Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats.

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Nicholson KL, Balster RL

Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats.

Psychopharmacology (Berl). 2003 Nov;170(2):215-24. Epub 2003 Jul 8.

PubMed ID
12851738 [ View in PubMed
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Abstract

RATIONALE: Because of their potential therapeutic effects, N-methyl-D-aspartate (NMDA) receptor antagonists have been investigated for clinical use. Unfortunately, many channel-blocking antagonists have been associated with the production of side effects, including motor impairment and phencyclidine (PCP)-like subjective effects. OBJECTIVE: This study investigated the relationship between NMDA receptor channel blockade and production of PCP-like side effects by evaluating a variety of NMDA channel blockers with different binding characteristics for the production of PCP-like discriminative stimulus effects. METHODS: The NMDA channel blockers were tested in rats trained to discriminate 2 mg/kg PCP, i.p., from saline using a standard two-lever drug discrimination procedure with responding under a fixed ratio (FR) 32 schedule of food reinforcement. RESULTS: The high-affinity channel blockers PD 138289, PD 137889 and FR 115427, produced full, dose-dependent substitution for PCP. Of the moderate-affinity channel blockers, MRZ 2/579 fully substituted for PCP while 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline and alaproclate produced partial substitution. Drugs with the lowest affinity for the channel site and/or higher affinity for non-NMDA CNS sites, antazoline, idazoxan, 1-phenyl-1,2,3,4-tetrahydroisoquinoline, alpha-benzyl- N-methylphenethylamine and orphenadrine, failed to substitute for PCP. CONCLUSIONS: The results demonstrate that the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA receptor specificity, are important determinants of their discriminative stimulus effects. While higher affinity channel blockers show a correlation between affinity and PCP-like discriminative stimulus effects, behavioral disruption through action at non-NMDA receptors probably prevents achieving sufficient concentrations of the lower affinity compounds at NMDA receptors to produce PCP-like discriminative stimulus effects.

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