Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists

Abstract

Evidence has accumulated that the discriminative stimulus effects of phencyclidine (PCP) may be transduced by a specific receptor in mammalian brain. Two major lines of evidence support this hypothesis. One is the structure-activity correlation that arylcyclohexylamine analogs of PCP have for PCP-like discriminative effects and displacement of [3H]PCP binding. The other, even stronger, evidence is that representatives of some nonarylcyclohexylamine classes of drugs are both generalized from PCP and have activity at PCP-binding sites. These include the psychotomimetic sigma-agonist opioids such as (+)-N-allylnormetazocine (NANM), the 1,3-substituted dioxolanes dexoxadrol and etoxadrol and some benz(f)isoquinolines. Early evidence suggested that there may be a complete overlap in the discriminative effects and receptor systems for PCP and sigma-agonists, and there continues to be evidence to support the commonality of these drug groups. On the other hand, binding studies with radiolabeled sigma agonists have revealed a non-PCP site. The role of this site in the behavioral actions of sigma-agonists is at present unknown. PCP analogs and other PCP-like drugs also can function as reinforcers for self-administration behavior, suggesting that the same cellular mechanisms may be responsible for both discriminative and reinforcing stimulus effects of these drugs. PCP has been shown to block many of the in vitro and in vivo effects of N-methyl-D-aspartate (NMDA), a putative specific agonist for a subtype of excitatory amino acid receptor. Recent evidence that NMDA antagonists are generalized from PCP in rats and pigeons provides evidence that modification of excitatory amino neurotransmission may be a physiological function of the PCP receptor and that this receptor complex may be involved in PCP's discriminative stimulus effects.