期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 51, 页码 13968-13976出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2808-07.2007
关键词
extrasynaptic glutamate; addiction; system x(c)(-); nucleus accumbens; nonvesicular; cystine-glutamate antiporter
资金
- NIDA NIH HHS [DA17328, R01 DA015758, R01 DA017328, R01 DA017328-03, DA15758, R01 DA017328-03S1] Funding Source: Medline
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 [S-35] 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.
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