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PubMed1998

Involvement of dopaminergic system in phencyclidine-induced place preference in mice pretreated with phencyclidine repeatedly.

In the conditioned place preference test, phencyclidine (PCP) produces place aversion in naive rats, whereas PCP produces place preference in rats treated with PCP repeatedly. Although the PCP-induced place aversion is thought to involve the serotonergic system, the mechanisms of the PCP-induced place preference are unclear. We investigated whether the dopaminergic system is involved in place preference induced by PCP in mice repeatedly treated with PCP, because it is well known that the dopaminergic system plays an important role in the rewarding effect of drugs. PCP (2-8 mg/kg s.c.) induced a dose-dependent place aversion in naive mice, whereas PCP (2-8 mg/kg s.c.) induced a dose-dependent place preference in mice pretreated with PCP (10 mg/kg/day s.c.) for 28 days. The place preference induced by PCP (8 mg/kg s.c.) was attenuated significantly by alpha-methyl-rho-tyrosine (100 mg/kg i.p.), a tyrosine hydroxylase inhibitor, 6-hydroxydopamine (100 micrograms/mouse i.c.v.), a dopaminergic neurotoxin, and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine (0.5 mg/kg s.c.), a dopamine D1 receptor antagonist. These agents themselves produced neither the place preference nor aversion. In contrast to the attenuating effects of these agents, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (30 mg/kg i.p.), a noradrenergic neurotoxin, ritanserin (1 mg/kg i.p.), a serotonin2 receptor antagonist, and (-) sulpiride (50 and 100 mg/kg i.p.), a dopamine D2 receptor antagonist, failed to affect the PCP-induced place preference. In mice pretreated with methamphetamine (1 mg/kg/day s.c.) for 14 days, PCP (8 mg/kg s.c.) induced the place preference, but not aversion. These results demonstrate that the PCP-induced place preference depends on dopaminergic, but not on serotonergic and noradrenergic, neuronal systems and suggest a role for D1 receptors in the mediation of the PCP-induced place preference.

Animals↗
PubMed1995

Risperidone prevents the development of supersensitivity, but not tolerance, to phencyclidine in rats treated with subacute phencyclidine.

We investigated whether risperidone, a 5-HT2/dopamine-D2 receptor antagonist, inhibits the development of tolerance and supersensitivity to PCP and whether subacute administration of PCP with risperidone affects the [3H]MK-801 binding in rat brain, in comparison with dopamine-D2 receptor antagonist haloperidol and 5-HT2 receptor antagonist ritanserin. In rats treated with PCP (10 mg/kg, i.p.) for 14 days, PCP (10 mg/kg, i.p.)-induced hyperlocomotion, rearing and sniffing were potentiated (supersensitivity), and head-weaving, head-twitch, backpedalling and turning were diminished (tolerance). The development of supersensitivity to PCP was blocked by oral co-administration of risperidone (2.4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) for 14 days, but not ritanserin (10 mg/kg, p.o.) and risperidone (0.8 mg/kg, p.o.), while no drugs prevented the development of tolerance to PCP. Both risperidone (2.4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) also inhibited the cross-supersensitivity to methamphetamine (MAP; 2.5 mg/kg, i.p.)-induced rearing in rats treated with PCP for 14 days. The profiles of [3H]MK-801 binding in discrete brain areas did not change after subacute administration of PCP alone or in combination with risperidone, haloperidol or ritanserin for 14 days. Therefore, it is suggested that subacute administration of PCP may cause functional changes in the dopaminergic neuronal transmission under conditions where the binding of [3H]MK-801 in discrete brain areas is unchanged, and that co-administration of risperidone may block these PCP-induced changes in neuronal function.

Animals↗
PubMed1988

Phencyclidine (PCP) and phencyclidine-like compounds: a molecular graphics-molecular mechanics study.

