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Recently, it has been suggested that isoflurane might reduce dopamine release from rat midbrain dopaminergic neurons, the neurobiological substrate implicated in the reinforcing effects of abused drugs and nondrug rewards. However, little is known about effects of isoflurane on neurobehavioral activity associated with chronic exposure to psychoactive substances.The present study was designed to investigate the effects of isoflurane on cocaine-reinforced behavior. Using behavioral paradigm in rats, we evaluated the effects of isoflurane on cocaine self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. We also tested the effects of isoflurane on lever responding by nondrug reinforcers (sucrose and food) in drug-naive rats to control for the nonselective effects of isoflurane on cocaine- and nicotine-taking behavior. To further assess the ability of isoflurane to modulate the motivation for taking a drug, we evaluated the effects of isoflurane on nicotine self-administration. Using different groups of rats, the effects of isoflurane on the locomotor activity induced by a single intraperitoneal injection of cocaine (15 mg/kg) were also examined.Isoflurane significantly suppressed the self-administration of cocaine and nicotine without affecting food consumption. Unlike food-reinforced responding, responding for sucrose reinforcement was decreased by isoflurane. Isoflurane reduced breaking points under a PR schedule of reinforcement in a dose-dependent manner, indicating its efficacy in decreasing the incentive value of cocaine. Isoflurane also attenuated acute cocaine-induced hyperlocomotion.The results provided evidence that isoflurane decreases cocaine- and nicotine-reinforced responses, while isoflurane effect is not selective for cocaine- and nicotine-maintained responding. These results suggest that isoflurane inhibitions of cocaine- and nicotine-maintenance responses may be related to decreased effects of dopamine, and further investigation will need to elucidate this relationship.