A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine

doi:10.1016/0014-2999(87)90573-5

European Journal of Pharmacology

Volume 141, Issue 3, 23 September 1987, Pages 497-501

https://doi.org/10.1016/0014-2999(87)90573-5 Get rights and content

Abstract

Ketamine and (+)-N-allylnormetazocine ((+)-NANM) were found to generalise in a rat operant drug discrimination paradigm to the interoceptive stimulus induced by phencyclidine (PCP). Intraperitoneal administration of the non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, MK-801, and intracerebroventricular injection of the competitive antagonist, 2-DL-amino-7-amino-7-phosphonoheptanoic acid (2-APH), also resultyed in dose-dependent generalisation to the PCP discriminative stimulus. The results suggest that NMDA receptor antogonism may play an important role in the mediation of the discriminative stimulus properties of PCP. The low potency of MK-801 and 2-APH to displace [³](+)-NANM binding in vitro argues against an involvement of the haloperidol-sensitive σ recognition site in the behaviour.

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[+]-Huperzine A treatment protects against N-methyl-d-aspartate-induced seizure/status epilepticus in rats
2008, Chemico-Biological Interactions
Citation Excerpt :
The protection we describe was observed in the absence of atropine and 2-PAM, suggesting that [+]-Hup A offers strong protection against OP-induced seizure/SE (data not included). NMDA receptor antagonists that block the ion-channel tend to produce phencyclidine (PCP) symptoms [41]. However, the physical activity data suggest that locomotor stimulation is not found in these animals after an effective treatment of [+]-Hup A.
The toxicity of organophosphorous (OP) nerve agents is attributed to their irreversible inhibition of acetylcholinesterase (AChE), which leads to excessive accumulation of acetylcholine (ACh) and is followed by the release of excitatory amino acids (EAA). EAAs sustain seizure activity and induce neuropathology due to over-stimulation of N-methyl-d-aspartate (NMDA) receptors. Huperzine A (Hup A), a blood–brain barrier permeable selective reversible inhibitor of AChE, has been shown to reduce EAA-induced cell death by interfering with glutamate receptor-gated ion channels in primary neuronal cultures. Although [−]-Hup A, the natural isomer, inhibits AChE approximately 38-fold more potently than [+]-Hup A, both [−]- and [+]-Hup A block the NMDA channel similarly. Here, we evaluated the protective efficacy of [+]-Hup A for NMDA-induced seizure in a rat model. Rats implanted with radiotelemetry probes to record electroencephalography (EEG), electrocardiography (ECG), body temperature, and physical activity were administered various doses of [+]-Hup A (intramuscularly) and treated with 20 μg/kg NMDA (intracerebroventricular) 20–30 min later. For post-exposure, rats were treated with [+]-Hup A (3 mg/kg, intramuscularly) 1 min after NMDA (20 μg/kg). Our data showed that pre- and post-exposure, [+]-Hup A (3 mg/kg) protects animals against NMDA-induced seizures. Also, NMDA-administered animals showed increased survival following [+]-Hup A treatment. [+]-Hup A has no visible effect on EEG, heart-rate, body temperature, or physical activity, indicating a reduced risk of side effects, toxicity, or associated pathology. Our results suggest that [+]-Hup A protects against seizure and status epilepticus (SE) by blocking NMDA-induced excitotoxicity in vivo. We propose that [+]-Hup A, or a unique combination of [+]- and [−]-Hup A, may prove to be effective for pre- and post-exposure treatment of lethal doses of OP-induced neurotoxicity.
Involvement of dopaminergic system in the nucleus accumbens in the discriminative stimulus effects of phencyclidine
2002, Neuropharmacology
The effects of microinjection of phencyclidine (PCP) and dizocilpine, non-competitive NMDA receptor antagonists, and dopamine into the nucleus accumbens were examined in rats trained to discriminate PCP (1.5 mg/kg i.p.) from saline under a two-lever fixed ratio 20 schedule of food reinforcement. Microinjection of PCP (2–40 μg) and dizocilpine (2–12 μg) into the bilateral nucleus accumbens produced a dose-dependent increase in PCP-appropriate responding and fully substituted for systemically administered PCP, whereas microinjection of dopamine (1–4 μg) did not produce PCP-like discriminative stimulus effects. The performance of PCP discrimination was assessed after bilateral destruction of the dopaminergic nerve neurons in the nucleus accumbens with dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA, 4 μg/1 μl/side). The destruction of dopaminergic nerve neurons in the nucleus accumbens failed to prevent the performance of PCP discrimination. There was no difference in the average percentages of PCP-appropriate responding between vehicle and 6-OHDA-treated rats in the dose–response tests. These results suggest that the dopaminergic system in the nucleus accumbens does not play a critical role in the discriminative stimulus effects of PCP.
Phencyclidine-induced discriminative stimulus is mediated via phencyclidine binding sites on the N-methyl-D-aspartate receptor-ion channel complex, not via sigma<inf>1</inf> receptors
2001, Behavioural Brain Research
