Phencyclidine-induced discriminative stimulus is mediated via phencyclidine binding sites on the N-methyl-D-aspartate receptor-ion channel complex, not via sigma1 receptors

Abstract

The effects of several N-methyl-D-aspartate (NMDA) receptor- and sigma receptor-related compounds on the discriminative stimulus effects of phencyclidine (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 reinforcement. PCP produced a dose-dependent increase in PCP-appropriate responding. A non-competitive NMDA receptor antagonist, dizocilpine (0.2 mg:kg, i.p.) and a putative sigma1 receptor agonist, ( )-SKF- 10047 (10 mg:kg, i.p.) fully substituted for PCP in every rat tested. Neither a competitive NMDA receptor antagonist, CGS-19755 (0.1–3 mg:kg, i.p.), sigma1 receptor agonist, ( )-pentazocine (10–30 mg:kg, i.p.) nor dextromethorphan (10–20 mg:kg, i.p.) produced PCP-like discriminative stimulus effects. The discriminative stimulus effects of PCP (1.5 mg:kg, i.p.), dizocilpine (0.2 mg:kg, i.p.) and ( )-SKF-10047 (10 mg:kg, i.p.) were significantly attenuated by CGS-19755 (1 mg:kg, i.p.), but not by sigma1 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 sigma1 receptors. In addition, the PCP-like discriminative stimulus effects of ( )-SKF-10047 were demonstrated to be mediated via PCP binding sites. © 2001 Elsevier Science B.V. All rights reserved.