Genetic variation in cerebellar nicotinic acetylcholine receptor (nAChR) function impacts efficacy of nicotine and varenicline treatment of alcohol withdrawal-induced motor impairment.
Source: PubMed, NCBI / U.S. National Library of Medicine
In the U.S., 10% of the population is diagnosed with Alcohol Use Disorder (AUD), and 80% of those individuals also use nicotine, making both substances major public health concerns. AUD is characterized by chronic alcohol (EtOH) consumption, dependence, and withdrawal, sustained by neurological adaptations, such as occurs in the cerebellum. Specifically, in the cerebellum, acute EtOH increases inhibition, but during prolonged exposure, homeostatic adaptations decrease cerebellar inhibition, which during withdrawal causes the onset of both motoric and emotional withdrawal symptoms. These aversive withdrawal symptoms are ameliorated by renewed EtOH use, thereby generating negative reinforcement for renewed EtOH consumption. Similarly, nicotine alleviates aspects of EtOH withdrawal symptoms, likely contributing to AUD-nicotine comorbidity. Relatedly, clinical trials are using the smoking cessation drug, varenicline, a full nAChRα7 and partial nAChRα4β2 agonist, to treat AUD. However, genetic variation in nAChR expression suggests this approach may not work for everyone. The goal of this study was to determine how genetic differences in nAChR function between C57BL6/N (B6N) and DBA/2J (D2) mice, two strains known for high EtOH withdrawal severity, influence the efficacy of nicotine and varenicline for treating EtOH withdrawal. We found that D2 mice had higher cerebellar nAChR function (manifested as increased synaptic GABA release onto primary cerebellar input g
Abstract
In the U.S., 10% of the population is diagnosed with Alcohol Use Disorder (AUD), and 80% of those individuals also use nicotine, making both substances major public health concerns. AUD is characterized by chronic alcohol (EtOH) consumption, dependence, and withdrawal, sustained by neurological adaptations, such as occurs in the cerebellum. Specifically, in the cerebellum, acute EtOH increases inhibition, but during prolonged exposure, homeostatic adaptations decrease cerebellar inhibition, which during withdrawal causes the onset of both motoric and emotional withdrawal symptoms. These aversive withdrawal symptoms are ameliorated by renewed EtOH use, thereby generating negative reinforcement for renewed EtOH consumption. Similarly, nicotine alleviates aspects of EtOH withdrawal symptoms, likely contributing to AUD-nicotine comorbidity. Relatedly, clinical trials are using the smoking cessation drug, varenicline, a full nAChRα7 and partial nAChRα4β2 agonist, to treat AUD. However, genetic variation in nAChR expression suggests this approach may not work for everyone. The goal of this study was to determine how genetic differences in nAChR function between C57BL6/N (B6N) and DBA/2J (D2) mice, two strains known for high EtOH withdrawal severity, influence the efficacy of nicotine and varenicline for treating EtOH withdrawal. We found that D2 mice had higher cerebellar nAChR function (manifested as increased synaptic GABA release onto primary cerebellar input granule cells) than B6N mice. Additionally, nicotine and varenicline improved motor impairment during EtOH withdrawal only in D2 mice, showing the necessity of functional cerebellar nAChRs for treatment EtOH withdrawal symptoms. Finally, we found that nicotine's rapid metabolism limits its therapeutic effect in D2 mice, which provides a possible explanation for the urge to chain smoke during withdrawal. These findings highlight the importance of genetic variability in AUD treatment, and support varenicline as a potential nicotine substitute during withdrawal.