Substitution and antagonism in rats trained to discriminate (+)-N-allylnormetazocine from saline.

The drug (+)-N-Allylnormetazocine (NANM) binds to two sites in the mammalian brain: a high-affinity site sensitive to haloperidol and a lower-affinity site known as the phencyclidine (PCP) receptor. In rats trained to distinguish (+)-NANM from saline, drugs that bind strongly to the haloperidol-sensitive site did not produce (+)-NANM-like effects, and only haloperidol partially blocked the drug's effects, and only at doses that disrupted behavior. In contrast, PCP-like drugs from various chemical classes fully substituted for (+)-NANM, with their potency matching their affinity for the PCP receptor. The findings indicate that the PCP receptor, not the haloperidol-sensitive site, mediates the discriminative stimulus properties of (+)-NANM.

Study at a glance

Abstract

(+)-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.