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Treating Addiction: Unraveling the Relationship Between N-acetylcysteine, Glial Glutamate Transport, and Behavior

  • Cassandra D. Gipson
    Correspondence
    Address correspondence to Cassandra D. Gipson, Ph.D., Department of Psychology, Arizona State University. 950 McAllister Avenue, Psychology Room 203, Tempe, AZ 85287.
    Affiliations
    Department of Psychology, Arizona State University, Tempe, Arizona
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      The study by Ducret et al. (
      • Ducret E.
      • Puaud M.
      • Lacoste J.
      • Belin-Rauscent A.
      • Fouyssac M.
      • Dugast E.
      • et al.
      N-acetylcysteine facilitates self-imposed abstinence after escalation of cocaine intake.
      ) in this issue of Biological Psychiatry is an important contribution to our understanding of the impact of glial glutamate transport restoration in addiction-related behaviors and offers insight into treatment of substance use disorders (SUDs) using N-acetylcysteine (NAC). Specifically, the authors found that NAC restored expression of the glial glutamate transporter (GLT-1), as well as increased sensitivity to punishment in animals given extended access to cocaine self-administration. Of note, the typical reduction in nucleus accumbens core GLT-1 after self-administered cocaine was found after “self-imposed abstinence” from cocaine in this study, rather than after experimenter-induced withdrawal, and this effect was access dependent. A reduction in GLT-1 also was found in the dorsolateral striatum. The NAC treatment regimen used to restore GLT-1 and reduce cocaine-related behaviors in this study was chronic (administered over the course of 23 sessions), and the dose used was lower (60 mg/kg) than that of some other preclinical studies [e.g., 100 mg/kg (
      • Reissner K.J.
      • Gipson C.D.
      • Tran P.K.
      • Knackstedt L.A.
      • Scofield M.D.
      • Kalivas P.W.
      Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.
      )], perhaps leading to biological levels more akin those that found in humans, given the poor bioavailability of NAC (
      • McClure E.A.
      • Gipson C.D.
      • Malcolm R.J.
      • Kalivas P.W.
      • Gray K.M.
      Potential role of N-acetylcysteine in the management of substance use disorders.
      ). The authors conclude that NAC aids in restoration of control over intake of cocaine after it is paired with a negative consequence (foot shock) by aiding in glutamatergic reorganization. Given the shift from ventral to dorsal striatum that has been found to underlie the development of compulsive drug seeking, the logical progression from the conclusions of this study is that NAC treatment may aid in the reversal of this shift to allow control over drug seeking to be re-established.
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