Verapamil and flunarizine inhibit phencyclidine-induced effects: an EEG and behavioural study in rats.

The influence of verapamil and flunarizine on phencyclidine-induced effects has been studied in adult male rats. Both verapamil (25 and 100 micrograms/10 microliters, i.c.v.) and flunarizine (40 and 60 mg/kg, i.p.) significantly reduced behavioural (mean intensity of ataxia, mean duration of head weaving) and the EEG (increase in the mean voltage of background activity of the EEG) effects induced by phencyclidine 5 mg/kg (i.p.). It was reported previously that nimodipine and diltiazem significantly potentiate effects induced by phencyclidine. The contrasting results obtained with verapamil and flunarizine, suggest that these drugs may modulate effects induced by phencyclidine by acting at sites other than NMDA receptor-coupled "L"-type calcium channel.     

Evidence of the involvement of D1 dopamine receptors in PCP-induced stereotypy and ataxia in rabbits

A behavioural study on the effects of D1 and D2 dopamine receptor antagonists (SCH 23390 and sulpiride respectively) and of an A1 adenosine receptor agonist (N6-L-phenylisopropyladenosine, L-PIA) against phencyclidine (PCP)-induced effects was assessed in adult male rabbits. SCH 23390 (0.003-0.01 mg/kg i.v.) and sulpiride (12.5 mg/kg i.v.) were able to significantly prevent PCP-induced stereotypy. Ataxia was reduced by SCH 23390 (0.003 mg/kg i.v.), while it was potentiated by sulpiride (12.5 mg/kg i.v.). Given alone at 12.5 mg/kg, sulpiride induced some EEG and behavioural effects in rabbits, while SCH 23390 (0.003 and 0.01 mg/kg) did not. L-PIA prevented both PCP-induced stereotypy and ataxia at the dose (0.1 mg/kg i.v.) devoid of behavioural or EEG effects by itself. Our results suggest that D1 dopamine receptors might play a more important role than D2 receptors in the expression of PCP-induced behaviour. They also propose that A1 adenosine receptors might be involved (e.g. via an influence on the dopamine release) in the behavioural effects of PCP.     

Calcium channel antagonists suppress nicotine-induced place preference and locomotor sensitization in rodents

The influence of calcium channel antagonists on the behavioral sensitization to nicotine-induced hyperlocomotion and place preference was investigated. Locomotor sensitization in mice was produced by injecting nicotine (0.5 mg/kg, i.p.) for 5 consecutive days before placement in an apparatus in which locomotor activity was evaluated for 1 h. One week later, activity of mice was recorded after challenge with the same dose of nicotine. The L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, i.p.), verapamil (5, 10 and 20 mg/kg, i.p.) and diltiazem (5, 10 and 20 mg/kg, i.p.) were injected 15 min before each injection of nicotine (induction of sensitization) or acutely 15 min before a challenge nicotine injection (expression of sensitization). It was shown that the calcium channel blockers attenuated both the induction and expression of nicotine-induced locomotor sensitization in a dose-dependent manner. In the place preference paradigm, nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., 4 drug sessions). Pretreatment with nimodipine (10 mg/kg, i.p.), verapamil (10 mg/kg, i.p.) and diltiazem (10 mg/kg, i.p.) blocked nicotine-induced place conditioning. These results suggest the common calcium-dependent mechanisms of nicotine-induced behavioral sensitization and place preference.     

Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, alpha(1)- and 5-HT(2A)-receptors.

