N-methyl-D-aspartate receptor antagonists and the development of toleranceto the discriminative stimulus effects of morphine in rats

Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor an tagonists prevent the development of analgesic tolerance to opiates. Some e ffects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Lon g-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from w ater (vehicle) using a standard, two-lever fixed ratio 10 schedule of food reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days b.i.d.) was administered, which induced tolerance-like rightward shifts in the dose-effect curves for both morphine's discriminative stimulus and res ponse rate-suppressing effects. Withdrawal-induced, response rate reduction s indicative of behavioral dependence appeared as well. Separate groups wer e then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizoc ilpine(0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene; 3 and 5.6 mg/kg i.p.), eliprodil (17.3 mg/kg i.p.), or R()-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The developm ent of tolerance to morphine's stimulus effects was attenuated by eliprodil and the higher dose of D-CPPene, but not by dizocilpine, the lower dose of D-CPPene, nor R(+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists preven ted the induction of tolerance to morphine's response rate effects. Dizocil pine and o-CPPene (5.6 mg/kg) appeared to prevent the induction of behavior al dependence as well. NMDA antagonists can prevent tolerance to the discri minative stimulus effects of morphine, and perhaps to its behavioral depend ence effects, but their site of action on the NMDA receptor complex confers a different ability to do so.