Alcoholism is a chronic relapsing disorder characterized by compulsive use of ethanol and loss of control over intake. The previous funding period identified critical neurotransmitters involved in the acute positive reinforcing effects of ethanol and the negative reinforcing effects of ethanol dependence. Animal models of ethanol self-administration in dependent rats and protracted abstinence have been established, and ethanol self-administration has been characterized in female rats during the estrous cycle. Motivationally significant recruitment of brain corticotropin-releasing factor (CRF) activity during the development of dependence has been shown to persist into protracted abstinence. Data suggest a role for neuropeptide Y (NPY) in stress modulation opposite to that of CRF. Norepinephrine (NE) systems have been implicated in stress, ethanol drinking and ethanol dependence and recently have been linked to interactions in the basal forebrain with CRF. A conceptual framework has been elaborated providing a heuristic basis for identifying specific changes within the neurocircuitry of the extended amygdala responsible for excessive alcohol intake associated with dependence. This proposal tests the hypothesis that increased CRF activity, decreased NPY activity, and increased NE activity in the extended amygdala are responsible for the enhanced drinking associated with early withdrawal and protracted abstinence.
Specific Aim 1 will explore the role of CRF in the extended amygdala on ethanol self-administration in rats during early withdrawal and protracted abstinence using acute administration of CRF antagonists.
Specific Aim 2 will explore the role of NPY in the extended amygdala in ethanol self-administration in rats during early withdrawal and protracted abstinence using acute administration of NPY agonists.
Specific Aim 3 will explore the role of NE in the extended amygdala on ethanol self-administration in rats during early withdrawal and protracted abstinence using acute administration of NE functional antagonists.
Specific Aim 4 will explore the role of CRF, NPY, and NE in selected regions of the extended amygdala on ethanol self-administration in female rats during early withdrawal and protracted abstinence using CRF antagonists, NPY agonists, and functional NE antagonists. The proposed studies will provide critical data to understand the neurobiologic changes in reward and stress systems in the extended amygdala associated with ethanol dependence and provide a framework for future diagnostic and medications development for alcoholism treatment ? ?
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