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Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse.

Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/2011; 108(1):385-90. DOI: 10.1073/pnas.1011265108
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ABSTRACT Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.

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    • "A decrease in expression of GLT-1 in the accumbens is one of the most consistent findings across drugs of abuse and administration protocols found following selfadministration of cocaine, heroin, alcohol and nicotine (Knackstedt et al. 2010; Fischer-Smith, Houston & Rebec 2012; Sari & Sreemantula 2012; Gipson et al. 2013). In addition, restored GLT-1 levels are observed following daily treatment with either NAC or ceftriaxone, two compounds that suppress reinstated cocaine, nicotine, alcohol, food and/or heroin seeking (Zhou & Kalivas 2007; Sari et al. 2009, 2011; Knackstedt et al. 2010; Moussawi et al. 2011; Ramirez-Nino, D'Souza & Markou 2013). NAC and ceftriaxone also restore cystineglutamate exchange in rats trained to self-administer cocaine (Trantham-Davidson et al. 2012). "
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    ABSTRACT: Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.
    Addiction Biology 02/2014; 20(2). DOI:10.1111/adb.12127 · 5.93 Impact Factor
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    • "Cocaine sensitization and NAC treatments. To examine whether NAC could prevent the accelerated habit learning observed following cocaine exposure, rats were assigned to receive either cocaine or saline and either 0, 60, or 120 mg/ kg of NAC administered i.p. 2 h before cocaine treatment (doses and timing based on previous studies; Madayag et al, 2007; Moussawi et al, 2011). Groups receiving each dose of NAC were further divided and received either saline or 30 mg/kg cocaine 2 h after the NAC treatment, thus generating six groups. "
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    ABSTRACT: Exposure to drugs of abuse can result in a loss of control over both drug- and non-drug-related actions by accelerating the transition from goal-directed to habitual control, an effect argued to reflect changes in glutamate homeostasis. Here we examined whether exposure to cocaine accelerates habit learning and used in-vitro electrophysiology to investigate its effects on measures of synaptic plasticity in the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas critical for actions and habits, respectively. We then administered N-acetylcysteine (NAC) in an attempt to normalize glutamate homeostasis and so reverse the cellular and behavioral effects of cocaine exposure. Rats received daily injections of cocaine (30 mg/kg) for six days and were then trained to lever-press for a food reward. We used outcome devaluation and whole-cell patch-clamp electrophysiology to assess the behavioral and cellular effects of cocaine exposure. We then examined the ability of NAC to reverse the effects of cocaine exposure on these measures. Cocaine treatment produced a deficit in goal-directed action, as assessed by outcome devaluation, and increased the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in the DMS but not in the DLS. Importantly, NAC treatment both normalized EPSC frequency and promoted goal-directed control in cocaine treated rats. The promotion of goal-directedcontrol has the potential to improve treatment outcomes in human cocaine addicts.Neuropsychopharmacology accepted article preview online, 17 February 2014; doi:10.1038/npp.2014.37.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2014; DOI:10.1038/npp.2014.37 · 7.83 Impact Factor
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    • "Because impaired glutamate homeostasis has been associated with reinstated drug-seeking, repairing glutamate levels via various drugs that target dysregulated proteins of the tripartite synapse (presynapse, postsynapse and glia; see Fig. 5) has been of pharmacotherapeutic interest. Of these pharmacotherapies, one is the commonly prescribed antibiotic ceftriaxone, and another is the antioxidant N-acetylcysteine (NAC), both of which restore levels of GLT1 and extracellular glutamate in the NAc of rats trained to selfadminister cocaine, nicotine or heroin (Knackstedt et al., 2010a; Moussawi et al., 2011; Shen et al., 2013). NAC also restores the ability to electrically induce LTP and LTD in cocaine-withdrawn animals (Moussawi et al., 2009). "
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    ABSTRACT: Chronic use of addictive drugs produces enduring neuroadaptations in the corticostriatal glutamatergic brain circuitry. The nucleus accumbens (NAc), which integrates cortical information and regulates goal-directed behavior, undergoes long-term morphological and electrophysiological changes that may underlie the increased susceptibility for relapse in drug-experienced individuals even after long periods of withdrawal. Additionally, it has recently been shown that exposure to cues associated with drug use elicits rapid and transient morphological and electrophysiological changes in glutamatergic synapses in the NAc. This review highlights these dynamic drug-induced changes in this pathway that are specific to a drug seeking neuropathology, as well as how these changes impair normal information processing and thereby contribute to the uncontrollable motivation to relapse. Future directions for relapse prevention and pharmacotherapeutic targeting of the rapid, transient synaptic plasticity in relapse are discussed. -- 132 words --
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