RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

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Abstract
Cocaine produces a persistent reduction in cystine–glutamate exchange via system xc− in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System xc− influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens, which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system xc− activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrugN-acetylcysteine was administered before daily cocaine to determine the impact of increased cystine–glutamate exchange on the development of plasticity-dependent cocaine seeking. AlthoughN-acetylcysteine administered before cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2–3 weeks after the last injection ofN-acetylcysteine, we examined whetherN-acetylcysteine administered before daily cocaine also prevented the persistent reduction in system xc− activity produced by repeated cocaine. Interestingly,N-acetylcysteine pretreatment prevented cocaine-induced changes in [35S]cystine transport via system xc−, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least 3 weeks after the lastN-acetylcysteine pretreatment. These findings indicate thatN-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system xc− activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking.

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