Systems neuroscienceBlunted cystine–glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking
Section snippets
Subjects
These experiments utilized male Sprague–Dawley rats (Harlan, Indianapolis, IN, USA) weighing 275–325 g upon arrival. Rats were individually housed in a temperature-controlled colony room with a 12-h reversed light/dark cycle. Housing conditions and experimental protocols were approved by the Marquette University Institutional Animal Care and Use Committee and carried out according to the NIH Guide for the Care and Use of Laboratory Animals (revised 1996). The studies were designed in order to
N-acetylcysteine blocks cocaine-primed reinstatement by targeting system xc−
In the present study, we tested the hypothesis that N-acetylcysteine blocks cocaine-induced reinstatement of drug seeking by targeting system xc−. Fig. 1 illustrates the impact of acute administration of N-acetylcysteine in the presence or absence of the cystine–glutamate exchange inhibitor CPG on cocaine-primed reinstatement of drug seeking. A comparison of lever pressing on the last day of extinction or the reinstatement test day produced an interaction between day and drug treatment (ANOVA: F
Discussion
Plasticity resulting in abnormal activation of corticostriatal pathways appears to contribute to craving in human drug abusers (Breiter et al 1997, Dackis and O'Brien 2005, Volkow et al 2005). Previous reports have provided indirect evidence that reduced nonvesicular glutamate release by system xc− may contribute to cocaine-primed reinstatement (Madayag et al., 2007), and that it represents a novel target in the treatment of cocaine addiction (Baker et al 2003, Larowe et al 2006, Mardikian et
Conclusion
These data reveal that acute administration of N-acetylcysteine targets system xc− to block cocaine-primed reinstatement in rats withdrawn from extended-access cocaine self-administration. Further, reduced cystine–glutamate exchange appears to be necessary for cocaine-primed reinstatement. Collectively, these data provide further support for cysteine prodrugs, including N-acetylcysteine, as potential treatments for cocaine addiction by demonstrating efficacy after acute and repeated
Acknowledgments
This work was supported by National Institute on Drug Abuse (NIDA) grants DA17328 (D.A.B.) and DA15758 (J.R.M.).
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