Vol. 290, Issue 1, 20-27, July 1999

N-Methyl-D-Aspartate Receptor Antagonists and the Development of Tolerance to the Discriminative Stimulus Effects of Morphine in Rats¹

Anton Yu. Bespalov², Robert L. Balster and Patrick M. Beardsley

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor antagonists prevent the development of analgesic tolerance to opiates. Some effects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water (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 response rate-suppressing effects. Withdrawal-induced, response rate reductions indicative of behavioral dependence appeared as well. Separate groups were then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizocilpine (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 development 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 prevented the induction of tolerance to morphine's response rate effects. Dizocilpine and D-CPPene (5.6 mg/kg) appeared to prevent the induction of behavioral dependence as well. NMDA antagonists can prevent tolerance to the discriminative stimulus effects of morphine, and perhaps to its behavioral dependence effects, but their site of action on the NMDA receptor complex confers a different ability to do so.