Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders

Abstract

Alcohol use disorders (AUDs) are complex, and developing effective treatments will require the combination of novel medications and cognitive behavioral therapy approaches. Epidemiological studies have shown there is a high correlation between alcohol consumption and tobacco use, and the prevalence of smoking in alcoholics is as high as 80% compared to about 30% for the general population. Both preclinical and clinical data provide evidence that nicotine administration increases alcohol intake and non-specific nicotinic receptor antagonists reduce alcohol-mediated behaviors. As nicotine interacts specifically with the neuronal nicotinic acetylcholine receptor (nAChR) system, this suggests that nAChRs play an important role in the behavioral effects of alcohol. In this review, we discuss the importance of nAChRs for the treatment of AUDs and argue that the use of FDA approved nAChR ligands, such as varenicline and mecamylamine, approved as smoking cessation aids may prove to be valuable treatments for AUDs. We also address the importance of combining effective medications with behavioral therapy for the treatment of alcohol dependent individuals.

Fig. 1

The neuronal nicotinic acetylcholine receptor (nAChR) structure and the possible subtypes. The nAChRs are pentameric ligand-gated ion channels forming either heteromeric or homomeric receptors. The heteromeric receptors (A) are α-bungarotoxin insensitive receptors consisting of α (α2–α6) and β (β2–β4) subunits with the ligand-binding site at the interface of α and β subunits. The α-bungarotoxin insensitive receptors (B) are predominantly homomeric consisting of α7, α8 or α9 subunits and can seldom be heteromeric with α7–8 or α9–10 subunit compositions and contains five identical ligand binding site.

Fig. 2

The diversity and localization of the possible nAChR subtypes in the brain. Several subunit compositions of nAChRs exist and are widely distributed as shown here in brain regions: ventral tegmental area (VTA), nucleus accumbens (NAcc), medial habenula, hippocampus, prefrontal cortex and cerebellum. The activation of nAChRs in the mid brain which consists of VTA and NAcc has been implicated to be important for ethanol mediated effects. Mecamylamine and α-conotoxin- MII are the only nAChR ligands that have been administered locally into the VTA resulting in a decrease of ethanol-induced dopamine overflow in the NAcc. Genetic-association studies have indicated nAChRs containing the α3*, α5* and β4* subunits to be important for alcohol dependence. Medial habenula (dashed line) indicates a brain region with the highest density of these subunits with afferent and efferent connections with the midbrain.