1. The electroencephalographic (EEG) effects of the propsychotic agent phencyclidine (PCP), were studied in conscious rats using power spectra (0 - 30 Hz), from the prefrontal cortex or sensorimotor cortex. PCP (0.1 - 3 mg kg(-1) s.c.) caused a marked dose-dependent increase in EEG power in the frontal cortex at 1 - 3 Hz with decreases in power at higher frequencies (9 - 30 Hz). At high doses (3 mg kg(-1) s.c.) the entire spectrum shifted to more positive values, indicating an increase in cortical synchronization. MK 801 (0.05 - 0.1 mg kg(-1) i.p.) caused similar effects but with lesser changes in power. 2. In contrast, the non-competitive AMPA antagonists GYKI 52466 and GYKI 53655 increased EEG power over the whole power spectrum (1 - 10 mg kg(-1) i.p.). The atypical antipsychotic clozapine (0.2 mg kg(-1) s.c.) synchronized the EEG (peak 8 Hz). The 5-HT(2A)-antagonist, M100907, specifically increased EEG power at 2 - 3 Hz at low doses (10 and 50 microg kg(-1) s.c.), whereas at higher doses (0.1 mg kg(-1) s.c.) the profile resembled that of clozapine. 3. Clozapine (0.2 mg kg(-1) s.c. ), GYKI 53655 (5 mg kg(-1) i.p.), prazosin (0.05 and 0.1 mg kg(-1) i.p.), and M100907 (0.01 and 0.05 mg kg(-1) s.c.) antagonized the decrease in power between 5 and 30 Hz caused by PCP (1 mg kg(-1) s.c.), but not the increase in power at 1 - 3 Hz in prefrontal cortex.     

Haloperidol-induced catalepsy is influenced by calcium channel antagonists

The effect of pretreatment of some voltage-dependent calcium channel antagonists was studied on haloperidol-induced catalepsy in male Wistar rats. Cataleptogenic effect of haloperidol (0.25 mg/kg, i.p.) was enhanced dose-dependently by nitrendipine (5, 10 and 20 mg/kg, i.p.) and the highest dose of nimodipine (20 mg/kg, i.p.). Neither verapamil (10 and 20 mg/kg, i.p.) nor diltiazem (10 and 20 mg/kg, i.p.) influenced the score of haloperidol-induced catalepsy in rats. These results suggest the involvement of calcium-dependent mechanisms in the generation of haloperidol-induced catalepsy. The possible involvement of dopaminergic mechanisms and modification by calcium channel antagonists are discussed.     

Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies

Administration of the non-competitive NMDA receptor antagonists phencyclidine (PCP) (0.6-5 mg/kg s.c.) and MK-801 (0.1-0.8 mg/kg s.c. ) dose-dependently increased locomotor activity in the rat. Pre-treatment of rats with SB 221284 (0.1-1 mg/kg, i.p.) a 5-HT(2C/2B) receptor antagonist or SB 242084 (1 mg/kg, i.p.) a selective 5-HT(2C) receptor antagonist, doses shown to block mCPP induced hypolocomotion, significantly enhanced the hyperactivity induced by PCP or MK-801. Neither compound altered locomotor activity when administered alone. Furthermore, systemic administration of PCP (5 mg/kg s.c.) increased nucleus accumbens dopamine efflux in the rat to a maximum of approximately 220% of basal, 40-60 min after administration. Pre-treatment with the 5-HT(2C/2B) receptor antagonist SB 221284 (1 mg/kg, i.p.) and the 5-HT(2C) receptor antagonist SB 242084 (1 mg/kg i.p.) failed to affect nucleus accumbens dopamine efflux per se but significantly enhanced the magnitude and duration of the increase induced by PCP. However, the time course of the neurochemical and behavioural effects were qualitatively and quantitatively different, suggesting the potential involvement of other neurotransmitter pathways. Nevertheless, the present results provide behavioural and neurochemical evidence which demonstrate that, in the absence of effects per se, blockade of 5-HT(2C) receptors enhanced the activation of mesolimbic dopamine neuronal function by the non-competitive NMDA receptor antagonists PCP and MK-801.     

