GABAergic mechanisms of adolescent and emerging adult vulnerability to alcohol

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DESCRIPTION (provided by applicant): Veterans and their families are disproportionately burdened by the medical and social consequences of alcohol abuse because the prevalence of alcoholism in veterans is over 3 times that of the general population. While the cause of increased alcohol abuse by veterans is not known, a growing body of evidence suggests a link between brain changes caused by alcohol drinking during adolescence or emerging adulthood and the later development of alcohol abuse in adults. Heavy drinking during adolescence / emerging adulthood may disrupt the maturation of vulnerable brain circuits and produce long-term changes in cognition, behavior, and sensitivity to ethanol. Because military personnel ages 18-25 use alcohol more frequently and at higher doses than civilians, veterans are more likely to have engaged in heavy drinking at a time when the brain may be particularly sensitive to the long-lasting consequences of ethanol exposure. Recent advances in the alcohol field are producing insights into the neurological mechanisms that underlie the unique ethanol sensitivity of the adolescent and emerging adult brain. In particular, extrasynaptic GABAA receptors (eGABAARs) have been identified as important ethanol targets. These developmentally regulated GABAARs control the excitability of neurons and brain circuits and modulate anxiety, learning, sleep, and ethanol drinking. Recent evidence suggests that 2 extrasynaptic GABAAR subtypes, �4�� and �5�?, regulate neuron excitability and ethanol sensitivity in the hippocampus and amygdala. Recently published studies have shown that binge-pattern ethanol exposure during adolescence produces long-term changes in the ethanol sensitivity of eGABAAR-mediated tonic inhibition, and these changes may involve �4�� and �5�? GABAARs. Two mechanisms control the ethanol sensitivity of eGABAAR-mediated tonic inhibition: the GABAAR subtype expressed and the ambient GABA concentration. Critical interactions between these mechanisms may underlie developmental changes in the ethanol sensitivity of neurons and brain circuits during adolescence and emerging adulthood. The aims of this project will (1) use targeted proteomics and electrophysiology in ex vivo brain slices to thoroughly characterize the roles of eGABAAR subtype expression and ambient GABA in controlling tonic inhibition in the dentate gyrus and amygdala; (2) antagonize the effects of ethanol on �4�� GABAARs to determine if they play an essential role in producing the long-term effects of binge-pattern ethanol exposure; and (3) pharmacologically manipulate eGABAARs in vivo to demonstrate a critical link between changes in eGABAAR-mediated tonic inhibition and ethanol-induced changes in cognition and ethanol self- administration. Drugs that regulate eGABAARs are currently available, and more are in development; therefore, these studies of tonic inhibition's role in producing ethanol's neurological effects may have near-term translational value. The results of these studies could lead to the identification of new treatments for alcohol abuse.