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The Journal of Neuroscience, December 19, 2007, 27(51):13968-13976; doi:10.1523/JNEUROSCI.2808-07.2007

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Neurobiology of Disease
Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Aric Madayag, Doug Lobner, Kristen S. Kau, John R. Mantsch, Omer Abdulhameed, Matthew Hearing, Mark D. Grier, and David A. Baker

Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53233

Correspondence should be addressed to Dr. David A. Baker, Department of Biomedical Sciences, Marquette University, Suite 426, 561 North 15th Street, Milwaukee, WI 53233. Email: david.baker{at}mu.edu

Cocaine produces a persistent reduction in cystine–glutamate exchange via system x_c– in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System x_c– 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 x_c– activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered before daily cocaine to determine the impact of increased cystine–glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-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 of N-acetylcysteine, we examined whether N-acetylcysteine administered before daily cocaine also prevented the persistent reduction in system x_c– activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in [³⁵S]cystine transport via system x_c–, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least 3 weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system x_c– activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking.

Key words: extrasynaptic glutamate; addiction; system x_c–; nucleus accumbens; nonvesicular; cystine–glutamate antiporter

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Received June 20, 2007; revised Oct. 24, 2007; accepted Oct. 25, 2007.

Correspondence should be addressed to Dr. David A. Baker, Department of Biomedical Sciences, Marquette University, Suite 426, 561 North 15th Street, Milwaukee, WI 53233. Email: david.baker{at}mu.edu

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