Protective effect of adenosine reuptake inhibitors in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes

Chronic administration of typical neuroleptics is known to cause persistent oral dyskinesia in rats, an alleged animal model of tardive dyskinesia (TD). The pathophysiology of the syndrome remains unclear. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides gamma-aminobutyric acid. Based on the hypothesis that adenosinergic receptor system may involve in the pathogenesis of TD, we investigated the effect of dipyridamole (5 and 10 mg/kg, i.p.), an adenosine reuptake inhibitor and nimodipine (10 and 20 mg/kg, i.p.) an adenosine transport inhibitor in haloperidol-induced TD by using different behavioural, biochemical and neurochemical parameters in rats. Chronic administration of haloperidol (1 mg/kg, i.p., for 21 days) significantly increased vacuous chewing movements, tongue protrusion, facial jerking which was prevented by adenosine reuptake inhibitors. Chronic administration of haloperidol also resulted in the development of dopamine sensitivity as suggested by increased locomotor activity and stereotypy and decreased % retention time on elevated plus maze paradigm. Pretreatment with adenosine reuptake/transport inhibitors, dipyridamole and nimodipine prevented all these behavioural changes. Chronic administration of haloperidol also resulted in increased oxidative damage in all brain regions which was prevented dose-dependently by both dipyridamole and nimodipine in different brain regions. Chronic administration of haloperidol resulted in decreased turnover of dopamine and norepinephrine in both cortex and subcortical regions which was dose-dependently prevented by adenosine reuptake/transport inhibitors. The major findings of the present study suggested that adenosine reuptake inhibitors dipyridamole and nimodipine could be a possible therapeutic option in neuroleptic induced TD.     

Dihydropyridine calcium channel antagonists as antidepressant drugs in mice and rats

A pharmacological profile of the effects of nimodipine, nifedipine and nitrendipine (2.5-20 mg/kg p.o.) in several models which are indicative of possible antidepressant activity, was tested in mice and rats. These compounds, as well as verapamil (short-lasting effect), but not diltiazem, reduced the hypothermia induced by a large dose of apomorphine in mice. Nimodipine and nifedipine slightly increased the behavioural action of L-DOPA in mice, and nimodipine facilitated the action of imipramine in the L-DOPA test. Nimodipine, nifedipine, verapamil and diltiazem slightly reduced the clonidine-induced hypoactivity in rats. The hypothermia induced by reserpine or clonidine in mice was not changed by these drugs. Various antidepressants (imipramine, amitriptyline, citalopram, mianserin) used in the behavioural despair test in mice, in doses which were not effective by themselves, increased the immobility-reducing effect when given jointly with 1,4-dihydropyridine calcium channel antagonists (5 mg/kg). The above results indicate that the psychopharmacological profile of nimodipine, nifedipine and nitrendipine resembles that of antidepressants in some tests only; moreover, these results support the assumption that concomitant administration of antidepressants and 1,4-dihydropyridine calcium channel antagonists may result in a greater antidepressant efficacy.     

Comparison of the behavioral and biochemical effects of the NMDA receptor antagonists, MK-801 and phencyclidine

The behavioral and biochemical effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 [+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) were compared with those of phencyclidine (PCP). In the dose range used in this study, MK-801 (0.125-0.5 mg/kg i.p.) produced ataxia and other behavioral responses which were similar to PCP (5-10 mg/kg i.p.). However, turning and backpedalling induced by MK-801 were not dose-dependent and less intense at the dose producing approximately the same level of ataxia as PCP. Neurochemically, MK-801 (0.5 mg/kg i.p.) increased dopamine turnover in the cortex and striatum, but had no effect on 5-HT systems. It was also 3.4 times less potent in inhibiting 5-HT uptake than PCP. These results suggest that the behavioral responses induced by MK-801 involve primarily the PCP receptor and the dopamine system, and that the differences from PCP reflect a reduced effect on the 5-HT neuronal system.     