The effects of several N-methyl-d-aspartate (NMDA) receptor- and sigma receptor-related compounds on the discriminative stimulus effects of phencyclidine (PCP) were examined in rats trained to discriminate PCP (1.5 mg/kg, i.p.) from saline under a two-lever fixed ratio 20 schedule of food reinforcement. PCP produced a dose-dependent increase in PCP-appropriate responding. A non-competitive NMDA receptor antagonist, dizocilpine (0.2 mg/kg, i.p.) and a putative sigma₁ receptor agonist, (+)-SKF-10047 (10 mg/kg, i.p.) fully substituted for PCP in every rat tested. Neither a competitive NMDA receptor antagonist, CGS-19755 (0.1–3 mg/kg, i.p.), sigma₁ receptor agonist, (+)-pentazocine (10–30 mg/kg, i.p.) nor dextromethorphan (10–20 mg/kg, i.p.) produced PCP-like discriminative stimulus effects. The discriminative stimulus effects of PCP (1.5 mg/kg, i.p.), dizocilpine (0.2 mg/kg, i.p.) and (+)-SKF-10047 (10 mg/kg, i.p.) were significantly attenuated by CGS-19755 (1 mg/kg, i.p.), but not by sigma₁ receptor antagonist BMY-14802 (10 mg/kg, i.p.) and NE-100 (5 mg/kg, i.p.). These results suggest that the discriminative stimulus effects of PCP are predominantly mediated via PCP binding sites on the NMDA receptor-ion channel complex, not via sigma₁ receptors. In addition, the PCP-like discriminative stimulus effects of (+)-SKF-10047 were demonstrated to be mediated via PCP binding sites.
N-methyl-D-aspartate antagonists and drug discrimination
1999, Pharmacology Biochemistry and Behavior
Excitatory amino acids (EAA), such as glutamate, are thought to be involved in various disorders (e.g., ischemic brain damage, epilepsy, Parkinson's disease), and EAA antagonists have been suggested as potential treatments for these disorders. Phencyclidine (PCP), with produces psychotomimetic effects in humans, has antagonist properties at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors that have been suggested to underlie some of its actions. This suggestion, and concern about possible psychotomimetic activity, has stimulated research aimed at examining to what extent the behavioral profile of other NMDA antagonists resembles that of PCP. Drug discrimination (DD) is prominent among the procedures used to carry out such comparisons. The results of clinical studies with NMDA antagonists provide feedback about the predictive validity of the DD procedures used to characterize their preclinical behavioral profile. Further, DD is used also to examine the ability of compounds to attenuate the discriminative stimulus (DS) effects of PCP-type drugs, and results of such studies have been suggested to provide evidence of antipsychotic potential. Finally, although many instances of intermediate responding in DD can be explained by low efficacy at the receptors that mediate the DS effects of the training drug, certain outcomes produced by PCP-type drugs do not offer valid measures of efficacy, and require more detailed behavioral analyzes.
Sexual dimorphism in the response to N-methyl-D-aspartate receptor antagonists and morphine on behavior and c-Fos induction in the rat brain
1999, Neuroscience
It has been suggested that there are sex differences in the neural response to drugs of abuse. Previous studies have shown that, upon administration of morphine, the immediate early gene c-Fos is induced in the striatum, nucleus accumbens and cortex of the rat brain. This induction of c-Fos is reduced by administration of the N-methyl-d-aspartate receptor antagonist dizocilpine maleate. However, in studies using immunocytochemistry, we found that the pattern of this expression differed markedly between the sexes. In male rats treated with morphine (10 mg/kg, s.c.) and killed 2 h later, there was an induction of c-Fos in the dorsomedial caudate–putamen, the nucleus accumbens and in the intralaminar nuclei of the thalamus. Administration of dizocilpine maleate (0.2 mg/kg, i.p.; 30 min before morphine) partially blocked the response in the caudate–putamen, but not in the thalamus. In females, morphine induced c-Fos in the caudate–putamen, but with more inter-animal variability than in males. In the midline intralaminar thalamic nuclei, female rats showed less induction than males. In male rats, dizocilpine maleate alone caused negligible induction of c-Fos, whereas in female rats, it caused a large induction in the rhomboid, reuniens and central medial nuclei of the thalamus, and in the cortex. Whereas dizocilpine maleate partially blocked the morphine-induced c-Fos expression in the caudate–putamen of males, it completely blocked this response in females. With dizocilpine maleate alone, there was little or no effect on behavior in male rats, whereas in female rats, it caused head bobbing, thrashing, hyperactivity and uncoordinated movements. These behavioral sex differences were not seen on treatment of rats with the competitive N-methyl-d-aspartate receptor antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphoheptanoic acid (NPC-17742; 10 mg/kg, i.p.) and this drug did not induce c-Fos expression in either sex. In the caudate–putamen, morphine-induced c-Fos expression was significantly reduced by NPC-17742 (30 min before morphine) in males and completely blocked in females.
These results suggest that the responses to both morphine and N-methyl-d-aspartate receptor antagonists differ between the sexes and emphasize that glutamate is involved in morphine-induced immediate early gene expression in the brain. These studies thus have important implications for gender differences in drug addiction.

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Short communicationA role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine

Abstract

Life Sci.

European J. Pharmacol.

Neurosci. Lett.

Brain Res.

The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate

Br. J. Pharmacol.

Short communication
A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine