Effects of N‐acetylcysteine on the behavioral‐stimulant, reinforcing, and neurochemical effects of cocaine in the squirrel monkey

Abstract

The stimulant and reinforcing effects of cocaine have been attributed largely to its actions at the dopamine transporter. However, other neurotransmitters can modulate cocaine-induced increases in dopamine. In rodents, glutamate receptor function in the striatum and nucleus accumbens plays a major role in the behavioral pharmacology of cocaine. Withdrawal from repeated exposure to cocaine results in decreased levels of glutamate by decreased cystine-glutamate transporter function. Systemic administration of N-acetylcysteine (NAC), which restores cystine-glutamate function, normalized glutamate levels. In the present studies, we examined the stimulant effects of cocaine in squirrel monkeys using a fixed-interval schedule of reinforcement. Systemic administration of cocaine increased extracellular dopamine levels in the striatum of squirrel monkeys, as measured by in vivo microdialysis. Pretreatment with NAC did not alter the stimulant effects of cocaine, but dose-dependently decreased cocaine-induced increases in dopamine in the striatum. Self-administration behavior maintained by a second-order schedule of i.v. cocaine delivery in squirrel monkeys was not altered by pretreatment with NAC. Hence, drug interactions in neurochemistry were not reflected in behavioral measures. Supported by USPHS grants DA00517, DA15902, DA13326, DA12514 and RR00165.