Elsevier

Neuroscience

Volume 155, Issue 2, 13 August 2008, Pages 530-537
Neuroscience

Systems neuroscience
Blunted cystine–glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking

https://doi.org/10.1016/j.neuroscience.2008.06.010Get rights and content

Abstract

Repeated cocaine alters glutamate neurotransmission, in part, by reducing cystine–glutamate exchange via system xc−, which maintains glutamate levels and receptor stimulation in the extrasynaptic compartment. In the present study, we undertook two approaches to determine the significance of plasticity involving system xc−. First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system xc−. Rats were trained to self-administer cocaine (1 mg/kg/200 μl, i.v.) under extended access conditions (6 h/day). After extinction training, cocaine (10 mg/kg, i.p.) primed reinstatement was assessed in rats pretreated with N-acetylcysteine (0–60 mg/kg, i.p.) in the presence or absence of the system xc− inhibitor (S)-4-carboxyphenylglycine (CPG; 0.5 μM; infused into the nucleus accumbens). N-acetylcysteine attenuated cocaine-primed reinstatement, and this effect was reversed by co-administration of CPG. Secondly, we examined whether reduced system xc− activity is necessary for cocaine-primed reinstatement. To do this, we administered N-acetylcysteine (0 or 90 mg/kg, i.p.) prior to 12 daily self-administration sessions (1 mg/kg/200 μl, i.v.; 6 h/day) since this procedure has previously been shown to prevent reduced activity of system xc−. On the reinstatement test day, we then acutely impaired system xc− in some of the rats by infusing CPG (0.5 μM) into the nucleus accumbens. Rats that had received N-acetylcysteine prior to daily self-administration sessions exhibited diminished cocaine-primed reinstatement; this effect was reversed by infusing the cystine–glutamate exchange inhibitor CPG into the nucleus accumbens. Collectively these data establish system xc− in the nucleus accumbens as a key mechanism contributing to cocaine-primed reinstatement.

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.).

References (47)

  • W. Zhou et al.

    N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking

    Biol Psychiatry

    (2008)
  • S.H. Ahmed et al.

    Transition from moderate to excessive drug intake: change in hedonic set point

    Science

    (1998)
  • K. Aoyama et al.

    Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse

    Nat Neurosci

    (2006)
  • D.A. Baker et al.

    Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats

    Psychopharmacology (Berl)

    (2001)
  • D.A. Baker et al.

    The origin and neuronal function of in vivo nonsynaptic glutamate

    J Neurosci

    (2002)
  • D.A. Baker et al.

    Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse

    Nat Neurosci

    (2003)
  • A. Baskys et al.

    Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus

    J Physiol

    (1991)
  • J.L. Cornish et al.

    Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction

    J Neurosci

    (2000)
  • C. Dackis et al.

    Neurobiology of addiction: treatment and public policy ramifications

    Nat Neurosci

    (2005)
  • C.A. Dackis

    Recent advances in the pharmacotherapy of cocaine dependence

    Curr Psychiatry Rep

    (2004)
  • M. D'Ascenzo et al.

    mGluR5 stimulates gliotransmission in the nucleus accumbens

    Proc Natl Acad Sci U S A

    (2007)
  • P. Di Ciano et al.

    Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability

    Behav Neurosci

    (2003)
  • P. Di Ciano et al.

    Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats

    J Neurosci

    (2004)
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