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.     

Baseline temperature in an animal model of schizophrenia: long-term effects of perinatal phencyclidine administration

Phencyclidine (PCP), a dissociative anaesthetic, acts as a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. PCP is a psychostimulant capable of producing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans. Perinatal phencyclidine administration to rats has been widely accepted as an animal model of schizophrenia. It has been known for a long time that schizophrenia patients may develop various thermoregulatory disturbances. The aim of this study was to assess the acute effects of phencyclidine administration on the temperature of newborn rats, the long-term effects on the baseline temperature of perinatal phencyclidine administration and the effects of a PCP challenge on the temperature of adult perinatally treated rats. The animals were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10 mg/kg) or saline. The interscapular skin temperature was measured during the first 40 postnatal days and subsequently the colonic temperature until PN day 62. The immediate effect of phencyclidine administration to pups was a significant decrease of the body temperature, while the application of PCP to adult rats perinatally treated with either saline or PCP caused a significant increase of the baseline temperature. Perinatal phencyclidine administration to rat pups produced a long lasting effect on the baseline temperature. It can be concluded that the nature of the response to acute phencyclidine administration differs between newborn and adult rats. Further experiments are necessary in order to clarify the role of specific neurotransmitter systems in the changes of temperature regulation provoked by phencyclidine administration.     

Differential regulation of chromogranin A, chromogranin B and secretogranin II in rat brain by phencyclidine treatment

Chromogranin A, chromogranin B and secretogranin II belong to the chromogranin family which consists of large protein molecules that are found in large dense core vesicles. Chromogranins are endoproteolytically processed to smaller peptides.This study was designed to elucidate the regulation of chromgranin expression by acute and subchronic phencyclidine administration. The behavioral syndrome produced by phencyclidine represents a pharmacological model for some aspects of schizophrenia [Jentsch and Roth (1999) Neuropsychopharmacology 20, 201-225]. Tissue concentrations of chromogranins were measured with specific radioimmunoassays. Alterations in secretogranin II gene expression were investigated by in situ hybridization. A single dose of phencyclidine (10mg/kg) led to a transient decrease in secretoneurin tissue levels in the prefrontal cortex after 4h followed by an increase in secretoneurin tissue levels after 12h. Repeated phencyclidine treatment (10mg/kg/day) for five days resulted in elevated secretoneurin levels in cortical areas whereas chromogranin A and chromogranin B tissue levels were unchanged. After the same treatment, a significant increase in the number of secretoneurin containing neurons was found in cortical layers II-III, and V-VI as revealed by immunocytochemistry. The increases in secretoneurin levels were paralleled by an increased number of secretogranin II messenger RNA containing neurons as well as by an increased expression of secretogranin II by individual neurons.The present study shows that secretoneurin II tissue concentration and secretogranin II messenger RNA expression is distinctly altered after acute and subchronic phencyclidine application. From these results we suggest that phencyclidine may induce synaptic alterations in specific brain areas and may contribute to a better understanding of synaptic dysfunction which may also occur in schizophrenia.     

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.     

Differential effects of amphetamine and phencyclidine on the expression of growth-associated protein GAP-43

The purpose of the present study was to test changes in the expression of growth-associated protein (GAP-43) after chronic treatment with two different psychotomimetic drugs: amphetamine and phencyclidine. Rats were treated chronically for 7 days (twice daily) with 5 mg/kg of amphetamine and phencyclidine and sacrificed after 2, 5 or 7 days of treatment, and following 7, 14 or 21 days of recovery after full treatment (7 days). Separate groups of rats were treated on the same regiment with haloperidol, and control group was treated with vehicle. To determine the effects of different psychotomimetic drugs on the expression of GAP-43 we have used Northern blotting and quantitative in situ hybridization. Treatment with amphetamine induced decrease of GAP-43 mRNA expression, that was detected also during recovery period, up to 14 days after the last day of 7 days treatments. On the contrary, PCP induced increase of GAP-43 mRNA expression, that was detectable from the first days of treatment until 21 days after the last day of treatment. Treatment with haloperidol did not produce significant changes in GAP-43 mRNA expression. It can be suggested that GAP-43 upregulation upon phencyclidine treatment occurs as a result of functional activation of pathways able to participate in remodeling, while amphetamine showed neurotoxic effect, decreasing expression of GAP-43 mRNA.     

Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats

Recent studies have reported that acute administration of the psychotomimetic drug phencyclidine results in considerable increases in the amounts of both extracellular glutamate and dopamine in the medial prefrontal cortex (mPFC). However, the effect of phencyclidine on the firing activity of mPFC neurons remains unknown. Here, we report the first data on phencyclidine-induced activation of mPFC neurons in freely moving rats. Unanesthetized rats received an intraperitoneal injection of either phencyclidine (5 mg/kg) or physiological saline (0.5 ml/kg) in order to investigate the impulse activity of mPFC neurons and behavioral activity. The phencyclidine injection induced a remarkable increase (two-fold or more) in the spontaneous discharge rate of the majority of mPFC neurons (20/23), and this increase lasted for more than 70 min. In addition, a considerable augmentation of behavioral activity was observed that nearly paralleled that of the mPFC neuronal activation. In contrast, microiontophoretically applied phencyclidine exerted little influence on the spontaneous firing activity of most mPFC neurons (25/29) in anesthetized rats, although systemically applied phencyclidine produced activation of mPFC neurons even under general anesthesia. These results suggest that the behavioral abnormalities induced by acute administration of phencyclidine may be caused by hyperactivation of mPFC neurons, and that this hyperactivation is elicited through excitatory inputs from brain regions outside the mPFC.     

Binding of [3H]phencyclidine to adrenal medullary cells: inhibition of 22Na influx, 45Ca influx, 86Rb efflux and catecholamine secretion caused by carbachol and veratridine

In bovine adrenal medullary cells, phencyclidine inhibited carbachol-induced influx of 22Na, 45Ca and secretion of catecholamines in a concentration-dependent manner with a similar potency (IC50 7.0 microM). Phencyclidine also suppressed veratridine-induced influx of 22Na, 45Ca and secretion of catecholamines (IC50 60.0 microM). High K-induced 45Ca influx and catecholamine secretion were not affected by phencyclidine. In the cells preloaded with 86Rb (an alternative tracer for 42K), phencyclidine inhibited the efflux of 86Rb caused by carbachol (IC50 10.0 microM) or by veratridine (IC50 56.0 microM), but had no effect on high K-induced 86Rb efflux. [3H]Phencyclidine bound specifically to adrenal medullary cells, and binding was saturable, reversible and with two different equilibrium dissociation constants (4.3 and 77.4 microM). In a competition experiment, the specific binding of [3H]phencyclidine was not inhibited by carbachol, muscarine, D-tubocurarine, hexamethonium, tetrodotoxin, veratridine and scorpion venom. The present findings suggest: (1) phencyclidine does not inhibit voltage-dependent Ca channels and Ca-dependent K channels; (2) phencyclidine binds to two populations of sites, each of which is functionally linked to nicotinic receptor-ion channel complex and to voltage-dependent Na channels, and inhibits Na influx caused by carbachol and veratridine. Inhibition of Na influx by phencyclidine leads to the reduction of Ca influx, K efflux and catecholamine secretion caused by carbachol and veratridine.     

Interaction of 4-aminopyridine with [3H]phencyclidine receptors in rat brain homogenates

The effect of 4-aminopyridine and its analogs on the specific binding of [3H]phencyclidine was investigated in rat brain homogenates. 4-Aminopyridine (4-AP) and 3,4-diaminopyridine displaced [3H]phencyclidine binding, while 3-aminopyridine was without effect. The concentrations of 4-AP required for inhibition of binding increased with increasing the ligand concentration, and the resultant Dixon plots indicated a competitive type of interaction. However, 4-AP also accelerated the dissociation rate of the ligand-receptor complex, suggesting that the effect of 4-AP on phencyclidine receptors in the brain might not be purely competitive.     