The low energy conformation of MK801. (+)-N-allyl-N-normetazocine, dexoxadrol, etoxadrol and ketamine was found to possess the unique pharmacophore geometry of a PCP pharmacophore hypothesis recently reported by Carroll et al. (1988). Moreover, the union of the volumes of these compounds in their proposed receptor bound conformation locked together such that equivalent groups were superimposed showed that none of the compounds extended into the binding site volume above and below the aromatic ring and along the nitrogen vector.

Animals↗
PubMed1983

In vitro and in vivo evaluation of cis-methyl-phencyclidine (CIS-MPCP) as a potential antagonist of phencyclidine (PCP).

In four preparations/tests (isolated nerve, ventricular strip, rotarod, and mouse acute lethality), cis-N-phenyl-4-methyl-cyclohexyl piperidine (cis-MPCP) was consistently less active than PCP and trans-MPCP. As expected, cis-MPCP, at 10(-4)M, which did not depress the action potential evoked on frog sciatic nerves, reduced by half both the nerve block and prolongation of relative refractory period caused by PCP. However, cis-MPCP at 10(-6)M, which by itself had little effect, failed to reduce the positive inotropic effect of PCP on the field-stimulated rat ventricular strip. Cis-MPCP also failed to decrease the ataxic effect of 6 mg/kg PCP (ED80) in the mouse rotarod test. Finally, at a dose that was neither ataxic nor lethal to mice (20 mg/kg), cis-MPCP failed to reduce the 24-hour LD50 of PCP. These data suggest that the actions of PCP are mediated through a multiple receptor system.

Action Potentials↗
PubMed1986

Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions.

The interaction of phencyclidine, dexoxadrol, their analogs and stereoisomers with phencyclidine receptors was compared to their ability to induce stereotyped behavior and ataxia after i.c.v. administration to rats. The order of potency for binding to phencyclidine receptors revealed that among the stereoisomers of phencyclidine derivatives, the (+) isomer was more potent than the (-) isomer. A similar order of potency of phencyclidine derivatives and degree of stereoselectivity was seen in the assays for stereotyped behavior and phencyclidine receptor interactions, which resulted in a good correlation between the relative potencies for binding to phencyclidine receptors and inducing stereotyped behavior. However, the order of potency for induction of ataxia and the stereoselectivity was different than that seen in the assays for phencyclidine receptor interactions and stereotyped behavior. A comparison of relative potencies for binding to phencyclidine receptors to induction of ataxia still resulted in a good fit to a straight line, but the line did not intersect the origin, indicating that a non-phencyclidine receptor component is also involved in mediating ataxia. Dextrorphan and 2-methyl-3,3-diphenyl-3-propylamine were equipotent as phencyclidine in phencyclidine receptor and behavioral assays. The order of potency for interacting with phencyclidine receptors and inducing phencyclidine-like behavior by the isomers of cyclazocine were opposite to that of other phencyclidine analogs. Also, the order of potency for induction of ataxia by the isomers of N-allylnormetazocine was opposite to that for phencyclidine receptor interactions. Ethylketocyclazocine did not induce any stereotyped behavior or ataxia, indicating that it is unlikely that a kappa opioid receptor interaction plays a role in mediating ataxia. Furthermore, stereotyped behavior and ataxia were not due to interactions with mu, kappa or delta opioid receptors as naloxone did not antagonize the behavioral effects of phencyclidine, (-)cyclazocine or (-)N-allylnormetazocine. These results indicate that stereotyped behavior is mediated by phencyclidine receptors, whereas ataxia is mediated by more than just phencyclidine receptors.

Animals↗
PubMed2001

Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia.

Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7, 9 and 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X(L) proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy.

Animals↗
PubMed1986

Effects of phencyclidine on ventral tegmental A10 dopamine neurons in the rat.

