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PubMed2004

Phencyclidine-induced behaviour in mice prevented by methylene blue.

Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like symptoms can be induced in humans by phencyclidine (PCP), a drug with marked psychotomimetic properties. Phencyclidine disrupts prepulse inhibition of acoustic startle in rodents, a measure which has also been shown to be disrupted in schizophrenic patients. This effect is blocked by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide plays an important role in this effect of phencyclidine. Methylene blue, a guanylate cyclase and nitric oxide syntase inhibitor, has shown therapeutic value as an adjuvant to conventional antipsychotics in the therapy of schizophrenia. The aim of the present study was to investigate if phencyclidine-(4 mg/kg)induced disruption of prepulse inhibition could be affected by methylene blue (50 or 100 mg/kg) in mice. Furthermore, the effect of methylene blue (50 mg/kg) on phencyclidine-(4 mg/kg)induced hyperlocomotion was investigated. The present study shows that phencyclidine readily disrupts prepulse inhibition in mice without affecting pulse-alone trials. It was also found that methylene blue prevents the decrease in prepulse inhibition caused by phencyclidine in a dose-related manner. Furthermore, the increase in locomotor activity caused by phencyclidine was reduced by pretreatment with methylene blue. The results from the present study further support the suggestion that the nitric oxide synthase/guanylate cyclase pathway is involved in pharmacological and behavioural effects of phencyclidine. Since phencyclidine as well exerts psychotomimetic characteristics, agents that interfere with the nitric oxide synthase/guanylate cyclase pathway may be of therapeutic value also in the treatment of schizophrenia.

Animals↗
PubMed1988

The discriminative stimulus effects of N-methyl-D-aspartate antagonists in phencyclidine-trained rats.

The discriminative stimulus effects of two competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-7-phosphonoheptanoate (APH) and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP), were assessed in rats trained to discriminate phencyclidine from saline. Systemically administered APH (10-60 mg/kg i.p.) failed to elicit phencyclidine-lever responding; however, partial generalization from phencyclidine occurred following intracerebroventricular (i.c.v.) administration of APH (1.5-30 micrograms). Systemic and central administration of CPP (3-30 mg/kg i.p.; 0.1-10 micrograms i.c.v.) also resulted in partial generalization from phencyclidine. Partial generalization was also obtained with methohexital (5-30 mg/kg i.p.). However, generalization to APH, CPP and methohexital was usually accompanied by decreased response rates, and response rate decreases frequently occurred without appreciable phencyclidine-lever selection, indicating that these drugs also had no phencyclidine-like behavioral effects. The drug di-ortho-tolyl guanidine (DTG) which binds with high-affinity to sigma receptors failed to elicit phencyclidine-lever responding, even at doses which reduced response rates. These findings suggest that although competitive NMDA antagonists share some discriminative stimulus properties with phencyclidine, there is not a complete overlap in the discriminative stimulus properties of competitive and non-competitive NMDA antagonists. Furthermore, the discriminative stimulus effects of APH and CPP were no more similar to phencyclidine than those of methohexital.

2-Amino-5-phosphonovalerate↗
PubMed1988

Receptor specific inhibition of N-methyl-D-aspartate stimulated 22Na flux from rat hippocampal slices by phencyclidine and other drugs.

Phencyclidine inhibited the flux of 22Na from hippocampal slices of the rat stimulated by N-methyl-D-aspartate (NMDA) in a concentration-dependent manner and consistent with the subclass of excitatory amino acid receptors, with a close interaction between NMDA and phencyclidine receptors. The inhibition by phencyclidine of the NMDA-stimulated flux of 22Na was non-competitive, in contrast to that produced by D-2-amino-5-phosphonovalerate. Other compounds which produce stereotyped behavior in vivo also inhibited the NMDA-stimulated flux of 22Na and the rank of the percentage inhibition of the NMDA-stimulated flux correlated with the affinities at the phencyclidine receptor with 97% confidence. The structural diversity and selectivity for the phencyclidine receptor of those compounds which inhibited the NMDA-stimulated flux of 22Na argue that the interaction was at the phencyclidine receptor. The presence of magnesium did not alter the relative magnitude of inhibition by phencyclidine, suggesting that the phencyclidine site is separate from the pressumably, channel-blocking magnesium site. Thus, the data of the present study support a model where the phencyclidine site is separate from the NMDA recognition site and from the presumed channel-blocking site of magnesium within the NMDA-associated ion channel.