Influence of some dopaminoceptor agents on nitrazepam-induced sleep in the domestic fowl (Gallus domesticus) and rats

The influence of apomorphine, levodopa and haloperidol was studied on nitrazepam sleep using young chicks and rats. In addition, the influence of dopamine and ADTN was studied in young chicks. Nitrazepam dose-dependently (0.4-51.2 mg/kg, i.p.) induced behavioural sleep in chicks. However, higher doses of nitrazepam (12.8-51.2 mg/kg, i.p.) were required to induce behavioural sleep in rats. Dopamine (12.5-100 mg/kg, i.p.) and ADTN (2.5-80 mg/kg, i.p.) delayed the onset but prolonged nitrazepam sleep in chicks: these effects were statistically significant. Levodopa (12.5-100 mg/kg, s.c.) and apomorphine (0.2-0.8 mg/kg, s.c.) profoundly delayed the onset and shortened the duration of nitrazepam sleep in both chicks and rats. Noradrenaline (20-80 mg/kg, i.p.) shortened the onset and prolonged nitrazepam sleep in chicks. Pimozide (1-8 mg/kg, i.p.) potentiated nitrazepam sleep and antagonized the effects of dopamine, levodopa and ADTN on nitrazepam sleep in chicks. Similarly, haloperidol (0.5-1.0 mg/kg, i.p.) potentiated nitrazepam sleep and antagonized the effects of levodopa and apomorphine on nitrazepam sleep in rats. The EEG synchronization and decreased EMG induced by nitrazepam (1.6 mg/kg, i.p., and 12.8 mg/kg, i.p., for chicks and rats, respectively) were antagonized by levodopa (12.5 mg/kg, s.c.). The behavioural and electroencephalographical results suggest that enhancement of dopaminergic neurotransmission may be involved in the mechanisms of wakefulness in both chicks and rats.     

The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse--3. Quinine.

It has been shown that caesium, which shares properties with quinine as a K(+)-channel blocker, enhanced 5-HT-mediated behaviour in both rats and mice. It was therefore of interest to investigate the effects of quinine on 5-HT-mediated behaviour in the rat and mouse. Quinine, dose-dependently (ED50 = 5 mg/kg), produced the 5-HT behavioural syndrome in rats pre-treated with tranylcypromine (TCP) (15 mg/kg, i.p.). p-Chlorophenylalanine (i.p., 300 mg/kg x2) or (-)-propranolol (20 mg/kg, i.p.), pindolol (4 mg/kg, i.p.) and ritanserin (0.4 mg/kg, s.c.), all prevented the behavioural syndrome induced by quinine (72 mg/kg, i.p.) plus TCP. The administration of quinine (72 mg/kg, i.p.) enhanced the 5-HT syndrome elicited by p-chloramphetamine (4 mg/kg, i.p.) and the 5-HT agonists, 8-OH-DPAT (0.5 mg/kg, s.c.), 5-MeODMT (2 mg/kg, i.p.), DOI (8 mg/kg, s.c.) and quipazine (25 mg/kg, i.p.) in rats. Pretreatment with quinine also potentiated the 5-HT2-mediated head-twitch in the mouse but had no effect on the hypothermia in the mouse, induced by 8-OH-DPAT (0.5 mg/kg, s.c.). Quinine also enhanced the rate of synthesis of 5-HT in the brain of the rat. On the basis of these findings, together with those in the preceding two papers, it is suggested that the effects of rubidium, caesium and quinine, to enhance differentially various aspects of 5-HT function are mediated by actions on 5-HT-modulated K(+)-channels. This conclusion is also discussed in relation to the actions of lithium and electroconvulsive shock on 5-HT function in brain and the treatment of manic-depressive disease.     