Mutation of structural determinants lining the N-methyl-D-aspartate receptor channel differentially affects phencyclidine block and spermine potentiation and block.

Spermine and other endogenous polyamines potentiate, block and permeate the N-methyl-D-aspartate receptor channel. To identify structural determinants of the N-methyl-D-aspartate channel that mediate spermine's actions, we generated mutant receptors with asparagine (N) to glutamine (Q) or arginine (R) substitutions in the selectivity filter of the channel. We demonstrate that mutation of the three critical asparagines in this domain differentially affects block by phencyclidine and both potentiation and block by spermine. N-to-Q and N-to-R mutations in the N site of the NR1 subunit (N598 in NR1(011), N619 in NR1(100)) and N-to-Q mutations in the N and N + 1 sites (N595 and N596 in NR2A, respectively) of the NR2 subunit (Q/NN, R/NN, N/QN, N/NQ, Q/QN and Q/NQ receptors) reduced affinity for phencyclidine. The Q/NN receptor showed markedly reduced potentiation by spermine, with little or no change in spermine block. The R/NN receptor showed markedly reduced spermine potentiation and affinity for spermine at its block site. The N/QN, N/NQ and Q/QN mutant receptors showed somewhat enhanced spermine block, while the Q/ NQ double mutant exhibited significantly more enhanced spermine block. Thus, the asparagine residues critical to Ca2+ permeability and Mg2+ block of N-methyl-D-aspartate channels are also critical to block by spermine and phencyclidine. To examine the interaction of spermine and phencyclidine within the channel, we performed competition studies. Spermine appeared to compete with phencyclidine for binding to the receptor; however, blocks by phencyclidine and by spermine were not additive. The findings suggest that spermine can bind to a site in the external vestibule of the channel to impede phencyclidine binding, but allow Na+ influx.     

Phencyclidine abuse. Clinical findings and concentrations in biological fluids after nonfatal intoxication

Phencyclidine concentrations were measured in the plasmas of 22 patients with nonfatal phencyclidine intoxication using gas-liquid chromatography with a nitrogen detector. Concentrations found ranged from less than 10 to 812 micrograms/l, and except for the systolic blood pressure (r = 0.60, P less than 0.05), showed no significant correlation with the physical findings. The most common physical findings were combativeness-agitation (64%), depressed level of consciousness (50%), hypertension (43%), moiosis (43%), and tachycardia (43%). Phencyclidine concentrations measured in the erythrocytes of seven of the patients were generally higher than concentrations in the corresponding plasmas (erythrocyte:plasma concentration ratios ranged from 3.1 to 37.9), suggesting that the binding of phencyclidine to plasma proteins is low. Erythrocytic concentrations also showed no significant correlation with either the physical findings or the plasma concentrations of phencyclidine. For 15 unselected urines the concentrations of phencyclidine showed no significant correlation with urinary pH.     

Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits

Long-term exposure to the psychotomimetic drug phencyclidine produces prefrontal cortical cognitive and dopaminergic dysfunction in rats and monkeys, effects possibly relevant to the frontal cortical impairments of schizophrenia. In the present study, the effects of subchronic phencyclidine administration (0.3 mg/kg twice-daily for 14 days) on monoamine systems in the monkey brain were examined and related to cognitive performance on an object retrieval/detour task, which has been linked with frontostriatal function. Long-term (14 days) administration of phencyclidine resulted in a marked and persistent reduction in dopamine utilization in the frontal cortex. Moreover, the degree of cognitive impairment in phencyclidine-treated monkeys correlated significantly with the magnitude of dopaminergic inhibition within the dorsolateral prefrontal cortex and prelimbic cortex. No specific correlation was measured for dopamine utilization in other cortical regions or for indices of serotonin transmission in any brain region. These data show that repeated exposure to phencyclidine reduces prefrontal cortical dopamine transmission, and this inhibition of dopaminergic function is associated with performance impairments on a task sensitive to frontostriatal cognitive dysfunction. Thus, the cognitive deficits of phencyclidine-treated monkeys, as in schizophrenia, appear to be mediated, in part, by reduced dopaminergic function in specific subregions of the frontal cortex.     

