An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: A pilot study
ABSTRACT Recent preclinical studies implicate N-acetylcysteine (NAC), a cysteine prodrug, as a potential medication for preventing relapse to cocaine use; however, little is known about the safety and tolerability of NAC in cocaine-dependent subjects in an outpatient setting. This pilot study examines the safety and tolerability of 3 doses of NAC for the treatment of cocaine dependence. Twenty three treatment-seeking cocaine-dependent patients participated in a 4-week medication trial and received NAC at doses of 1200 mg/day, 2400 mg/day or 3600 mg/day. Results suggested that the three doses were well tolerated. Overall, the retention rates appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n=16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine on an outpatient basis.
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ABSTRACT: Canonically, opiates influence cells by binding to a G protein-coupled opiate receptor (GPCR), initiating intracellular signaling cascades such as protein kinase (PKA) (Bernstein and Welch, 1998), phosphoinositide-3 kinase (PI3K) (Yin et al., 2006), and extracellular receptor kinase (ERK) pathways (Muller and Unterwald, 2004). This results in several downstream effects, including decreased levels of the reduced-form of glutathione (GSH) and elevated oxidative stress (Goudas et al., 1999), as well as epigenetic changes, especially in retrotransposons and heterochromatin (Sun et al., 2012), although the mechanism and consequences of these actions are unclear. We characterized the acute and long-term influence of morphine on redox and methylation status (including DNA methylation levels) in cultured neuronal SH-SY5Y cells. Acting via μ opiate receptors (MORs), morphine inhibits EAAT3-mediated cysteine uptake via multiple signaling pathways, involving different G-proteins and protein kinases in a temporal manner. Decreased cysteine uptake was associated with decreases in both the redox and methylation status of neuronal cells, as defined by the ratios of reduced (GSH) to oxidized (GSSG) forms of glutathione and S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) levels, respectively. Further, morphine induced global DNA methylation changes, including CpG sites in LINE-1 retrotransposons, resulted in increased LINE-1 mRNA. Together, these findings illuminate the mechanism by which morphine, and potentially other opioids can, influence neuronal-cell redox and methylation status including DNA methylation. Since epigenetic changes are implicated in drug addiction and tolerance phenomenon (Renthal and Nestler, 2008), this study could potentially extrapolate to elucidate a novel mechanism for action of other drugs of abuse.Molecular pharmacology 02/2014; 85(5). DOI:10.1124/mol.114.091728 · 4.12 Impact Factor
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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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ABSTRACT: Until very recently addiction-research was limited by existing tools and strategies that were inadequate for studying the inherent complexity at each of the different phenomenological levels. However, powerful new tools (e.g., optogenetics and designer drug receptors) and high throughput protocols are starting to give researchers the potential to systematically interrogate "all" genes, epigenetic marks, and neuronal circuits. These advances, combined with imaging technologies (both for preclinical and clinical studies) and a paradigm shift towards open access have spurred an unlimited growth of datasets transforming the way we investigate the neurobiology of substance use disorders (SUD) and the factors that modulate risk and resilience.Neuropharmacology 05/2013; DOI:10.1016/j.neuropharm.2013.05.007 · 4.82 Impact Factor