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: 9.67). 01/2011; 108(1):385-90. DOI: 10.1073/pnas.1011265108
Source: PubMed


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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    • "The expression of system x À c was found to be higher in astrocytes as compared to other body tissues known to release nonvesicular glutamate for the regulation of synaptic activity (Baker et al., 2002b; Kupchik et al., 2012; Moran et al., 2005; Pow, 2001). Owing to the pivotal role of system x À c in the maintenance of neuronal plasticity as well as glutathione production, any aberration in this system could contribute to pathophysiological changes in cystine and glutamate related functions in brain (Moussawi et al., 2011). This assumption has been corroborated with the research findings documented in various investigations carried out on epileptic seizures and glioma (De Bundel et al., 2011; Lewerenz et al., 2014; Takeuchi et al., 2013), neurodegenerative diseases like Alzheimer's disease (AD) (Barger, 2004; Qin et al., 2006; Schallier et al., 2011), Parkinson's disease (PD) (Massie et al., 2011), and multiple sclerosis (MS) (Pampliega et al., 2011). "
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    ABSTRACT: System is an antiporter belonging to the hetero(di)meric amino acid transporter family. It is located on astrocytes as well as on blood-brain barrier within the CNS. It plays a pivotal role in free radical neutralization as well as neuronal signalling by regulating the glutathione production which occurs via the exchange of intracellular glutamate with extracellular cystine at 1:1 molar ratio. Understandably, it is a vital component responsible for the maintenance of neuronal homeostasis (e.g. redox state). Hence, it could be postulated that any perturbation in system function may contribute, directly or indirectly, to the pathophysiology of a variety of CNS disorders like Alzheimers disease, schizophrenia, drug addiction, depression, multiple sclerosis, hypoglycemic neuronal cell death, glioma, and excitotoxicity, making system a promising target for treating CNS disorders. In recent times, recognizing the potential of this target, variety of inhibitors has been synthesized by modifying commercially available potent inhibitors including sulfasalazine, erastin, and sorafenib. Although, they have demonstrated efficacy, the in-depth data is still lacking to warrant their use for the treatment of aforementioned CNS disorders. In this review, we discuss the in-depth role of system transporter in maintaining normal physiology as well as in the pathophysiology of CNS diseases. Additionally, we have also listed some of the potent inhibitors of system. In conclusion, the critical role of system in multiple CNS disorders and advanced research on its inhibitors have promising future prospects for better management of the CNS ailments. © 2015 Taylor & Francis All rights reserved: reproduction in whole or part not permitted.
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    • "However, in contrast to the latter drugs, which show persisting effects after 3 months of abstinence, the effects of cocaine are largely dissipated (Kolb et al., 2003a,b,c), a result consistent with the behavioral and neurophysiological effects of cocaine (Henry and White, 1995). Not only does the effect of cocaine diminish over time, it has recently been shown that it is possible to reverse the effects of cocaine on synaptic function in nucleus accumbens by administering a cystine prodrug, N-acetylcysteine (Moussawi et al., 2011). This result is obviously important for its implications in treating cocaine dependence but more generally in that it shows that neural plastic changes can be reversed. "
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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.
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