Animals↗
PubMed1984

Effects of pentobarbital and d-amphetamine on oral phencyclidine self-administration in rhesus monkeys.

Three rhesus monkeys self-administered phencyclidine (0.25 mg/ml) during daily 3-hr sessions. Water was also available under a concurrent fixed-ratio (FR) 16 schedule. In Experiment 1, saline or three doses of pentobarbital (2.5, 5 or 10 mg/kg) were injected 10 min before phencyclidine (and water) self-administration sessions. The 2.5 mg/kg pentobarbital dose increased phencyclidine-maintained responding, the 5 mg/kg dose produced mixed effects among the three monkeys, and the 10 mg/kg dose consistently decreased phencyclidine-maintained responding. Subsequently, a saccharin solution (0.03% wt/vol) replaced phencyclidine, and the pentobarbital pretreatment procedure was repeated. Pentobarbital produced dose-related decreases in saccharin-maintained responding. In Experiment 2, saline or three doses of d-amphetamine (0.05, 0.1 or 0.2 mg/kg) were injected 10 min before the phencyclidine self-administration sessions. The 0.05 mg/kg dose produced increases in phencyclidine-maintained responding, while the two higher doses produced dose dependent decreases in responding. When a saccharin solution (0.03%, wt/vol) replaced phencyclidine during the daily sessions, d-amphetamine produced only dose-related decreases in saccharin-maintained responding. These results indicate that pentobarbital and d-amphetamine have a biphasic effect on phencyclidine-maintained behavior; low doses increased responding and high doses decreased responding.

Animals↗
PubMed1984

The effect of second-order schedule history on fixed-ratio performance maintained by orally-delivered phencyclidine in rhesus monkeys.

Thirteen monkeys were trained to self-administer orally-delivered phencyclidine (0.25 mg/ml) and water under a concurrent fixed ratio (FR) 16 schedule. Phencyclidine was available from one lip-operated drinking device and water was available from another drinking device during daily 3-hr sessions. Seven monkeys were trained to respond under a second-order FR 240 (FR 20: brief stimulus) schedule. Upon completion of 4800 responses, the monkeys were allowed to self-administer 300 phencyclidine deliveries under an FR 1 schedule. After a mean of 33.3 sessions of second order schedule training, including 10 sessions at the terminal parameter, the monkeys were returned to the concurrent FR 16 schedule. Phencyclidine-maintained responding persisted at rates that were 42 percent higher than before second-order schedule training; however, concurrent water-maintained behavior increased only slightly. A second group of three monkeys were treated in an identical manner except that during second-order schedule training they received a saccharin solution (0.05%, wt/vol) instead of phencyclidine. After a mean of 30 sessions of second-order schedule training, including 10 sessions at the terminal parameter, the monkeys were returned to the concurrent FR 16 schedule, and there was no consistent change in phencyclidine or water deliveries. A third group of three monkeys received 300 phencyclidine deliveries at the same time after session onset and for the same total number of sessions as the monkeys that received second-order schedule training with phencyclidine; however, this group was not required to respond under the second-order schedule to gain access to the phencyclidine deliveries.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Asymmetric cross-sensitization to the locomotor stimulant effects of phencyclidine and MK-801.

Chronic administration of a psychomotor stimulant has been shown to produce progressively enhanced effects, a phenomenon called "reverse tolerance" or sensitization. Sensitization which develops to the psychomotor stimulant effect of a drug generalizes to drugs with similar neurochemical mechanisms of action, a phenomenon called cross-sensitization. The present study compared the psychomotor stimulant effects of phencyclidine and MK-801, examined the effects of the daily injection of phencyclidine and MK-801 on locomotor activity and investigated whether reciprocal cross-sensitization occurred between phencyclidine and MK-801. Adult female Sprague-Dawley rats were used. Their locomotor activity was measured automatically for a 2 h period following drug injection. Phencyclidine and MK-801 both increased locomotor activity. Four daily injections of phencyclidine in a dose of 3.2 mg/kg i.p., or MK-801 in a dose of 0.32 mg/kg i.p., produced sensitization to locomotor activity. Moreover, MK-801 sensitized rats showed cross-sensitization to phencyclidine. However, phencyclidine sensitized rats did not show cross-sensitization to MK-801. This finding suggests that there are significant differences in the neurochemical mechanisms underlying phencyclidine-induced and MK-801-induced sensitization. Phencyclidine sensitization may not be mediated by NMDA receptors.

