration of MK-801 with PCP did not alter the effect of PCP on striatal neurotensin-like immunoreactivity content. This lack of effect suggests that the actions of PCP on NMDA receptors was not involved in the neurotensin response. The PCP effect on neurotensin striatal pathways also appeared not to be associated with the dopamine D 2 or γ-aminobutyric acid (GABA) systems: a possible role for the sigma receptor in this effect could not be eliminated. Administration of multiple doses of PCP also affected neurotensin-like immunoreactivity content in the nucleus accumbens (160% compared to control) and frontal cortex (40% compared to control), but not the substantia nigra. The neurotensin effects of PCP are compared to those of another psychotomimetic drug of abuse, methamphetamine.