Globally, harmful use of alcohol killed more than 3 million people in 2016. This is a greater effect on mortality than diabetes, hypertension, digestive diseases, or road injuries. In the USA alone, alcohol use disorder (AUD) is estimated to affect 17 million people, with great costs to the individual and to society. Although available therapies and counseling can be effective in some drinkers, AUD is a severely undertreated condition and long-term recovery remains difficult to achieve. Glucagon-like peptide-1 (GLP-1) is a peptide that has both hormone and neurotransmitter functions. It is produced in the digestive tract and regulates blood sugar and food intake, and GLP-1 receptor agonists are used clinically to manage type-2 diabetes and obesity. GLP-1 is also produced in the brain, and GLP-1 receptors are expressed in brain regions important in addictions. Evidence suggests that one or more GLP-1 receptor variants are associated with AUD and modulate effects of ethanol in humans, and that GLP-1 receptor agonists can reduce ethanol intake in laboratory animals. The long-term goal of this research, in a collaboration spanning molecular and behavioral studies in laboratory animals to a clinical trial, is to validate and optimize GLP-1 receptor agonists as a treatment approach for AUD. The present application is to support a well-defined project within this ongoing line of investigation. The goal for the present studies is to understand how GLP-1 receptor agonists modulate alcohol use at a circuit level and at a behavioral level.
In Aim 1, the roles of GABAergic and glutamatergic neurons in hippocampus and in lateral septum in GLP-1 receptor agonist-mediated decreases in voluntary alcohol intake will be evaluated.
Aim 1 a will combine genetically engineered male and female mice expressing GLP- 1 receptors in specific neuron types with systemic and intracranial microinfusions of the selective GLP-1 receptor agonist exendin-4 to test the hypothesis that stimulation of GLP-1 receptors in glutamatergic or GABAergic neurons, respectively, is sufficient to reduce alcohol intake.
Aim1 b will use a genetically encoded dopamine indicator with high temporal resolution to test the hypothesis that exendin-4 microinfusion into the hippocampus or lateral septum suppresses alcohol-induced increases in extracellular dopamine in the nucleus accumbens.
In Aim 2, the effects on alcohol withdrawal symptoms of daily GLP-1 receptor agonist treatment (given during alcohol access or during forced abstinence, two experiments) will be evaluated. Alcohol-containing liquid diet will be used to induce alcohol dependence in male and female mice, and the severity of withdrawal symptoms will be assessed using endpoints of acute somatic symptoms, as well as more prolonged affective symptoms using tests of anxiety-like behavior, anhedonia, diurnal activity patterns, and change in voluntary alcohol consumption, over four weeks of abstinence. Blood ethanol levels will be determined in all experimental groups.
The long-term goal of the proposed research is to develop new treatments that target brain glucagon-like peptide 1 (GLP-1) receptors. The research is aimed at treating alcohol use disorder specifically, but is likely to also advance treatment of other substance use disorders such as cocaine, for which no effective medications currently exist. Finally, GLP-1 drugs are already used to treat type 2 diabetes and obesity, and a better understanding of how they work may lead to better treatments of obesity and diabetes.
