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Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse

Abstract

Repeated cocaine treatment and withdrawal produces changes in brain function thought to be involved in relapse to drug use. Withdrawal from repeated cocaine reduced in vivo extracellular glutamate in the nucleus accumbens of rats by decreasing the exchange of extracellular cystine for intracellular glutamate. In vivo restoration of cystine/glutamate exchange by intracranial perfusion of cystine or systemically administered N-acetylcysteine normalized the levels of glutamate in cocaine-treated subjects. To determine if the reduction in nonvesicular glutamate release is a mediator of relapse, we examined cocaine-primed reinstatement of drug seeking after cocaine self-administration was stopped. Reinstatement was prevented by stimulating cystine/glutamate exchange with N-acetylcysteine and restoring extracellular glutamate. Thus, withdrawal from repeated cocaine increases susceptibility to relapse in part by reducing cystine/glutamate exchange, and restoring exchanger activity prevents cocaine-primed drug seeking.

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Figure 1: Basal levels of extracellular glutamate were lower in the nucleus accumbens, but not in the striatum or prefrontal cortex, after 3 weeks of withdrawal from experimenter-delivered repeated cocaine administration (15–30 mg/kg, i.p. for 7 d).
Figure 2: Three weeks withdrawal from repeated cocaine (× 7 days) treatment produced a significant increase in the Km of cystine/glutamate exchange without altering Vmax.
Figure 3: Cystine/glutamate exchange accounted for reduced extracellular glutamate in the nucleus accumbens following 3 weeks withdrawal from repeated cocaine treatment (× 7 days).
Figure 4: Three weeks after discontinuing from repeated cocaine (× 7 days), systemic administration of the cysteine pro-drug N-acetylcysteine elevated extracellular glutamate by increasing cystine/glutamate exchange.
Figure 5: Infusion of cystine into the nucleus accumbens prevented the increase in extracellular glutamate by an acute cocaine injection given at 3 weeks withdrawal from repeated cocaine.
Figure 6: Cocaine-primed reinstatement of lever pressing and the increase in extracellular glutamate was blocked by pretreatment with N-acetylcysteine or (−)-2-oxothiazolidine-4-carboxylic acid (OTC).
Figure 7: Neither N-acetylcysteine nor OTC blocked food-primed reinstatement or cocaine reward, and were still effective against a lower cocaine-priming dose.

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Acknowledgements

This research was supported in part by United States Public Health Service grants MH-40817, DA-03960, DA-06074 and DA-07288.

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Correspondence to Peter W Kalivas.

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Baker, D., McFarland, K., Lake, R. et al. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6, 743–749 (2003). https://doi.org/10.1038/nn1069

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