IDENTIFYING AND TARGETING CEREBELLAR ADAPTATIONS DURING WITHDRAWAL AS TREATMENT FOR ALCOHOL USE DISORDER

Nadia McLean

Alcohol Use Disorder (AUD) is a leading substance use disorder, making up about 10% of the U.S. population aged 12 and older. AUD has many defining characteristics, such as excessive alcohol (EtOH) intoxication, tolerance, and withdrawal, but the diagnoses criterion and symptoms present themselves differently for each individual, making it challenging to treat. Therefore, the Cycle of Addiction breaks AUD into smaller components including binge intoxication, craving, and withdrawal, all of which are sustained via neuroadaptations. Importantly, EtOH impacts all regions of the brain, but the cerebellum is particularly sensitive, responding to concentrations as low as 9 mM. Despite this sensitivity and clear role in motor impairment during intoxication, the cerebellum is an understudied structure for the acquisition, maintenance, and treatment of AUD. Therefore, the overarching aims of this dissertation are: 1) characterize cerebellar adaptations to chronic EtOH use and determine if they contribute to withdrawal severity, and 2) investigate if genetic variability in cerebellar expression of nicotinic and cannabinoid receptors contributes to withdrawal treatment efficacy. To address the first aim, I exposed mice to 24, 48, and 72 hours of EtOH vapor. During withdrawal, I tested cerebellar granule cell (GC) inhibition, motor impairment, and emotionality. I determined that after 48 hours of EtOH exposure, there is a homeostatic reduction in GC inhibition via a decrease in spontaneous inhibitory post-synaptic current (sIPSC) frequency which coincides with the onset of motor impairment and negative emotional affect. Furthermore, I determined that selective chemogenetic inhibition of GCs reduces motor impairment and selective pharmacological inhibition of GCs, via Compound 6, reduces negative emotional affect during withdrawal. Together, this suggests that decreases in cerebellar GC inhibition are required for the onset of somatic and affective EtOH withdrawal symptoms and highlights the cerebellum as a promising selective therapeutic target. To address the second aim, I compared differences in nicotinic acetylcholine receptors (nAChRs) that contained the α7 subunit and cannabinoid receptors between C57BL6/N (B6N) and DBA2/J (D2) mice, two strains that are sensitive to aversive EtOH withdrawal symptoms. Furthermore, I determined that B6N mice have more functional cerebellar cannabinoid receptors, and D2 mice have more functional cerebellar nAChRs, both respectively increasing GC inhibition. Additionally, CBD, a weak agonist of cannabinoid receptors, shows a trend for improving motor coordination and reducing EtOH consumption during EtOH withdrawal in B6N mice and varenicline, a full nAChRα7 agonist, significantly improves motor coordination in D2 mice. Together, this highlights the importance of considering genetic variability when treating EtOH withdrawal. Additionally, this suggests that even with pharmacological treatments that are not cerebellar selective, increasing cerebellar GC inhibition is required for treatment of EtOH withdrawal-mediated motor impairment. In conclusion, the cerebellum plays a critical role in the emotional and motoric EtOH withdrawal symptoms making it a key target for understanding the acquisition and maintenance of AUD.

IDENTIFYING AND TARGETING CEREBELLAR ADAPTATIONS DURING WITHDRAWAL AS TREATMENT FOR ALCOHOL USE DISORDER

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