Extracellular single unit recordings were used to determine the effects of systemically and iontophoretically applied phencyclidine on electrophysiologically-identified A10 dopamine neurons within the ventral tegmental area of the rat. Intravenous injections of phencyclidine inhibited, as well as excited A10 cells. Approximately 42% of the inhibitions induced by phencyclidine were completely reversed by an injection of haloperidol. The excitatory effects of phencyclidine most often resulted in a state of depolarized inactivation and were not sensitive to haloperidol. The alteration of the activity of A10 cells by systemically-applied phencyclidine was effectively prevented in all animals pretreated with a combination of reserpine and alpha-methyl-p-tyrosine, which depleted stores of central catecholamines by over 90%. In contrast to the data obtained with intravenous injections, iontophoretic applications of phencyclidine produced only inhibition of the activity of the A10 cells and, in a few of these cases the decreased firing rate was accompanied by an increase in the amplitude of the action potential. A comparison of the response patterns of dopaminergic neurons to systemically- and iontophoretically-applied phencyclidine would suggest that excitations induced by phencyclidine are not mediated at the level of the A10 cell bodies but through a site outside the ventral tegmental area. The results of this study also indicate that some of the effects of phencyclidine on the activity of A10 neurons are clearly dependent upon an interaction with dopamine and thus, would support the hypothesis that phencyclidine can act as an indirect dopamine agonist. However, other effects of phencyclidine which are not apparently linked to dopamine may represent the response of a pharmacologically-distinct subpopulation of A10 neurons to phencyclidine.

Action Potentials↗
PubMed1987

Self-administration of orally-delivered phencyclidine and ethanol under concurrent fixed-ratio schedules in rhesus monkeys.

Five monkeys were trained to self-administer orally-delivered phencyclidine (0.25 mg/ml) and water under concurrent fixed-ratio 16 (FR 16) schedules during daily sessions that lasted 3 h. An 8% (w/v) ethanol solution was substituted for water and then the following series of phencyclidine concentrations was presented: 0.25, 0.5, 1, 0.03, 0.06, 0.12, 0 (water), and 0.25 mg/ml (retest). Next, the phencyclidine concentration was held constant (0.25 mg/ml), and the ethanol concentration was varied as follows: 8, 16, 32, 1, 2, 4, 0 (water), and 8% w/v (retest). Each drug concentration series was tested again with water concurrently available. At low phencyclidine concentrations the ethanol solution was preferred, but phencyclidine deliveries exceeded ethanol deliveries at higher phencyclidine concentrations. Ethanol-maintained responding was increased by the lower phencyclidine concentrations (0.03, 0.06 and 0.12 mg/ml), and it was slightly suppressed by the highest concentration (1 mg/ml). Phencyclidine was preferred to all concentrations of ethanol except 4%. Ethanol (8%) suppressed phencyclidine-maintained behavior at lower concentrations, but it had no effect at higher phencyclidine concentrations. The ethanol concentration-response functions were nearly identical whether phencyclidine (0.25 mg/ml) or water was concurrently present. Drug preferences were usually evident within the first 10 min of the session, suggesting they were based on olfaction, taste, or other immediate postingestional effects. These results show that two orally-delivered drugs may be concurrently self-administered under independently-operating FR schedules. Behavior maintained by one drug depends on the magnitude of the concurrently available, alternative reinforcing drug.

Administration, Oral↗
PubMed1989

Comparison of the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat.

Some of the dioxolanes produce pharmacological effects that have much in common with phencyclidine and phencyclidine-like drugs. Dioxadrol can be resolved into two enantiomers, dexoxadrol and levoxadrol. Dexoxadrol has an affinity for phencyclidine receptors that is much greater than that of levoxadrol, but dexoxadrol and levoxadrol have nearly equal affinities for sigma receptors. The systematic analysis of the relative potencies of dexoxadrol and levoxadrol can be used as an approach to define effects mediated by phencyclidine vs sigma receptors. Compounds that act on phencyclidine receptors, as well as affecting behavior, alter body temperature in the rat. The purpose of the present study was to compare and contrast the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Dexoxadrol and levoxadrol (5.0, 10.0, 20.0 or 40.0 mg/kg), MK-801 (0.12, 0.6 or 1.2 mg/kg) or phencyclidine (5.0, 10.0 or 20.0 mg/kg) were administered subcutaneously and body temperature was measured. Both dexoxadrol and MK-801 produced hyperthermia but levoxadrol did not affect body temperature. In contrast to the hyperthermic effects of dexoxadrol and MK-801, phencyclidine produced hypothermia. These findings indicate that hypothermia induced by phencyclidine is not due to interactions with phencyclidine receptors and, while dexoxadrol, MK-801 and phencyclidine may share some similar receptor binding and behavioral characteristics, they can be differentiated on the basis of their effects on body temperature.

