The published literature offers emerging evidence that the hypothalamic-pituitary-adrenal (HPA) axis may play a role in promoting alcohol self-administration. The overall hypothesis tested in our proposal is that modifications in the activity of the HPA axis, specifically those induced by prior exposure to alcohol, increase vulnerability to this drug because the individual may consume it in order to restore pre-alcohol HPA axis activity. Testing this hypothesis will require that we first identify the type of long-term changes in this axis, that are caused by an initial exposure to alcohol and investigate the mechanisms responsible for these responses. These experiments are described under Specific Aim 1, where we will continue our investigation of the phenomenon of neuroendocrine tolerance to alcohol, a term we use to describe the fact that when rats that received an initial alcohol treatment are re-exposed to the drug following a drug-free period, their HPA axis response is significantly blunted, compared to the response to the first challenge or that of alcoholnaive animals. We had proposed that once an initial alcohol exposure has altered the set-point of the HPA axis in non-dependent, unselected rats, the animals will consume alcohol in an attempt to regain their original neuroendocrine status. We will now determine whether neuroendocrine tolerance to alcohol is permanent or temporary; whether it can only be induced in adult animals or whether prepubertal treatment with alcohol induces changes that can be observed in adults; whether it is present in both males and females; and finally, we will examine some of the mechanisms mediating these responses. The second set of experiments we describe here, which are grouped under Specific Aim 2, derive from the observation that once alcohol is removed from animals made dependent, the changes induced in their HPA axis by the drug persist beyond the time of acute withdrawal. This led to the hypothesis that at least some animals may resume drug consumption in order to either """"""""medicate"""""""" the dysregulation of their HPA axis, or return to the pre-withdrawal state. In order to test this hypothesis, we will investigate the role of the HPA axis in promoting alcohol consumption in models of dependence as well as in rats selected for high alcohol consumption. These experiments will indicate whether there is a relationship between vulnerability to relapse and the magnitude of the HPA axis response axis to a stressor, and whether corticotropin-releasing factor plays a role in this phenomenon.
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