Phencyclidine-induced discriminative stimulus is mediated via phencyclidine binding sites on the N-methyl-D-aspartate receptor-ion channel complex, not via sigma(1) receptors

The effects of several N-methyl-D-aspartate (NMDA) receptor- and sigma rece ptor-related compounds on the discriminative stimulus effects of phencyclid ine (PCP) were examined in rats trained to discriminate PCP (1.5 mg/kg, i.p .) from saline under a two-lever fixed ratio 20 schedule of food reinforcem ent. PCP produced a dose-dependent increase in PCP-appropriate responding. A non-competitive NMDA receptor antagonist, dizocilpine (0.2 mp/kg, i.p.) a nd a putative sigma, receptor agonist, (+)-SKF-10047 (10 mg/kg, i.p.) fully substituted for PCP in every rat tested. Neither a competitive NMDA recept or antagonist, CGS-19755 (0.1-3 mg/kg, i.p.), sigma, receptor agonist, (+)- pentazocine (10-30 mg/kg, i.p.) nor dextromethorphan (10-20 mg/kg, i.p.) pr oduced PCP-like discriminative stimulus effects. The discriminative stimulu s effects of PCP (1.5 mg/kg, i.p.), dizocilpine (0.2 mg/kg, i.p.) and (+)-S KF-10047 (10 mg/kg, i.p.) were significantly attenuated by CGS-19755 (1 mg/ kg, i.p.), but not by sigma, receptor antagonist BMY-14802 (10 mg,kg, i.p.) and NE-100 (5 mg;kg, i.p.). These results suggest that the discriminative stimulus effects of PCP are predominantly mediated via PCP binding sites on the NMDA receptor-ion channel complex, not via sigma, receptors. In additi on, the PCP-like discriminative stimulus effects of (+)-SKF-10047 were demo nstrated to be mediated via PCP binding sites. (C) 2001 Elsevier Science B. V. All rights reserved.