We study the neural circuits and molecular mechanisms that are critical for alcohol use disorder (AUD). Alcohol is one of the oldest drugs of abuse, yet we still do not understand all the mechanisms underlying alcohol use disorder. In 2024, an estimated 28 million people in the United States had alcohol use disorder (AUD). We aim to understand how cholinergic signaling and nicotinic acetylcholine receptors contribute to AUD.
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.
A long-standing focus in the lab is the role of cholinergic signaling and the nicotinic acetylcholine receptors (nAChRs) in the mechanisms of AUD. 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, particularly in AUD. Insights we gain from understanding the role of nAChRs in AUD will help us better understand the overlapping mechanisms in alcohol and nicotine co-use.
Cholinergic signaling in AUD
A major project in our lab is to determine how cholinergic signaling from the brainstem modulates alcohol withdrawal, aversion and consumption. Our recent work has uncovered a novel role for the nAChRs in alcohol withdrawal in C57BL/6J mice that is dramatically different in males compared with females. We found that alcohol exposure and withdrawal up-regulates cholinergic neuron activity and nAChR expression in the brainstem and midbrain in a sex-dependent manner, with male mice showing an increase in cholinergic signaling that persists into prolonged alcohol withdrawal, whereas female mice do not show this increase (Mulloy et al., 2024). We have recently shown that the increased anxiety- and compulsive-like behavior in protracted alcohol withdrawal in male mice is mediated by cholinergic activity, since pre-treatment with cholinergic drugs such as mecamylamine and varenicline attenuates these withdrawal signs (Payne et al., 2026). Importantly, female mice show different alcohol withdrawal signs compared with male mice, and cholinergic antagonists do not reduce alcohol withdrawal in female mice. Our data has significant clinical implications for the treatment of alcohol withdrawal in men versus women.
Chronic alcohol comorbidity with Alzheimer's Disease
We have an active collaboration with Dr. Steven Graves to investigate the role of chronic heavy alcohol consumption in Alzheimer's Disease (AD)-related pathology in mice, focusing on the role of early degeneration in the locus coeruleus in a mouse model of AD. Our work has found that chronic, voluntary alcohol consumption increases AD-related pathology in a mouse model that is genetically predisposed to develop AD (APP/PS1 model) (Engel et al., 2025). Our current work is focused on the underlying mechanisms by which alcohol enhances AD pathology in this model.
Interactions between chronic alcohol & chronic pain
The Lee lab is part of the Minnesota Pain and Alcohol Research Consortium (MNPARC), a new consortium at the University of Minnesota that brings together basic scientists, human laboratory researchers and clinicians from across the University of Minnesota Academic Health Center. Our mission is to advance a comprehensive understanding of how alcohol affects pain and how pain shapes alcohol use, with the goal of accelerating discovery to improve outcomes. Our goals are to promote bidirectional translation, integrate clinical perspectives with preclinical research, and foster innovative ideas to better understand the complex interactions between pain and alcohol to improve quality of life. Please visit the MNPARC website for more information.