Abstract
Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism.
Highlights
In the last years, numerous studies have supported the idea that, at least in part, motivational and neuropharmacological effects of ethanol are mediated by its first brain-derived metabolite, acetaldehyde (ACD) and/or its bioderivates
Pre-Clinical Studies with D-Penicillamine involvement of ACD in the motivational and reinforcing effects of ethanol has been, for years, the pharmacological manipulation of the enzyme system activity implicated in the brain metabolism of this drug
Behavioral studies have demonstrated that DP is able to: (i) dose-dependently prevent the ethanol- and ACD-induced conditioned place preference (CPP) in rodents (Font et al, 2006a,b; Peana et al, 2008, 2009); (ii) attenuate either behavioral depression caused by ACD or behavioral locomotion induced by ethanol in mice (Font et al, 2005); and (iii) prevent, in a dose-dependent manner, the motor activation induced by intra-ventral tegmental area (VTA) ethanol administration (Martí-Prats et al, 2010, 2013)
Summary
Numerous studies have supported the idea that, at least in part, motivational and neuropharmacological effects of ethanol are mediated by its first brain-derived metabolite, acetaldehyde (ACD) and/or its bioderivates (for extensive review, see Deehan et al, 2013; Peana et al, 2016). The reported data demonstrate that this therapeutic strategy, of combining two drugs with complementary actions—opioid receptor blockade (by NTX) and chemical ACD inactivation (by DP), shows adequate alcohol anti-relapse-like drinking efficacy in long-term ethanolexperienced rats It overcomes some therapeutic limitations of either drug alone, since this combination is able to block the delayed increase in ethanol consumption, typically occurring after chronic opioid antagonist administration, but it allows the administration of sub-threshold DP doses. To sum up, we were able to replicate our previous outcomes in a different laboratory (Laboratory of Psychobiology, Complutense University of Madrid) and using a different paradigm, (interlab reliability) leading to more robust conclusions on the use of DP as a potential new pharmacotherapy in the treatment of alcoholism
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