Binge alcohol drinking is the most prevalent form of alcoholism in the United States, with high rates of binge drinking reported in adolescents and young adults. This is concerning as adolescence/early adulthood is a period of robust neurodevelopment during which forebrain glutamate neurons establish their connectivity with subcortical structures within the extended amygdala that regulate emotionality and motivated behavior. Thus, binge drinking during this critical period is likely to grossly perturb the developmental trajectories of glutamate systems within the extended amygdala, which may contribute to the high prevalence of comorbid affective and alcohol use disorders. Indeed, an early history of alcohol abuse is reported to advance significantly the onset of psychiatric symptoms of affective disorders in humans. Consistent with the human condition, alcohol-nave male and female adolescent mice are hyper-reactive to stressors and voluntarily binge drink greater amounts of alcohol, than their adult counterparts. Also consistent with the human condition, adolescent-onset binge drinkers are insensitive to the hang-over-related anxiogenic state produced by early alcohol withdrawal, but their stressor reactivity incubates during protracted withdrawal. Thus, it is hypothesized that developmental differences exist in alcohol-induced perturbations within the extended amygdala neural circuitry underpinning emotionality, which impact the manifestation of negative affect during alcohol withdrawal. The present proposal seeks to answer a number of research questions pertaining to the impact of excessive voluntary binge alcohol intake on affective behavior as a function of the interactions between age of binge drinking onset X duration of alcohol abstinence using a novel, but well-validated, murine model. As age of drinking onset X sex interactions are reported for affective and alcohol use disorder comorbidity, Aim 1 will carefully control early life experiences and alcohol exposure to characterize the ontogeny of binge drinking-induced negative affect in both male and female subjects. These studies will chart how the manifestation of withdrawal-induced changes in affect vary as a function drug abstinence, potentially vary with reproductive cycle and relate to subsequent binge drinking.
Aim 2 will employ immunoblotting procedures to identify subject factor interactions in the biochemical correlates of alcohol withdrawal-induced hyper-anxiety and binge drinking.
Aim 3 will then employ behavioral neuropharmacological approaches to determine the functional relevance of alcohol withdrawal- induced changes in glutamate neurotransmission within the central nucleus of the amygdala for subject factor interactions in anxiety and depression measures. The results of these studies will provide novel insight into the neurobiological impact of adolescent binge drinking upon excitatory neurotransmission within a neural circuit critical for emotionality and motivated behavior and will determine the relevance of such changes for affective and alcohol use disorder comorbidity. Such information will not only further our understanding of the molecular mechanisms regulating individual differences in excessive alcohol intake, but provide greater insight into the etiology of alcoholism-affective disorder comorbidity to direct more effective treatment.
Over the past 10 years, there has been a marked rise in adolescent binge alcohol drinking in both males and females reported within the United States and alcohol abuse during early life is associated with a faster onset of psychiatric symptoms in individuals co-morbid for an alcohol use and affective disorder. Adolescence/early adulthood is a critical period of brain development during which glutamate neurons establish their connectivity within forebrain structures subserving emotionality and motivated behavior. Current reports suggest that adolescent binge drinking can impact indices of forebrain maturation in humans, particularly in females. Thus, it is imperative that we understand how adolescent binge alcohol drinking interacts with sex to impact forebrain excitatory neurotransmission and the relevance of these changes for the development of affective disorders, which exhibit an unusually high rate of comorbidity with alcoholism. To this end, this project will employ a novel, but well-validated, murine model of binge alcohol drinking to disentangle the role for the subject factors of sex, age of binge drinking onset, and duration of alcohol abstinence, in the emotional disturbances and problem drinking characteristic of alcohol use disorders and co-morbidity between alcohol use and affective disorders.
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