The contribution of projection-specific endocannabinoid signaling in ethanol-related behaviors

The National Institute on Alcohol Abuse and Alcoholism awarded Northwestern University $100,228 on December 18, 2026, under the Alcohol Research Programs (CFDA 93.273) to investigate projection-specific endocannabinoid signaling mechanisms in ethanol-related behaviors.

The research examines how ethanol affects endocannabinoid-cannabinoid receptor type 1 signaling at dorsolateral striatum terminals in the external segment of the globus pallidus, and how altered signaling at these terminals contributes to ethanol consumption behaviors. The work focuses on identifying neuronal sources of endocannabinoid synthesis and testing whether deletion of CB1 receptors from dorsolateral striatum-globus pallidus terminals decreases ethanol consumption by altering synaptic signaling and influencing downstream reward-related circuits. The research responds to persistent increases in alcohol-related deaths following the COVID-19 pandemic by establishing fundamental mechanisms underlying alcohol consumption.

Performance period runs from the award date through December 17, 2027, with work performed in Chicago, Illinois. This is a project grant, the standard assistance type under the Alcohol Research Programs.

Abstract

Although the covid-19 pandemic occurred five years ago, its lingering effects, such as increased alcohol consumption, have persisted, leading to an increase in alcohol related deaths. Thus, highlighting the importance of understanding the mechanisms that contribute to alcohol consumption. The endocannabinoid (ECB) system has been shown to modulate ethanol intake. However, the projection-specific effects of ethanol on the ECB system, and how these changes contribute to further ethanol consumption is unclear. In this proposal, i will examine ethanol induced changes to ECB mobilization at specific projections and the contributions that cannabinoid receptor type 1 (CB1) receptor signaling at specific projections may have in ethanol consumption. This proposal aims to establish the mechanisms by which ethanol affects ECB-CB1 signaling at dorsolateral striatum (DLS) terminals in the external segment of the globus pallidus (GPE). Additionally, i aim to determine how altered ECB-CB1 receptor signaling at these terminals may contribute to ethanol behaviors. Preliminary data suggest that ethanol dampens GPE ECB mobilization. As a result, i hypothesize that ethanol decreases ECB mobilization through 2-AG mediated mechanisms to decrease ethanol consumption. However, the neuronal source of these ecbs in the GPE is unclear. Potential neuronal sources of ECB synthesis may be parvalbumin and FOXP2, cell types in the GPE that represent prototypic and arkypallidal subtypes, respectively. Additionally, i have shown that deletion of CB1 receptors from DLS terminals in the GPE show increasing trends in the sedative effects of ethanol. I hypothesize that DLS-GPE CB1 receptor deletion decreases ethanol consumption, as CB1 receptors may result in altered synaptic signaling at DLS-GPE terminals which influences downstream reward- related circuits. To test these hypotheses, i will use EX vivo brain slice photometry, pharmacology, and fluorescent in situ hybridization to determine the mechanisms by which ethanol affects ECB-CB1 receptor signaling at DLS- GPE terminals (aim 1). Then, i will utilize an intersectional viral deletion strategy to evaluate the contributions of ECB-CB1 receptor signaling at DLS-GPE terminals on voluntary ethanol drinking and its sedative effects (aim 2). This proposal will provide insight into the mechanisms by which ECB-CB1 receptor signaling at DLS-GPE projections contribute to ethanol behaviors. Over the course of this fellowship, i will become proficient in technical research skills such as electrophysiology, sophisticated viral targeting strategies, and ethanol- behaviors. This is in addition to developing skills in teaching, science communication, grantsmanship, and networking. I will expand on my knowledge of alcohol and its effects on the brain and body through conferences, seminars, and annual meetings with other experts in alcohol research. This fellowship will support my goal of being an independent researcher studying how changes in neural circuits contribute to addiction and other maladaptive behaviors.