Animals↗
PubMed1988

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.

Adrenal Medulla↗
PubMed1998

Differential effects of the strychnine-insensitive glycine site antagonist (+)-HA-966 on the hyperactivity and the disruption of prepulse inhibition induced by phencyclidine in rats.

The amplitude of the acoustic startle response is reduced by a preceding weak stimulation which by itself does not elicit the startle response. This phenomenon is named prepulse inhibition (PPI) and is thought to reflect the operation of the sensorimotor gating system, which is deficient in schizophrenic patients. It has been reported that an antagonist at the strychnine-insensitive glycine site has atypical neuroleptic properties in experimental animals. To evaluate the effect of an antagonist at the site on disrupted PPI, we examined whether (+)-HA-966 antagonizes phencyclidine-induced (3 mg/kg s.c.) and apomorphine-induced (1 mg/kg s.c.) disruption of PPI in rats. In addition, its effect on phencyclidine-induced hyperactivity was tested. The effects of (+)-HA-966 were compared with those of haloperidol, a typical neuroleptic. (+)-HA-966 antagonized phencyclidine-induced hyperactivity, but not phencyclidine-induced disruption of PPI, which is thought to be a model of refractory symptoms in schizophrenia. Furthermore, (+)-HA-966 did not improve the deficit in PPI induced by apomorphine. On the other hand, haloperidol antagonized phencyclidine-induced hyperactivity and the disruption of PPI by apomorphine, but not by phencyclidine. The results of this study might mean that (+)-HA-966 antagonizes the behavioral change induced by excessive dopamine release (the increment of locomotor activity due to phencyclidine), but not the effect induced by a direct dopamine agonist or the dopamine-independent effect of phencyclidine (the disruption of PPI). Thus, as regards antagonism of phencyclidine-induced disruption of PPI, (+)-HA-966 does not appear to have an atypical neuroleptic-like effect.

Animals↗
PubMed1999

A further study on asymmetric cross-sensitization between MK-801 and phencyclidine-induced ambulatory activity.

Our previous study found that MK-801-sensitized rats showed cross-sensitization to the locomotor stimulant effects of phencyclidine, but phencyclidine sensitized rats did not show cross-sensitizaton to MK-801. This study was designed to determine whether the asymmetric cross-sensitization was due to injection-environment conditioning or possibly reduced phencyclidine-like effects following further repeated injections of phencyclidine. Adult female Sprague-Dawley rats were used in this study, and their activity was assessed with an automated photoelectric system. Results confirmed the early finding that four daily injections of phencyclidine (3.2 mg/kg) or MK-801 (0.32 mg/kg) produced locomotor sensitization, and that the two drugs showed asymmetric cross-sensitization. Moreover, injection-environment conditioning was ruled out as a possible cause for cross-sensitization from MK-801 to phencyclidine, and possibly reduced phencyclidine-like effects following further repeated injections was also ruled out as a cause for the failure of cross-sensitization from phencyclidine to MK-801. These additional results further confirm our previous finding, and indicate that there are significant differences in the neural mechanisms underlying phencyclidine- and MK-801-induced sensitization.

Animals↗
PubMed2005

Long-lasting impairment of associative learning is correlated with a dysfunction of N-methyl-D-aspartate-extracellular signaling-regulated kinase signaling in mice after withdrawal from repeated administration of phencyclidine.