Animals↗
PubMed1994

Phencyclidine induction of the hsp 70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels.

Non-competitive N-methyl-D-aspartate receptor antagonists, including phencyclidine, ketamine, and MK801, produce vacuoles and induce the hsp 70 stress gene in layer III pyramidal neurons of the rat cingulate cortex. This study shows that phencyclidine (50 mg/kg) induces hsp 70 messenger RNA and HSP70 stress protein primarily in pyramidal neurons in posterior cingulate and retrosplenial cortex, neocortex, insular cortex, piriform cortex, hippocampus, and in the basal nuclei of the amygdala. Several neurotransmitter receptor antagonists inhibited induction of HSP70 produced by phencyclidine (50 mg/kg): haloperidol (ED50 = 0.8 mg/kg), clozapine (ED50 = 1 mg/kg), valium (ED50 = 1 mg/kg), SCH 23390 (ED50 = 7 mg/kg) and muscimol (ED50 = 3 mg/kg). Baclofen had no effect. Nifedipine blocked the induction of HSP70 produced by phencyclidine in some regions (cingulate, neocortex, insular cortex) but only partially blocked HSP70 induction in other regions (piriform cortex, amygdala). These results suggest that phencyclidine injuries pyramidal neurons via dopamine D1, D2, D4, sigma and other receptors. Several factors appear to contribute to this unusual multi-receptor mediated injury. (1) Phencyclidine blocks N-methyl-D-aspartate receptors on GABAergic interneurons resulting in decreased inhibition of pyramidal neurons. This may help to explain why multiple excitatory receptors mediate the injury and why GABAA agonists decrease the injury produced by phencyclidine. (2) Phencyclidine blockade of an amine transporter helps explain why dopamine receptor antagonists ameliorate injury. (3) Phencyclidine depolarizes neurons and produces high, potentially damaging intracellular calcium levels probably by blocking K+ channels that may be linked to sigma receptors. Since nifedipine prevents injury in cingulate, insula, and neocortex, it appears that calcium entry through L-type voltage gated calcium channels plays a role in the pyramidal neuronal injury produced by phencyclidine in these regions. There are similarities between the cingulate neurons injured by phencyclidine and circuits recently hypothesized to explain receptor changes in cingulate gyrus of schizophrenic patients. The present and previous studies also provide approaches for decreasing the clinical side effects of N-methyl-D-aspartate receptor antagonists to facilitate their possible use in the treatment of ischemia and other disorders.

Animals↗
PubMed1999

The delayed effects of phencyclidine enhance amphetamine-induced behavior and striatal C-Fos expression in the rat.

The ability for the delayed effects of phencyclidine to model schizophrenia-like symptomatology was investigated by assessing the effects of phencyclidine pretreatment on amphetamine-induced behavior. Corresponding changes in striatal, nucleus accumbens and anterior cingulate cortex c-Fos induction were also assessed in order to test the hypothesis that alterations in the neurochemistry of these regions accompany phencyclidine-induced changes in amphetamine-induced behaviors. Rats were treated with 15.0 mg/kg phencyclidine or vehicle 24 h prior to behavioral testing following vehicle, 0.5, 2.5 or 5.0 mg/kg amphetamine. Phencyclidine pretreatment significantly increased amphetamine-induced locomotion and rearing in response to 0.5 mg/kg amphetamine. Likewise, phencyclidine pretreatment produced an increase in the number of striatal cells expressing c-Fos following treatment with 0.5 mg/kg amphetamine. Phencyclidine pretreatment did not alter c-Fos induction in the nucleus accumbens, but did decrease the basal number of c-Fos-containing cells in the anterior cingulate cortex. While stereotypy rating revealed that phencyclidine pretreatment enhanced the behavioral response to 5.0 mg/kg amphetamine over time, no other alterations in behavior or c-Fos expression in response to the higher doses of amphetamine were induced by phencyclidine pretreatment. These data demonstrate that the delayed effects of a single dose of phencyclidine alter anterior cingulate cortex neurochemistry, and enhance the behavioral and striatal c-Fos response to a low dose of amphetamine. These findings suggest that the delayed effects of a single dose of phencyclidine may produce a reasonable animal model for schizophrenia.