3H]Spiperone binding in the rat striatum during the development of physical dependence on phencyclidine and after withdrawal

Binding of [3H]spiperone to dopamine D2 receptors was measured in the striatum of male rats that were infused with phencyclidine (PCP, 45 mg/kg per day) or vehicle (saline) via an intrajugular cannula for 1, 3.5, or 7 days. The 7-day PCP infusion, which was shown previously to induce physical dependence, produced a significant 30% decrease in receptor density (Bmax). Two days after termination of the 7-day PCP infusion, Bmax values were no longer significantly lower than those of saline-infused controls. The acute administration of PCP (20 mg/kg, i.p.) did not alter receptor density 45 min later.     

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.     

Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats

The effect of systemically administered amphetamine, cocaine, phencyclidine and nomifensine on the extracellular concentrations of dopamine in freely moving rats was estimated by microdialysis in the nucleus accumbens and in the dorsal caudate. All the drugs tested stimulated dopamine output in both areas but more effectively in the accumbens as compared to the caudate. Low doses of cocaine (1.0 mg/kg s.c.) stimulated dopamine output only in the nucleus accumbens. Nomifensine (1.25-5.0 mg/kg s.c.) increased by a similar extent peak dopamine output in the two dopaminergic areas but the duration of the effect was longer in the accumbens as compared to the caudate. The effect of cocaine, phencyclidine and nomifensine was prevented by systemic gamma-butyrolactone (700 mg/kg i.p.) and by omitting Ca2+ from the Ringer used for dialysis, the effect of amphetamine was insensitive to these manipulations. Thus, in contrast with amphetamine, cocaine, phencyclidine and nomifensine increase synaptic dopamine concentrations in vivo by a mechanism which depends on intact activity of dopaminergic neurons and by an exocytotic process.     

Therapeutic vaccines for substance dependence

Several immunotherapies are under development for nicotine, cocaine and phencyclidine and a cocaine vaccine has started human trials. These therapies promise a new approach to diseases that have had limited treatment success and tremendous morbidity. Both the cocaine and nicotine addiction immunotherapies have reduced 'relapse' to drug use in animal model systems. To date, the active cocaine vaccine has few side effects and induces considerable antibody titers after active immunization in humans. Studies with the monoclonal phencyclidine immunotherapy provide intriguing evidence of sustained protection for months after single-dose administration. Other immunotherapy may include treatment of drug overdose, prevention of brain or cardiac toxicity and protection of a fetus during pregnancy in a drug abuser.     

Interactive effects of chronic phencyclidine and delta 9-tetrahydrocannabinol on spermatogenesis in mice

In this study, the combined effects of chronic phencyclidine (PCP) and delta 9-tetrahydrocannabinol on spermatogenesis in mice were examined. Mice were treated with THC (50 mg/kg, PO) and PCP (15 mg/kg, IP) alone or in combination for 16 days and with PCP alone for 35 days. THC had a significant effect on spermatogenesis and decreased the number of all germinal cells. PCP, on the other hand, affected all germinal cells except spermatids after 35 days of treatment. Combination of THC and PCP treatment caused a significant decrease in resting and pachytene spermatocytes. Similarly, combination of these two drugs caused a significant increase in cauda epididymal abnormal sperms. These results suggest that THC and PCP may cause greater disruption in spermatogenesis when they are abused together.     