In humans, the administration of phencyclidine causes schizophrenic-like symptoms that persist for several weeks after withdrawal from phencyclidine use. We demonstrated here that mice pretreated with phencyclidine (10 mg/kg/day s.c. for 14 days) showed an enduring impairment of associative in a Pavlovian fear conditioning 8 days after cessation of phencyclidine treatment. Extracellular signaling-regulated kinase (ERK) was transiently activated in the amygdalae and hippocampi of saline-treated mice after conditioning. In the phencyclidine-treated mice, the basal level of ERK activation was elevated in the hippocampus, whereas the activation was impaired in the amygdala and hippocampus after conditioning. Exogenous N-methyl-D-aspartate (NMDA), glycine, and spermidine-induced ERK activation was not observed in slices of hippocampus and amygdala prepared from phencyclidine-treated mice. Repeated olanzapine (3 mg/kg/day p.o. for 7 days), but not haloperidol (1 mg/kg/day p.o. for 7 days), treatment reversed the impairment of associative learning and of fear conditioning-induced ERK activation in repeated phencyclidine-treated mice. Our findings suggest an involvement of abnormal ERK signaling via NMDA receptors in repeated phencyclidine treatment-induced cognitive dysfunction. Furthermore, our phencyclidine-treated mice would be a useful model for studying the effect of antipsychotics on cognitive dysfunction in schizophrenia.

Amygdala↗
PubMed1984

Bias of phencyclidine discrimination by the schedule of reinforcement.

Pigeons, trained to discriminate phencyclidine from saline under a procedure requiring the bird to track the location of a color, received cumulative doses of phencyclidine, pentobarbital, or d-amphetamine with a variety of schedules of reinforcement in effect (across phases). When the same second-order schedules were used to reinforce responding after either saline or phencyclidine administration, stimulus control by phencyclidine did not depend on the schedule parameter. When different second-order schedules were used that biased responding toward the phencyclidine-correlated key color, pigeons responded on the phencyclidine-correlated key at lower doses of phencyclidine and pentobarbital than when the second-order schedule biased responding toward the saline key color. A similar but less marked effect was obtained with d-amphetamine. Attempts to produce bias by changing reinforcement magnitude (duration of food availability) were less successful. A signal-detection analysis of dose-effect curves for phencyclidine under two of the second-order schedules employed suggested that at low doses of phencyclidine, response bias is a major determinant of responding. As doses were increased, position preferences occurred and response bias decreased; at higher doses both response bias and position preference decreased and discriminability increased. With low doses of pentobarbital, responding again was biased but increasing doses produced position preference with only small increases in discriminability. At low doses of d-amphetamine responding also was biased, but bias did not decrease consistently with dose nor did discriminability increase. These experiments suggest that the schedule of reinforcement can be used to bias responding toward or away from making the drug-correlated response in drug discrimination experiments, and that signal-detection analysis and analysis of responding at a position can be used to separate the discriminability of the drug state from other effects of the drug on responding.

Animals↗
PubMed1983

Negative chronotropic and positive inotropic actions of phencyclidine on isolated atrial muscle in guinea pigs and rats.

Chronotropic and inotropic actions of phencyclidine were studied in spontaneously beating right atrial muscle and electrically paced left atrial muscle preparations isolated from guinea-pig or rat hearts. In right atrial muscle preparations, phencyclidine (10-100 microM) decreased the frequency of spontaneous beating. Guinea-pig and rat heart preparations had similar sensitivities to this action of phencyclidine. The negative chronotropic effect was not altered by atropine. A high concentration of naloxone failed to affect the chronotropic effect of phencyclidine in guinea-pig muscle, but significantly reduced the effect in rat heart muscle preparations. Phencyclidine (1-100 microM) caused positive inotropic effects in both guinea-pig and rat heart left atrial muscle electrically stimulated at 1.5 Hz; rat heart preparations had a higher sensitivity to the positive inotropic action of phencyclidine. The positive inotropic effect was reduced by verapamil, nifedipine and relatively high concentrations of diltiazem, but was not affected by propranolol, phentolamine, tripelennamine, atropine or ryanodine, indicating that the effect is not mediated by adrenergic, histaminergic or cholinergic systems or does not involve ryanodine-sensitive calcium pools. Inactivation of the fast sodium channels by partial membrane depolarization, and subsequent restoration of the contraction by raising the extracellular Ca++ concentration, did not abolish the positive inotropic action of phencyclidine. These results suggest that the negative chronotropic effect of phencyclidine is not mediated by a stimulation of the muscarinic receptor. The positive inotropic effects of phencyclidine seem to result from an increase in Ca++ influx through the slow channels of the cardiac cell membrane.

Action Potentials↗
PubMed1994

Genetic differences in the locomotor response to single and daily doses of phencyclidine in inbred mouse strains.

