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Age differences in the manifestation & neurobiology of negative affect during alcohol withdrawal in a mouse model of binge drinking

  • Author(s): Lee, Kaziya Mai
  • Advisor(s): Szumlinski, Karen K
  • et al.
Abstract

The research presented in this dissertation characterizes the manifestation and neurobiological underpinnings of negative affect during alcohol withdrawal in adult and adolescent mice using an animal model of voluntary binge drinking. A history of binge drinking elicits changes in glutamate-related protein expression within regions of the extended amygdala relevant to emotional regulation. Studying withdrawal-induced changes in protein expression may provide insight into the mechanisms mediating age-dependent differences in the negative affective consequences of alcohol abuse. The results of this work demonstrate that, similar to the human population, adult and adolescent mice differ both in their pattern of alcohol consumption and also in the consequences of that consumption. Although adolescent animals typically consume larger quantities of alcohol, adolescents are less sensitive than adults to negative affect during early withdrawal. However, adolescents binge drinkers show an emergence of negative affect later in adulthood, as well as elevated alcohol consumption. Moreover, these studies identify specific changes in protein expression within two brain regions critically involved in both emotion and addiction neurobiology- the central nucleus of the amygdala (CEA) and the nucleus accumbens shell (AcbSh). Withdrawal from binge drinking is associated with increased neuronal activity within the AcbSh, concomitant with increased glutamate-related protein expression in adult animals. Conversely, decreased expression of protein indices of Homer2-dependent mGluR signaling was observed within the CEA of both adult and adolescent animals. Reversing these changes using neuropharmacological or virus-mediated transgene delivery approaches reduced behavioral signs of withdrawal-induced anxiety. Together, these studies identify neurobiological substrates and pathophysiology of relevance to the negative reinforcing properties of alcohol and characterize ontogenetic differences in the behavioral and neurobiological consequences of alcohol abuse.

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