Phencyclidine (PCP) binds to many sites in brain, including PCP receptors located within the N-methyl-D-aspartate (NMDA) receptor-operated cation channel and sigma (σ) receptors. In this study, we compare mechanisms by which PCP, dizocilpine (MK-801), the prototypical σ receptor agonist (+)- pentazocine, and the proposed endogenous σ receptor ligand neuropeptide Y regulate potassium (K+)-stimulated [3H]dopamine release from slices of rat nucleus accumbens. (+)-Pentazocine inhibits K+-stimulated [3H]dopamine release, and neuropeptide Y enhances it. Both effects are blocked by σ1 and neuropeptide Y receptor antagonists, suggesting possible inverse agonism at a subpopulation of σ/neuropeptide Y receptors. In contrast, PCP and MK-801 both enhance K+-stimulated [3H]dopamine release via σ1 and σ2 receptor subtypes, as demonstrated by antagonist sensitivity. Regulation of release by both (+)-pentazocine and neuropeptide Y persists in the presence of tetrodotoxin suggests that the σ/neuropeptide Y receptors mediating the modulation are located presynaptically on dopaminergic nerve terminals, but tetrodotoxin eliminates regulation by PCP and MK-801, suggesting that receptors mediating their effects are located upstream from dopaminergic nerve terminals
