Alcohol dependence is a debilitating disorder with current therapies displaying limited efficacy and/or compliance. Consequently, there is a critical need for improved pharmacotherapeutic strategies to manage alcohol use disorders (AUDs). Previous studies have shown that the development of alcohol dependence involves repeated cycles of binge-like ethanol intake and abstinence. Therefore, we used a model of binge-ethanol consumption (drinking-in-the-dark) in mice to test the effects of compounds known to modify the activity of neurotransmitters implicated in alcohol addiction. From this, we have identified the FDA-approved antihypertensive drug pindolol, as a potential candidate for the management of AUDs. We show that the efficacy of pindolol to reduce ethanol consumption is enhanced following long-term (12 weeks) binge-ethanol intake, compared with short-term (4 weeks) intake. Furthermore, pindolol had no effect on locomotor activity or consumption of the natural reward sucrose. Because pindolol acts as a dual beta-adrenergic antagonist and 5-HT partial agonist, we examined its effect on spontaneous synaptic activity in the basolateral amygdala (BLA), a brain region densely innervated by serotonin and norepinephrine-containing fibres. Pindolol increased spontaneous excitatory post-synaptic current frequency of BLA principal neurons from long-term ethanol-consuming mice but not naïve mice. Additionally, this effect was blocked by the 5-HT receptor antagonist methiothepin, suggesting that altered serotonergic activity in the BLA may contribute to the efficacy of pindolol to reduce ethanol intake following long-term exposure. Although further mechanistic investigations are required, this study demonstrates the potential of pindolol as a new treatment option for AUDs that can be fast-tracked into human clinical studies.

In mice, varenicline reduces binge-like ethanol consumption both after short- and long-term exposure in the DID and this effect is independent of β4 nAChR subunit.

While the co-morbidity of alcohol (ethanol) and tobacco (nicotine) dependence is well described, the processes that underpin this strong connection are still under debate. With the increasing popularity of electronic cigarettes (e-cigarettes), it is now becoming more important to look to the neurobiological mechanisms involving alcohol and nicotine interactions to effectively treat a new generation of co-dependent individuals. Researchers have already recognized that the neuropathology produced by the combination of nicotine and ethanol is likely to produce an addictive nature very different to that of either one alone, and are employing a mixture of pre-clinical techniques to establish and investigate every stage in the development of both nicotine and ethanol-seeking behaviors. While it is agreed that multiple pathways orchestrate the complex reward profile of alcohol and nicotine co-addiction, several lines of evidence suggest the convergent site of action is within the mesolimbic dopaminergic system, at neuronal nicotinic acetylcholine receptors (nAChRs). A whole host of strategies are currently being employed to discover and unravel previously unknown or ill understood neurobiological processes in the brain, contributing greatly toward the development of novel pharmacotherapies with the aim of improving patient outcomes. This review intends to shed some light on the most influential and most recent pre-clinical work that is leading the charge in modeling this complicated relationship.