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.
"Recognition of the importance of redox and epigenetic mechanisms in addiction brings the prospect of novel targets. Use of N-acetylcysteine in symptomatic treatment of alcohol (Ferreira Seiva et al., 2009), cocaine dependence (Mardikian et al., 2007), and withdrawal (Reichel et al., 2011) presents efforts in exploiting this pathway. EAAT3 itself may provide a potential site for pharmacologic intervention, along with factors/systems which regulate its activity. "
[Show abstract][Hide abstract] 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.
"Results presented here support a critical role for druginduced downregulation of accumbens GLT-1 in the vulnerability to relapse, and that the restoration of GLT-1 by daily NAC treatments is a critical mechanism whereby NAC inhibits reinstated cocaine seeking. Importantly, while a number of studies demonstrate pre-clinical and clinical efficacy of NAC against cocaine seeking, results are not unilaterally positive (Mardikian et al. 2007; Berk et al. 2013). For example, in a recent double-blind placebo-controlled study of NAC for cocaine dependence over 8 weeks for outpatient, treatment-seeking users, overall use was not statistically different between groups (LaRowe et al. 2013). "
[Show abstract][Hide abstract] 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.
"Some success was had with N-acetylcysteine, which promotes the replacement of intracellular glutamate for cysteine via anti-porters and so reduced glutamate transmission. In a pilot study, it was found to diminish the taking of cocaine by the majority of patients after treatment in the study (Mardikian et al., 2007). This may encourage future studies aiming to tone down Glu transmission in cocaine addiction. "
[Show abstract][Hide abstract] ABSTRACT: Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA) concentration within the striatum. The main DA Guanine nucleotide binding protein couple receptors (GPCRs) expressed by medium-sized spiny neurons of the striatum are the D1R and D2R, which are positively and negatively coupled to cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behavior induced by drugs of abuse. A major downstream target of striatal D1R is the extracellular signal-regulated kinase (ERK) kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signaling. Once activated, ERK can trigger chromatin remodeling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioral changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signaling and is liable to prove relevant for addictive drug-induced signaling, plasticity, and behavior. Herein, we review the evidence that built our understanding of the consequences of this synergistic signaling for the actions of drugs of abuse.
Frontiers in Pharmacology 01/2014; 4:172. DOI:10.3389/fphar.2013.00172 · 3.80 Impact Factor
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