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Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci 2007 Dec 19;27(51):13968-76

Date

12/21/2007

Pubmed ID

18094234

Pubmed Central ID

PMC2996827

DOI

10.1523/JNEUROSCI.2808-07.2007

Scopus ID

2-s2.0-38449086396   177 Citations

Abstract

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.

Author List

Madayag A, Lobner D, Kau KS, Mantsch JR, Abdulhameed O, Hearing M, Grier MD, Baker DA

Author

John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylcysteine
Animals
Cocaine
Compulsive Behavior
Drug Administration Schedule
Male
Motor Activity
Neuronal Plasticity
Nucleus Accumbens
Rats
Rats, Sprague-Dawley
Self Administration
Substance-Related Disorders