Modulation of the ethanol-like discriminative stimulus effects of diazepam and phencyclidine by L-type voltage-gated calcium-channel ligands in rats

Rationale: Administration of voltage-gated calcium-channel (VGCC) modulators with ethanol can result in enhancement or attenuation of some behavioral effects of ethanol, including its discriminative stimulus effects. Objectives: The present study used a drug- discrimination paradigm to characterize modulation of the ethanol-like discriminative stimulus effects of a γ-amino-butyric acid (GABA)_A and N-methyl-d-aspartate (NMDA) ligand by administration of VGCC ligands. Methods: Two groups of adult male Long-Evans rats were trained to discriminate either 1.0 g/kg ethanol (n=8) or 2.0 g/kg ethanol (n=9) from water under a fixed-ratio (FR) 20 schedule of food presentation. Following training, ethanol substitution tests were conducted with cumulative doses of the GABA_A-positive modulator diazepam (0.3–10 mg/kg, i.p.) (DZP) and the uncompetitive NMDA antagonist phencyclidine (0.3–5.6 mg/kg, i.p.) (PCP). Next, a single dose of the VGCC antagonist nimodipine, nifedipine, isradipine, or the VGCC agonist (–)-BAY k 8644 (0.3 mg/kg, i.p.) was administered prior to a cumulative DZP or PCP dose–response determination. Results: None of the VGCC modulators produced robust or consistent alterations in the ethanol-like discriminative stimulus effects of DZP in animals trained with either 1.0 g/kg or 2.0 g/kg ethanol. However, the ethanol-like discriminative stimulus effects of PCP were significantly enhanced in the presence of the VGCC antagonists and attenuated in the presence of the agonist in animals trained with 2.0 g/kg ethanol. Conclusions: Overall, these data show that VGCC modulation is not a robust component of ethanol-like discriminative stimulus effects of DZP in animals trained with 1.0 g/kg or 2.0 g/kg ethanol. However, the ethanol-like effects of PCP, particularly at higher training doses, appear to be modulated by dihydropyridine-sensitive VGCCs. Received: 26 August 1999 / Final version: 22 October 1999     

Behavioural and anti-psychotic effects of Ca2+ channel blockers in rhesus monkey

The potential utility of Ca2+ channel blockers in the treatment of various psychiatric disorders has been recently suggested. In the present study, the behavioural and anti-psychotic effects of Ca2+ channel blockers were investigated in unrestrained rhesus monkeys (Macaca mulatta) living together in a colony. The different behaviours categorised as social, solitary and abnormal were video recorded and analysed. Graded doses of verapamil (5-20 mg/kg, i.m.) and nimodipine (7.5-30 mg/kg, p.o.) produced a mild decrease in social and solitary behaviour without producing any cataleptic posture in the tested monkeys. In order to determine potential antipsychotic effects, Ca2+ channel blockers were studied in the model of amphetamine-induced psychosis. Amphetamine, at the dose of 2 mg/kg, i.m., induced suppression of approach, contact, grooming, and feeding, whilst vigilance (checking), stereotyped behaviour and oral hyperkinesia were increased in the monkeys. Pre-treatment with verapamil (10 and 20 mg/kg, i.m.) significantly suppressed amphetamine-induced hypervigilance, stereotypy, oral hyperkinesia and tachypnoea but was unable to reverse other amphetamine-induced behavioural effects. Nimodipine showed insignificant anti-psychotic effects at both 15 and 30 mg/kg doses. These results suggest that verapamil has a definite antipsychotic effect without any extrapyramidal side effects and thus may be of clinical significance in the treatment of psychosis.     

The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor

Using a two-lever operant drug discrimination paradigm, rats have been trained to discriminate between the administration of saline and R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one, 30 mg/kg i.p.) an antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. Drug-appropriate responding was not induced in stimulus generalisation experiments when the non-competitive NMDA receptor antagonist, phencyclidine (PCP, 1-8 mg/kg i.p.) was substituted for (+)-HA-966. Similarly, (+)-HA-966 (6-50 mg/kg i.p.) did not induce drug-appropriate responding in animals trained to discriminate PCP (3 mg/kg i.p.) from saline. The results suggest that the behavioural profile of compounds attenuating the actions of NMDA via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMDA receptor complex.     

MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain

A novel selective sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), inhibits phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced behaviors in animal models. In this study, we measured extracellular dopamine and serotonin levels in the rat brain after treatment with MS-377 alone, using in vivo microdialysis. We also examined the effects of MS-377 on extracellular dopamine and serotonin levels in the rat medial prefrontal cortex after treatment with PCP. MS-377 itself had no significant effects on dopamine release in the striatum (10 mg/kg, p.o.) nor on dopamine or serotonin release in the medial prefrontal cortex (1 and 10 mg/kg, p.o.). PCP (3 mg/kg, i.p.) markedly increased dopamine and serotonin release in the medial prefrontal cortex. MS-377 (1 mg/kg, p.o.), when administered 60 min prior to PCP, significantly attenuated this effect of PCP. These results suggest that the inhibitory effects of MS-377 on PCP-induced behaviors are partly mediated by inhibition of the increase in dopamine and serotonin release in the rat medial prefrontal cortex caused by PCP.     

The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse--2. Caesium.

Rats and mice were given either CsCl (3 mmol/kg, s.c.) or saline (as control), twice daily for 3 days. The administration of tranylcypromine (TCP) (15 mg/kg, i.p.) to rats pretreated with CsCl produced the 5-HT behavioural syndrome. Pretreatment with CsCl also enhanced the syndrome induced by p-chloroamphetamine (3 mg/kg, i.p.) or by TCP (15 mg/kg, i.p.) plus L-tryptophan (50 mg/kg, i.p.). p-Chlorophenylalanine (300 mg/kg, i.p., daily on 2 consecutive days) or (-)-propranolol (20 mg/kg, i.p.), pindolol (4 mg/kg, i.p.) and ritanserin (0.4 mg/kg, s.c.), all prevented the behavioural syndrome induced by CsCl and TCP in rats. Pretreatment of rats with CsCl potentiated the 5-HT syndrome, elicited by the 5-HT agonists, 8-OH-DPAT (0.5 mg/kg, s.c.), 5-MeODMT (2 mg/kg, s.c.) and quipazine (25 mg/kg, i.p.). Pretreatment with CsCl potentiated the 5-HT2-mediated head-twitches in the mouse but had no effects on hypothermia in the mouse induced by 8-OH-DPAT (0.5 mg/kg, s.c.). The rate of synthesis of 5-HT in the whole brain (excluding cerebellum) was enhanced by pretreatment with CsCl. The enhancement of 5-HT neuronal function by caesium may be related to its ability to block K(+)-channels in neuronal membranes.     

Calcium channel antagonists attenuate cross-sensitization to the rewarding and/or locomotor effects of nicotine, morphine and MK-801

The present study focused on the evaluation of behavioural cross-sensitization, particularly in locomotor activities and conditioned rewarding effects, between nicotine and morphine, cocaine, amphetamine or MK-801. Nicotine (0.5 mg kg(-1))-experienced mice manifested an enhanced locomotor response to morphine (5 mg kg(-1)) or MK-801 (0.3 mg kg(-1)). No cross-sensitization was observed between nicotine and amphetamine (2 mg kg(-1)) or cocaine (15 mg kg(-1)). Additionally, the L-type voltage-dependent calcium-channel antagonists, nimodipine and verapamil, but not diltiazem, at a dose of 20 mg kg(-1) injected before morphine or MK-801 challenge, blocked the expression of this cross-sensitization. In the second test, an enhancement of morphine place conditioning in rats pre-exposed to nicotine (0.5 mg kg(-1), injected daily for 5 days) was demonstrated. After two conditioning sessions, morphine (5 mg kg(-1)) induced a clear place preference only in animals that had previously received nicotine injections. The administration of nimodipine (10 and 20 mg kg(-1)), verapamil (10 and 20 mg kg(-1)) and diltiazem (10 and 20 mg kg(-1)) prior to nicotine dose-dependently prevented this sensitization to the rewarding effect of morphine produced by prior injections of nicotine. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in the appetitive effects of nicotine and morphine and in the sensitized locomotor stimulant effects of nicotine and morphine or MK-801.     

