Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats
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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.
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.
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.
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, α-benzyl-N-methylphenethylamine and orphenadrine, failed to substitute for PCP.
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.
KeywordsPhencyclidine NMDA receptor antagonists Drug discrimination Side effects Rats
Portions of this study were presented previously at the annual Society for Neuroscience Meeting New Orleans, Louisiana (October 1997), and/or reported in K.L. Nicholson's Ph.D. Dissertation (September 1998). Research supported by NIDA grants DA-01442 and DA-07027. Special thanks to Drs. Chris Parsons and Wojciech Danysz of Merz Pharmaceuticals GmbH for providing MRZ 2/579; Drs. Christopher Bigge and Peter Boxer of Parke-Davis Pharmaceutical Research Division for providing PD 138289 and PD 137889; Dr. Nakanishi of the Fujisawa Pharmaceutical Co. for providing FR 115427; Drs. Nancy Gray, Patricia Contreras, and Brian Cheng of G.D. Searle & Co. for providing the other tetrahydroisoqionolines, 8-MPTIQ, 1-MPTIQ, and 1-PTIQ; and Dr. John Woodward of VCU for providing the BNMPA. The technical assistance of Hua Li is greatly appreciated.
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