Turning the Clock Ahead: Potential Preclinical and Clinical Neuropharmacological Targets for Alcohol Dependence

Abstract

Treating alcohol use disorders represents a main goal in public health, but the effect of current medications is modest. Thus, in the last few years, research has been focusing on identifying new neuropharmacological targets for alcohol dependence. This review will summarize recent research, which has identified new targets to treat alcohol dependence. A variety of systems have been investigated, such as the endocannabinoid system, modulators of glutamatergic transmission, corticotropin-releasing factor (CRF), neuropeptide Y (NPY), nociceptin, glial cell line-derived neurotrophic factor (GDNF), acetaldehyde (ACD), substance P and Neurokinin 1 (NK1) receptor, nicotinic acetylcholine receptors (nAchRs), alpha-adrenergic receptor, and many others. Compared to preclinical studies, only a few clinical studies have been conducted so far. Thus, there is a critical need to translate successful preclinical results into human clinical trials. However, since some clinical studies have failed to replicate preclinical findings, future research will have not only to identify more efficacious medications, but also delineate the best match between a particular pharmacotherapy with a specific alcoholic subtype.

Opioid antagonists block acetaldehyde-induced increments in dopamine neurons activity

“…Among the therapies available today for alcohol abuse (Leggio et al, 2010;Addolorato et al, 2012), one of the most widely used is NTX and the present results suggest that EtOH-derived ACD may participate in its mechanism of action.…”

Current and Promising Pharmacotherapies, and Novel Research Target Areas in the Treatment of Alcohol Dependence: A Review

“…There are a myriad of different neuropharmacological targets for AD that are under investigation, mostly at a preclinical level (for an extensive review, see [103]). Here, we only report a few examples.…”

“…In contrast, blocking of this receptor decreases alcohol consumption (reviewed in: [103,104]). One potential CB1 antagonist, rimonabant has shown promise as a potential blocker of this receptor and decreasing ethanol intake in animal studies [105].…”

“…Preclinical data suggests acute ethanol withdrawal increases CRF levels in the central nucleus of amygdala [111] and in the bed nucleus of the stria terminalis [112] facilitating stress and anxiety responses. A large body of evidence demonstrates that upregulated activity of the CRF system confers susceptibility for excessive self-administration of alcohol and relapse (reviewed [103]). Furthermore, some studies have shown a link between genetic polymorphisms in CRF1 and risky-drinking behaviors [113,114], suggesting that the impact of stress on heavy drinking could be more evident among individuals carrying a particular genotypic variant of CRF1 gene.…”

Molecular Targets of Alcohol Action

“…The treatment of alcohol use disorders (AUD) represents a main goal in public health, but the currently available, Food and Drug Administration-(FDA) approved medications are limited and have mixed efficacy in the heterogeneous clinical population (42, 45–48). Presently, the FDA has approved only 4 medications for the treatment of AUDs: These are disulfiram, an aldehyde dehydrogenase inhibitor ( Antabuse™ ), acamprosate, a functional glutamatergic antagonist ( Campral™ ), and two of these are based on naltrexone, a pan-opioid antagonist ( ReVia™ , oral form, and Vivitrol™ for depot administration) (49–51).…”