Substitution and antagonism in rats trained to discriminate (+)-N-allylnormetazocine from saline.
(+)-N-Allylnormetazocine (NANM) binds to at least two sites in the mammalian central nervous system, a high-affinity, haloperidol-sensitive site and a lower-affinity site identified as the phencyclidine (PCP) receptor. The relevance of these sites to the discriminative stimulus properties of (+)-NANM was evaluated in rats trained to discriminate (+)-NANM from saline. Drugs with a high affinity for the haloperidol-sensitive site, including haloperidol, (+)-ketocyclazocine, 1,3-di-ortho-tolyl-guanidine and (-)-butaclamol failed to substitute for the (+)-NANM stimulus. In addition, when they were tested in combination with (+)-NANM, only haloperidol evidenced any antagonistic effects. The antagonistic effects of haloperidol were incomplete and only occurred at doses that substantially disrupted responding. Evidence obtained earlier that (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine could antagonize (+)-NANM was not replicated. On the other hand, PCP-like drugs from diverse chemical classes, including PCP, ketamine, MK-801, (-)-2-methyl-3,3-diphenyl-3-propanolamine, etoxadrol and dextrorphan, all substituted fully for the (+)-NANM stimulus with a potency predicted by their relative potency for PCP-like discriminative stimulus effects and relative affinity for the PCP receptor. Taken together, these results fail to provide evidence for an important role for the high-affinity haloperidol-sensitive binding site for (+)-NANM in its discriminative stimulus properties. Instead, activity at the PCP receptor is predictive of (+)-NANM-like effects.
Balster
R L
RL
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002069:Butaclamol / Q000494:pharmacology; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D016314:Ethylketocyclazocine / Q000031:analogs & derivatives*; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D017478:Receptors, Phencyclidine
D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D016314:Ethylketocyclazocine; C012395:ketazocine; C012134:SK&F 10047; D002069:Butaclamol; D010620:Phenazocine; D003496:Cyclazocine; D006220:Haloperidol