Amphetamine↗
PubMed1987

Concurrent access to two concentrations of orally delivered phencyclidine: effects of feeding conditions.

Two experiments addressed the effects of food satiation and deprivation on oral self-administration of two concurrently available phencyclidine concentrations. In the first experiment, 8 rhesus monkeys self-administered either of two concentrations of phencyclidine ("PCP, angel dust") and water under concurrent fixed-ratio 16 schedules. One concentration was always held constant (0.25 mg/mL) while a series of other phencyclidine concentrations, ranging from 0 (water) to 1.0 mg/mL, was presented in a nonsystematic order. Initially the monkeys were tested while food satiated, and the procedure was then repeated during food deprivation. The monkeys usually selected the higher concentration within the first few minutes of the session, indicating that taste and/or other immediate postingestional effects were important factors. Contrary to a number of previous reports, there were no consistent differences across subjects in the mean number of liquid deliveries or mean drug intake (mg/kg) during food satiation and deprivation. However, for all monkeys the within-session time course of responding during food satiation consistently differed from that during deprivation. A second experiment assessed whether the failure to find consistent differences in drug intake during food satiation and deprivation had been due to the history of concurrent access to different phencyclidine concentrations or to the extended experience with phencyclidine under food-satiation conditions. Six additional monkeys (Group 2) were exposed to the phencyclidine self-administration procedure (during food satiation and deprivation) for the same length of time as the monkeys in Experiment 1 (Group 1), except they received only concurrent access to phencyclidine (0.25 mg/mL) and water. Both groups then received concurrent access to phencyclidine and water during five repeated cycles of food deprivation and satiation. There were also marked individual differences in Group 2: During food satiation, 2 of the monkeys' responding increased, 1 showed no change, and 3 decreased. Examination of a number of historical variables indicated that the greater the percentage of total sessions spent during food satiation with phencyclidine available (before these experiments began), the greater the amounts of phencyclidine consumed during food satiation and the smaller the differences in phencyclidine intake when the two feeding conditions were compared.

Animals↗
PubMed1989

Interaction of the discriminative stimulus effects of phencyclidine with those of (+)-N-allylnormetazocine, pentobarbital and d-amphetamine.

Pigeons trained to discriminate 1.0 mg/kg phencyclidine from saline were used to study the interaction between the stimulus effects of phencyclidine and those of (+)-N-allylnormetazocine [(+) NANM], pentobarbital and d-amphetamine using a cumulative-dosing procedure. Both (+) NANM and pentobarbital enhanced the discriminative stimulus effects of phencyclidine. The enhancement of the phencyclidine stimulus by pentobarbital was predicted by adding the effects of the individual drugs, but the enhancement of the phencyclidine stimulus by (+) NANM was sometimes more than would have been expected from adding the effects of the individual drugs. d-Amphetamine did not enhance the discriminative stimulus effects of phencyclidine, but neither did it interfere with these effects. Combinations of (+) NANM or pentobarbital with phencyclidine also enhanced the rate-decreasing effects of phencyclidine, but to a lesser extent than they enhanced the discriminative stimulus effects of phencyclidine. d-Amphetamine only slightly enhanced the rate-decreasing effects of phencyclidine.

Amphetamines↗