Glucagon-Like Peptide-1 Receptor Signaling in the Ventral Tegmental Area Reduces Alcohol Self-Administration in Male Rats.

Abstract

The misuse and abuse of alcohol is a major public health issue. However, available treatments are limited with variable efficacy. Recently, preclinical studies show that glucagon-like-peptide-1 (GLP-1) and its analogue Exendin-4 (Ex4) potently reduce a range of alcohol intake behaviors, thus highlighting its potential as a treatment for alcohol use disorders. However, the neural mechanisms and sites of action mediating the effects of Ex4 on alcohol intake behaviors remain to be characterized. This study examined the ventral tegmental area (VTA) as a site of action for the effects of GLP-1 on alcohol intake. Male Long-Evans rats were given intermittent access to 20% alcohol and trained to nose poke for 20% alcohol. Rats received intra-VTA injections of Ex4 (vehicle, 0.01, 0.05μg), and the effects of VTA Ex4 on alcohol self-administration, motivation, and relapse were assessed. When compared to vehicle treatment, intra-VTA Ex4 (0.01, 0.05μg) delivery significantly reduced alcohol self-administration, an effect that was particularly prominent in high alcohol drinkers. However, VTA Ex4 did not reduce reacquisition of alcohol self-administration after extinction nor the motivation to obtain alcohol. Importantly, the lower dose of Ex4 (0.01μg) used had no effect on food intake or locomotor activity, suggesting that the reduction in alcohol self-administration observed was not secondary to caloric intake or motor deficits. Together, these findings provide support for the VTA as a key site of action for GLP-1 on alcohol self-administration but not the reacquisition of alcohol self-administration or motivation to work for alcohol.