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

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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    • "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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    • "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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