Genetic differences in the locomotor stimulant effects of both single and daily administration of phencyclidine were investigated in four inbred strains of male mice A/J, C57BL/6J, C57BL/6ByJ and BALB/cByJ. Each mouse was injected i.p. once in Experiment 1, or daily for 5 or 11 days in Experiments 2, 3 and 4. Locomotor activity was assessed with an automated photoelectric system. Significant strain differences were found in the response to a single as well as repeated doses of phencyclidine. A/J mice showed the greatest initial response to phencyclidine and developed tolerance to daily phencyclidine. C57BL/6ByJ mice showed initial resistance to acute phencyclidine, but developed sensitization to daily phencyclidine. The responses of both C57BL/6J and BALB/cByJ mice to acute phencyclidine were low to moderate, and did not change significantly following daily phencyclidine. The results of this study indicate that different genetic mechanisms are involved in responses to single and daily injections of phencyclidine.

Journal Article↗
PubMed1983

The effects of an in vivo administration of phencyclidine on sodium-dependent high affinity choline uptake in rat hippocampus and striatum in vitro.

The effect of phencyclidine and other drugs on sodium-dependent high-affinity uptake of choline in the rat hippocampus and/or striatum was investigated and related to the behavioral changes induced by these agents. In contrast to atropine (40.0 mg/kg), which increased the uptake of choline in synaptosomes from both the rat hippocampus and striatum, the administration of phencyclidine (54.4 mg/kg), 30 min prior to sacrifice, caused a significant decrease in the uptake of choline in synaptosomes from rat striatum (but not hippocampus). This effect of phencyclidine could be seen up to 1 hr after administration of drug, but by 3.5 hr the uptake of choline was essentially back to normal. The inhibition of striatal uptake of choline occurred at a time when brain levels of phencyclidine and its metabolites were at their highest, and the animals were essentially immobile; it did not appear to correlate with behavioral changes (including stereotypy and catalepsy) seen at later times after this dose of phencyclidine (54.4 mg/kg), or at earlier times after smaller doses. Amphetamine (6.0 mg/kg) also decreased the uptake of choline in the striatum. Haloperidol (2.0 and 3.0 mg/kg) blocked both the phencyclidine and amphetamine-induced inhibition of the uptake of choline but only the behavioral effects of amphetamine. The data suggest that phencyclidine may be exerting an indirect effect on the uptake of choline in the striatum via its interaction with the dopaminergic system. However, this neurochemical effect of phencyclidine could not be related in any simple way to the immobility, stereotypy or catalepsy caused by this drug.

Amphetamine↗
PubMed1989

Effect of dopaminergic drugs on enhancement of the binding of quinuclidinyl benzilate by phencyclidine in vivo.

Phencyclidine has been shown to enhance the specific binding of [3H]quinuclidinyl benzilate (QNB) in the brain of the mouse when both compounds are given in vivo. Since a variety of studies indicate that dopaminergic (DA) systems are involved in the action of phencyclidine, it seemed that DA systems might mediate the enhancement of the binding of QNB by phencyclidine. The results of the present studies demonstrate that the neurotoxin 6-hydroxydopamine, the DA D1 antagonist (R)-8-[chloro]-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine-7- ol) (SCH23390), the DA D1 agonist p-dibenzylamino benzonitrile (SKF38393) and the DA D2 antagonist spiperone, all failed to modify the ability of phencyclidine to enhance the accumulation of QNB in brain. Quinpirole, a DA D2 agonist diminished accumulation of QNB after phencyclidine, however, this effect was confounded by quinpirole decreasing the non-specific binding of QNB, as well as increasing concentrations of QNB in plasma, when given with phencyclidine. In contrast, haloperidol, a DA antagonist, decreased the enhanced specific binding of QNB after phencyclidine without any apparent confounding influences. Since haloperidol is also known to strongly inhibit the binding of ligands to the sigma receptors, it was hypothesized that the actions of phencyclidine and haloperidol on the binding of QNB in vivo may be through sigma receptors rather than DA systems.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats.

