Effects of N-methyl-D-aspartate receptor antagonists on reinstatement of cocaine-seeking behavior by priming injections of cocaine or exposures to cocaine-associated cues in rats

The reinstatement of extinguished cocaine self-administration behavior was studied in rats pretreated with N-methyl-D-aspartate receptor antagonists. Rats were trained to self-administer intravenous cocaine (0.32 mg/kg/infusi on) during five consecutive daily sessions that were followed by five conse cutive daily extinction sessions, during which cocaine was unavailable and cocaine-associated cues (sound and light) were absent. Neither the competit ive N-methyl-D-aspartate receptor antagonist D-CPPene (0.3-3 mg/kg) nor the low-affinity N-methyl-D-aspartate receptor channel blocker memantine (1-10 mg/kg) reinstated extinguished responding. Priming injections of intraveno us cocaine (Experiment 1), and exposures to cocaine-associated stimuli (buz zer and light; Experiment 2) engendered responding on the reinforced lever in excess of that on the non-reinforced lever. In Experiment 1, administrat ion of D-CPPene or memantine prior to the priming injection of cocaine elim inated the difference between reinforced-lever and non-reinforced-lever res ponse rates. For both D-CPPene and memantine, however, this effect was larg ely due to increased responding upon the non-reinforced lever rather than t o decreased reinforced-lever responding. In Experiment 2, D-CPPene, but not memantine, abolished in a dose-dependent manner the selective increase in reinforced-lever over non-reinforced-lever responding that was induced by e xposures to cocaine-related stimuli. This effect of D-CPPene was not due to increased non-reinforced-lever responding. These data help define the boun daries within which N-methyl-D-aspartate receptor antagonists can prevent r einstatement of cocaine-seeking behavior (e.g. type of antagonist used and reinstatement procedure). (C) 2000 Lippincott Williams & Wilkins.