One of the most insidious clinical features of addiction is the vulnerability to relapse following extended abstinence. Existing evidence suggests that a disruption in glutamate homeostasis within the nucleus accumbens is a contributing mechanism to this chronic relapse vulnerability. Glutamate homeostasis refers to the balance between extrasynaptic and synaptic neuronal glutamate concentrations that regulate synaptic plasticity. Among the long-lasting neuroadaptations which occur following chronic exposure to cocaine are decreased function and protein expression of the catalytic subunit of the cystine-glutamate exchanger (xCT) and high affinity glial glutamate transporter GLT-1, two integral regulators of nonsynaptic extracellular glutamate. Accordingly, decreased extracellular glutamate concentrations are measured following cocaine self-administration in the nucleus accumbens. Systemic treatment with either N-acetylcysteine (NAC) or ceftriaxone impairs reinstatement to cocaine and increases expression of both GLT-1 and xCT. [As a means of understanding more fully the allostatic mechanisms responsible for enduring disruptions of glutamate homeostasis and their contribution to addiction, I have employed an antisense knockdown strategy to determine the relative contributions of GLT-1 and xCT in a rat reinstatement model of addiction. Preliminary data indicate that expression of glial GLT-1, but not xCT, is the critical mediator of the therapeutic effect of NAC. Thus, a goal of this proposal i to test the hypothesis that adaptations in glia following cocaine exposure influence the release and uptake of glutamate, in turn affecting the homeostatic balance of glutamate and the cellular and synaptic neuroadaptations induced by cocaine.] This will be accomplished during the mentored phase of the award using (i) in vivo microdialysis to measure glutamate concentrations following genetic manipulation of GLT-1, and (ii) patch clamp electrophysiology to compare physiological properties of medium spiny neurons (mEPSCs, AMPA:NMDA ratios, [glial-derived slow inward currents]) under these same conditions. Experiments proposed for the independent phase of the award will go on to continue these studies and investigate (iii) the engagement of metabotropic glutamate receptors in these processes.

Public Health Relevance

Because high rates of drug relapse represent a major cause of lost health and quality of life, identification of candidate therapeutic mechanisms is imperative. Investigation of glial mechanisms responsible for disruptions in glutamate homeostasis will elucidate how deregulation of the tightly controlled balance of glutamate levels contributes to synaptic and behavioral pathologies associated with addiction, and represents a direct avenue for therapeutic intervention.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Career Transition Award (K99)
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Human Development Research Subcommittee (NIDA)
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Sorensen, Roger
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Medical University of South Carolina
Schools of Medicine
United States
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Reissner, Kathryn J; Gipson, Cassandra D; Tran, Phuong K et al. (2015) Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Addict Biol 20:316-23
Reissner, Kathryn J (2014) The cystine/glutamate antiporter: when too much of a good thing goes bad. J Clin Invest 124:3279-81
Reissner, Kathryn J; Brown, Robyn M; Spencer, Sade et al. (2014) Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology 39:499-506
Gipson, Cassandra D; Kupchik, Yonatan M; Shen, Haowei et al. (2013) Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77:867-72
Gipson, Cassandra D; Reissner, Kathryn J; Kupchik, Yonatan M et al. (2013) Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci U S A 110:9124-9
Trantham-Davidson, Heather; LaLumiere, Ryan T; Reissner, Kathryn J et al. (2012) Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. J Neurosci 32:12406-10