A behavioral pattern monitor was used to assess the effects of dizocilpine (MK-801) and phencyclidine on the spatial and temporal patterns of locomotion and investigatory behavior in rats. The monitor provided both quantitative measures of crossovers, rearings and holepokes and qualitative measurement of the spatial and temporal patterns of locomotion. Dizocilpine (0.004-0.5 mg/kg) and phencyclidine (0.25-5.0 mg/kg) produced similar, dose-dependent increases in locomotor activity. At small doses, dizocilpine and phencyclidine increased investigatory holepokes, while at larger doses, both drugs significantly decreased the number of holepokes. Rearings were reduced similarly by the larger doses of each drug. Both dizocilpine and phencyclidine produced perseverative spatial patterns of locomotion, especially at larger doses. However, the locomotor patterns produced by these drugs were found to be dissimilar in spatial quality. After phencyclidine, animals frequently circled the perimeter of the monitor chamber or moved repetitively in horseshoe or figure-8 patterns. By contrast, rats given dizocilpine completed small rotations about either end of the chamber. Pretreatment with a small dose (0.02 mg/kg) of haloperidol, prior to either dizocilpine (0.5 mg/kg) or phencyclidine (5.0 mg/kg) had no effect on the increase in locomotor activity or the decreases in investigatory holepokes produced by the drugs. However, haloperidol altered the effects of phencyclidine on the spatial and temporal patterns of locomotion, suggesting that sigma receptors or other haloperidol-sensitive binding sites, may influence the quality but not the quantity of phencyclidine-induced hyperactivity.

Animals↗
PubMed1982

Tolerance to the behavioral effects of orally self-administered phencyclidine.

Three rhesus monkeys self-administered fixed doses (4, 8 or 16 mg/kg) of an orally-delivered phencyclidine solution (0.25 mg/ml) under a one response, fixed-ratio (FR 1) schedule. They self-administered a saccharin 0.05% (wt/vol) solution, under an FR 8 schedule, 40 minutes after phencyclidine access began. After behavior stabilized over at least five daily sessions at each dose, water was substituted for phencyclidine for four sessions, and then phencyclidine was reinstated at the same dose, and behavior was allowed to stabilize. A comparison of saccharin-maintained behavior before and after the four sessions of water substitution yielded a two-fold shift in the dose effect curve indicating a rapid loss of tolerance to phencyclidine. Phencyclidine produced a biphasic effect on saccharin-maintained behavior: response rates increased at the low dose and decreased at the high dose. Subsequently, the FR requirement for saccharin was increased to 16 and the number of sessions of water substitution was varied: 1, 4, 8 or 16. The results indicated that tolerance was lost after four days of phencyclidine absence but not one, and complete tolerance was acquired within four to five days. This procedure produced a reliable measure of tolerance under limited access conditions whereby orally-delivered phencyclidine was also demonstrated to be functioning as a reinforcer.

Animals↗
PubMed1999

Nitric oxide synthase inhibitors do not substitute in rats trained to discriminate phencyclidine from saline.

Release of nitric oxide occurs as a consequence of glutamate stimulation of NMDA receptors and is dependent upon calcium-calmodulin activation of the enzyme nitric oxide synthase. Since nitric oxide may serve as an intracellular messenger for NMDA glutamatergic neurons, it could be hypothesized that blockade of its synthesis may produce pharmacological effects similar to those of NMDA receptor antagonists. The purpose of the present study was to compare the effects of nitric oxide synthase inhibitors to those of the high affinity NMDA open channel blocker phencyclidine in drug discrimination, a pharmacologically selective procedure in which phencyclidine produces distinctive effects. Rats were trained to discriminate 2 mg/kg phencyclidine from saline in a standard two-lever discrimination task with food reward. Whereas phencyclidine dose-dependently substituted for itself, 7-nitroindazole, L-NAME (N(G)-nitro-L-arginine methyl ester), and L-NOARG (N(G)-nitro-L-arginine) failed to substitute for phencyclidine when administered intraperitoneally. L-NAME and 7-nitroindazole were tested up to doses that disrupted responding, providing evidence that a behaviorally-relevant dosage range was evaluated. Although these results conflict with those of a previous study which found that nitric oxide synthase inhibitors substituted for phencyclidine and produced phencyclidine-like catalepsy in pigeons, they are consistent with research showing that these drugs did not produce phencyclidine-like pharmacological effects in behavioral procedures in rats.

Animals↗