Analysis of extracellular DOPAC, HVA and 5-HIAA in rat striatum in vivo by differential pulse voltammetry: effect of phencyclidine, haloperidol and their coadministration

Phencyclidine (PCP, 10 mg/kg s.c.) produced a marked reduction in the extracellular concentrations of DOPAC and HVA in the rat striatum in vivo, as measured by differential pulse voltammetry. In contrast, extracellular 5-HIAA levels were significantly elevated. Haloperidol (1 mg/kg i.p.) increased DOPAC and HVA, and reduced 5-HIAA, in agreement with previous studies. When PCP and haloperidol were injected together, the effects of PCP were abolished. These results suggest that PCP administration leads to increased activation of dopamine receptors, which results in a decrease in striatal dopamine turnover and an increase in striatal serotonin turnover.     

Chronic phencyclidine,like amphetamine,produces a decrease in [3H]spiroperidol binding in rat striatum

Rats were treated with d-amphetamine sulfate (5 and 10 mg/kg i.p.) and phencyclidine (PCP) (5 mg/kg i.p.) twice per day. After 21 days, [³H]spiroperidol binding in striatum was reduced by all treatments; receptor number (B_max) and not affinity (K_D) was affected. These results suggest that the psychotic effect of PCP may, like those of amphetamine, involve changes in dopamine receptors.     

Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit

The non-competitive NMDA receptor antagonist phencyclidine (PCP) is known to produce a discriminative stimulus in rats. The first aim of the present study was to investigate which NMDA receptor subtype(s) is involved in this effect of PCP. Rats were trained to discriminate PCP (2 mg/kg; i.p.) from saline in a two lever operant task. The NMDA channel blocker, (+)MK-801 (0.1 mg/kg; i.p.) and the competitive NMDA receptor antagonist SDZ 220-581 (3 mg/kg; i.p.) produced 76% of PCP-lever selection (ED50=0.045 and 2 mg/kg, respectively), whereas their respective inactive enantiomers (-)MK-801 (0.025-0.1 mg/kg) and SDZ 221-653 (2-5 mg/kg) induced less than 30% of PCP-appropriate responding. Another competitive NMDA antagonist, SDZ EAB-515 (30 mg/kg; i.p.), induced 63% of PCP-lever responding (ED50=23.48 mg/kg). The selective antagonist of NMDA receptors containing the NR1A/NR2B-subunits Ro 25-6981 (20 mg/kg; i.p.) resulted in a complete substitution (more than 80% of PCP-lever selection) for PCP (ED50=8.59 mg/kg). In contrast, the NR1A/NR2A NMDA receptor-preferring antagonist NVP-AAM077 (2-10 mg/kg; i.p.) failed to produce PCP-like discriminative stimuli. At high doses SDZ 220-581 (ED50=2.44), NVP-AAM077 (ED50=8.33) and SDZ EAB-515 (ED50=25.81) decreased the performance of the rats in this operant task. The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied. PCP (0.5-2 mg/kg; s.c.), SDZ 220-581 (0.5-5 mg/kg; s.c.), SDZ EAB-515 (1-30 mg/kg; i.p.) and Ro 25-6981 (5-20 mg/kg; i.p.) disrupted PPI and at high doses produced hyperlocomotion. In contrast, NVP-AAM077 (5-20 mg/kg; i.p.) did not disrupt PPI and reduced locomotor activity. In conclusion, it appears that the NMDA receptor containing the NR2B, rather than the NR2A subunit, may play a major role in the PCP-like discriminative stimulus. In addition, sensory motor gating disturbances associated with NMDA antagonists do not seem to result from a blockade of NR1/NR2A-containing NMDA receptors.