Research

Tackling alcohol use disorder and its comorbidities

We use a combination of pharmacology, molecular biology and genetic targeting to manipulate specific receptors and neural circuits in mouse models of alcohol use disorder.

We study the neural circuits and molecular mechanisms that are critical for drugs of abuse, with particular emphasis on alcohol and nicotine. Alcohol and nicotine are the two most widely abused substances in the world. Alcohol is one of the oldest drugs of abuse, yet we still do not understand all the mechanisms underlying alcohol use disorder. Excessive alcohol use was estimated to cost the US $249 billion dollars in 2014 (Sacks et al., 2015, Am J Prev Med). Nicotine is the primary substance that maintains tobacco dependence, and tobacco-related diseases will result in the death of 1 out of every 2 smokers. One of our central goals is to understand how cholinergic signaling and nicotinic acetylcholine receptors contribute to alcohol use disorder and nicotine dependence.

Alcohol and its comorbidities. Alcohol use disorder is frequently associated with other serious conditions such as nicotine dependence, chronic pain and dementia. In particular, the connection between alcohol and tobacco use disorders is supported by human twin research demonstrating a significant, shared genetic overlap between the two conditions. Patients that are co-dependent on alcohol and nicotine have more severe drug dependence, have a more difficult time maintaining drug abstinence and show more severe withdrawal symptoms compared with patients dependent on one drug. The goal of our work is to understand the mechanisms that contribute to alcohol use disorder and its comorbidities. One central objective of our work is to discover the behavioral and molecular mechanisms that are shared between alcohol and tobacco use disorder, which will enable us to inform drug development efforts to design better, more effective drugs to treat alcohol and nicotine co-addiction. Our work has focused on the contribution of cholinergic signaling and the nicotinic acetylcholine receptors (nAChRs) in reward and aversion circuitry.

Current research projects

A long-standing focus in the lab is the role of cholinergic signaling and the nicotinic acetylcholine receptors (nAChRs) in the mechanisms of alcohol use disorder. These receptors are widely expressed ligand-gated ion channels that are primarily found on pre-synaptic terminals and on neuronal cell bodies, and thus are poised to modulate neurotransmission and regulate neural circuits. As such, nAChRs are implicated in addiction, anxiety, depression and learning/memory. Our goal is to identify how different nAChR subtypes, and how regulation of nAChRs can affect neuronal activity, circuit function and behavior.

We currently have several projects: 1) Cholinergic regulation of alcohol aversion and reward. A major project in our lab is to determine how cholinergic signaling from the brainstem modulates alcohol reward, aversion and consumption. Our recent work has uncovered a novel role for the nAChRs in alcohol aversion and found that alcohol itself up-regulates cholinergic neuron activity and nAChR expression in the brainstem. Our goal is to identify how brainstem cholinergic signaling and nAChR expression changes modulate the effects of alcohol. 2) Sex dependent regulation of nAChR gene expression. We recently discovered novel regulation of the alpha6 and beta3 nAChR subtypes by protein kinase C epsilon and sex hormones, resulting in oppositional expression of addiction-related behaviors in mice. Our goal is to determine how molecular regulation of these nAChR genes differs between sexes. 3) Collaborations focused on alcohol comorbidities. We have active collaborations with Dr. Steven Graves on the role of chronic heavy alcohol consumption in Alzheimer's related pathology, and with Drs. Vulchanova and Stone on the role of chronic alcohol consumption in pain pathology.