Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes.

Phencyclidine (PCP) and similar drugs block NMDA-type glutamate receptors. In rat brain postsynaptic densities, binding of a PCP analogue was enhanced nearly 4-fold by the excitatory amino acids L-glutamate and NMDA, but not by other related compounds. Excitatory amino acid agonists and antagonists showed potencies in the PCP analogue binding assay that matched their affinities for NMDA-sensitive glutamate binding sites. Dissociative anesthetics and sigma-opiates inhibited PCP analogue binding but did not affect glutamate binding. The data indicate that PCP binding sites are linked to NMDA receptors, and that PCP and related drugs bind preferentially to the activated configuration of the NMDA receptor channel complex.

Study at a glance

Abstract

In functional studies, phenycyclidine (PCP) and similar drugs non-competitively antagonize neuronal responses to the excitatory amino acid, N-methyl-D-aspartate (NMDA). Here we show that, in crude postsynaptic densities from rat brain, the binding of [3H]TCP (a PCP analogue) was enhanced almost 4-fold by L-glutamate and NMDA, but not by quisqualate, kainate or gamma-aminobutyric acid. The potencies of excitatory amino acid agonists and antagonists in the [3H]TCP binding assay closely paralleled their affinities for NMDA-sensitive L-[3H]glutamate binding sites. In contrast, dissociative anaesthetics and sigma-opiates inhibited [3H]TCP binding (with a profile characteristic of PCP binding sites), but had no effect on L-[3H]glutamate binding. These data indicate that PCP binding sites are linked to NMDA receptors, and that PCP and related drugs bind preferentially to the activated configuration of the NMDA receptor channel complex.