Stress Sensitization of CRF-Induced Withdrawal Behaviors

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In further support of Ballenger and Post (1978) that a kindling process occurs with repeated chronic ethanol exposures, work in our laboratory demonstrated that repeated withdrawals from chronic ethanol results in withdrawal-induced sensitization of anxiety-like behavior [i.e., a decrease in social interaction & deficit in the elevated plus-maze] in P-rats. Like multiple withdrawals, recent data also indicate that repeated stresses prior to a single withdrawal from chronic ethanol exposure results in sensitization of withdrawal-induced anxiety-like behavior in the P-rats. Additionally, stress during multiple withdrawals increases voluntary drinking of ethanol in P-rats. Preliminary data have implicated corticotropin releasing factor (CRF)--a major neurotransmitter peptide in brain-- and the CRF-1 receptor subtype in the sensitization of anxiety-like behavior associated with the repeated withdrawal and stresses/withdrawal protocols, as well as in the increased drinking induced by stress during repeated withdrawals. The purpose of the present series of investigations is to define the neuroanatomical and neurobiological basis of the CRF contribution to the sensitization of the withdrawal-induced anxiety-like behavior induced by repeated withdrawals and the stresses in P-rats. Based upon a CRF-1 receptor antagonist blocking sensitization of anxiety-like behavior induced by the repeated withdrawal as well as by the repeated stress/withdrawal protocols, Specific Aim 1 will test the hypothesis that a CRF-1 receptor antagonist microinjected into amygdala or other selected brain sites with CRF receptors will block the persistent consequence of repeated stress and multiple withdrawal sensitization of anxiety-like behavior. While focus will be on defining the site where a CRF- 1 receptor antagonist blocks sensitization of anxiety-like behavior by stress and repeated withdrawals, microinjection of a CRF-2 antagonist into specific sites will determine if this CRF receptor subtype can contribute to this sensitization. Specific Aim 2 will test the hypothesis that multiple stresses and withdrawals that induce increased drinking linked to the alcohol deprivation effect is dependent upon CRF at brain sites identified in Aim 1 that related to sensitization of anxiety-like behavior. Finally, Specific Aim 3 will test the hypothesis that increased CRF release, altered CRF receptor number, or an increased responsiveness to CRF is critical for the sensitization of withdrawal-induced anxiety-like behavior and the increased voluntary ethanol drinking at the brain sites identified in Specific Aims 1 & 2 in the P-rats. Thus, this proposal tests the overall hypothesis that multiple withdrawal and the stress/withdrawal protocols that sensitize anxiety-like behavior and the increased voluntary ethanol drinking are dependent upon activation of adaptive change(s) in CRF mechanisms within specific brain sites of ethanol preferring rats. Since both stress and withdrawal symptoms from chronic ethanol exposure have been implicated in sustaining alcohol abuse, this basic effort can be expected to provide data that will assist in defining the pathological adaptive processes that contribute to withdrawal symptoms and craving during abstinence and that facilitate loss of control upon relapse in the alcoholic. New treatment strategies could emerge from such knowledge