Ketamine and MK801 attenuate paired pulse inhibition in the olfactory bulb of the rat

Summary We have investigated the effects of the phencyclidine like-compounds ketamine and MK801 on the evoked field potentials of rat olfactory bulb. Low doses of ketamine (3–6 mg/kg) blocked the inhibition of mitral cells by granule cells evoked by stimulation of lateral olfactory tract fibres or by stimulation of olfactory nerve. This blockade was not accompanied by a decrease in granule cell excitation as revealed by field potential recording. MK801 had a similar effect on the inhibition of mitral cells evoked by stimulation of the lateral olfactory tract. As ketamine does not influence the inhibitory action of GABA (Anis et al. 1983) these results suggest that both ketamine and MK801 block inhibition by an action on intrinsic excitatory feed-back circuits in the olfactory bulb.     

Effect of subchronic phencyclidine administration on sucrose preference and hippocampal parvalbumin immunoreactivity in the rat

Persistent blockade of NMDA receptor function by repeated phencyclidine dosing produces pathophysiological changes that model deficits observed in schizophrenia. The present study investigates the effects of subchronic phencyclidine administration (PCP; 2 or 5 mg/kg bi-daily for 7 days followed by a drug-free period) on sucrose choice, a measure of anhedonia. Sucrose preference in a two-bottle sucrose–water choice test was assessed 1 and 2 weeks after PCP. Results showed no differences in sucrose intake between PCP rats and controls, nor a difference in water intake or total volume of liquid consumed at either time-point. Six weeks post-PCP, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and CA2/3 regions. These results demonstrate that while subchronic PCP may not be a valid model for the negative symptom of anhedonia observed in schizophrenia, it induces pathology in the brain in hippocampal subregions that are reminiscent of changes observed in schizophrenia.     

Strain-Specificity in Nicotine Attenuation of Phencyclidine-Induced Disruption of Prepulse Inhibition in Mice: Relevance to Smoking in Schizophrenia Patients

Schizophrenia patients may exhibit high tobacco smoking rates in part to self-medicate sensory gating deficits with nicotine contained in tobacco. To test this hypothesis, we induced sensori-motor gating deficits in four mouse strains with phencyclidine, a noncompetitive antagonist of glutamatergic N -methyl-d-aspartate receptors. Nicotine attenuated the disruption in prepulse inhibition induced by phencyclidine in DBA/2J and C3H/HeJ but not in C57BL/6J or 129T2/SvEmsJ mice. These results highlight genetic variations in the regulation by nicotinic cholinergic systems of the dysfunction in glutamatergic transmission contributing to gating deficits in schizophrenia. Further, these findings support the hypothesis of self-medication of gating deficits in schizophrenia through tobacco smoking, and suggest that treatments targeting genetic dysfunctions in nicotinic-glutamatergic interactions that would treat cognitive deficits will assist schizophrenia patients in minimizing tobacco smoking.     

Interaction of Mg2+ and phencyclidine in use-dependent block of NMDA channels.

The interaction between Mg2+ and phencyclidine (PCP) in blocking open N-methyl-D-aspartate (NMDA) channels was investigated in Xenopus oocytes injected with rat brain mRNA. These receptors exhibit the pharmacological and physiological properties of the neuronal receptors, and the oocyte is readily amenable to electrical recording and application of well-controlled chemical stimuli. We found that Mg2+ at physiological concentrations greatly impeded the ability of PCP to block the NMDA channel. The interaction between Mg2+ and PCP was competitive; 0.5 mM Mg2+ caused a four-fold decrease in the potency of PCP in blocking open NMDA channels. Moreover, Mg2+ speeded the recovery from PCP block in the presence of agonist, suggesting that Mg2+ reduced reblock of NMDA channels by PCP that had escaped from open channels. Our observations suggest that the presence of Mg2+ in the channel tends to prevent PCP entry and block. Since depolarization is likely to reduce channel occupancy by Mg2+ more than that by PCP, neural activity may have an important influence on the actions of PCP and related drugs.