Corticostriatal mechanisms of action learning and habit formation

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

Behavioral, Neurobiological and Metabolic Factors Influence Alcohol Drinking in Mice Control of alcohol (ethanol) intake is crucial to prevention of misuse and alcohol use disorder. We have used mouse models to examine the roles of neural circuitry in ethanol intake. The Cortico-thalamo-basal ganglia (CTBG) circuitry controls action learning and action selection. This circuitry is altered by acute and chronic ethanol exposure, and these neuropharmacological effects contribute to many alcohol-related behaviors including drinking (Lovinger, Alcohol 2025). Recent studies indicate that endocannabinoid signaling in the striatonigral pathway within the CTBG circuitry has important roles in controlling the sedative effects of ethanol as well as ethanol intake (Augustin et al., Neuropsychopharmacology 2023). Specifically, preventing production of the endocannabinoid 2-arachidonoyl glycerol (2-AG) in striatonigral neurons reduces the duration of ethanol-induced loss of righting reflex, and decreases ethanol preference (in this case only in male mice). This role for 2-AG may be related to the well-known inhibition of ethanol intake produced by cannabinoid receptor inhibitors that interfere with 2-AG signaling. We are also currently exploring how different basal ganglia subregions and neurons contribute to ethanol-related behavior changes. Previous studies in our laboratory indicated that ethanol inhibits the firing of a subclass of neurons in the Globus Pallidus External Segment that send GABAergic projections to the striatum (Abrahao et al., Neuropsychopharmacology 2017). These "arkypallidal" neurons inhibit the firing of neurons in the striatum and appear to have roles in stopping the production of unwanted actions. We are currently combining recordings of these neurons in vivo with analysis of behaviors involved in assessing actions as well as ethanol seeking and drinking to determine how ethanol effects on these neurons may influence decision making related to maladaptive behaviors, including excessive ethanol intake. In collaboration with the Laboratory of Liver Diseases (LLD) in NIAAA We are also examining the role of ethanol and its metabolites in behavioral changes and brain injury produced by the drug. Our previous findings indicated that acetate, the secondary metabolite of ethanol, contributes to loss of motor coordination after ethanol exposure (Jin et al., Nature Metabolism 2021). Ethanol metabolism to acetaldehyde is followed by conversion to acetate via Aldehyde Dehydrogenase 2 (ALDH2). In the cerebellum, a brain region involved in fine motor control, ALDH2 is expressed in astrocytes (a form of glial cell). The acetate produced in these cells after ethanol exposure is converted to the neurotransmitter gamma-aminobutyric acid. This process enhances inhibition of neurons in cerebellum, and this enhanced inhibition plays a role in motor incoordination. We have also observed other roles for neural ALDH2 in spinal cord (Jin et al., British Journal of Anaesthesia 2021). These findings indicate that acetate production in the central nervous system following ethanol ingestion or exposure contributes to intoxication. This collaboration also extended to examination of the role of ethanol metabolism to acetaldehyde. Studies in LLD have examined the function of Alcohol Dehydrogenase 1 (ADH1), the enzyme responsible for the majority of ethanol metabolism in the body. These studies revealed decreased ethanol drinking in mice that lack this enzyme, or when the enzyme is inhibited pharmacologically (Mackowiak et al., Alcohol Clinical and Experimental Research 2025). We implemented a system to measure licking during ethanol intake to examine how loss of this enzyme alters drinking structure and time course. Using this approach, we found that intake is similar to wild-type mice early in drinking sessions, but lick numbers and duration fall off in mice lacking ADH1 after 30 minutes of ethanol access in a "drinking in the dark" paradigm. These findings suggest that mice titrate their ethanol consumption to reach blood and brain levels that produce mild intoxication without aversive effects observed at higher levels. These findings support the idea that ethanol itself is involved in the intoxication and drinking processes. This idea is not surprising, but the sum total of the ongoing work on the roles of ethanol and its metabolites supports roles for ethanol, acetaldehyde and acetate. We will continue to explore which enzymes in which organ and cellular locations contribute to the many acute and chronic behavioral effects of the drug. Finally, we noticed that mice drinking from plastic sipper tubes that included rubber components drink less ethanol than mice drinking from glass tube. We worked with the laboratory of Dr. Max Joffe at the University of Pittsburgh who had noted this drinking difference to document and report this effect (Haggerty et al., Alcohol 2025). This information will be useful not only for investigators studying ethanol drinking in rodents, but in cases where humans may be drinking from vessels containing plastic and rubber components.