Epidemiological evidence suggests that there is an inverse correlation between the age of first exposure to a drug of abuse and the likelihood of developing dependence, suggesting that periadolescence is a time of high vulnerability to drugs of abuse compared with adulthood. One key difference between periadolescents and adults is in their respective responses to stressors. Periadolescence is associated with a period of increased risk-taking, which is accompanied by hyporesponsiveness to many stressors compared to adults. In contrast, periadolescent animals have higher basal levels of circulating corticosterones, and under certain contexts appear more anxious than adults. Stress and anxiety play critical roles in drug abuse, thus an understanding of the basic mechanisms underlying these age-specific differences in anxiety-related behaviors will lead to more specific and age-appropriate therapeutic interventions both for drug abuse and anxiety disorders in general. The ventral noradrenergic bundle (VNAB) emanating from the nucleus of the solitary tract plays a key role in stress/anxiety responses. Lesions of the VNAB or manipulations of noradrenergic transmission within the major target of this projection, the bed nucleus of the stria terminalis (BNST), abolish stress-induced reinstatement of cocaine intake and conditioned place aversion to morphine withdrawal. The BNST is an assembly of sub-nuclei within the extended amygdala with rich interconnections between stress and reward centers. Stimulation of the anterolateral regions of the BNST evokes firing of dopaminergic neurons of the VTA, as well as increases PVN output, increasing peripheral corticosterone levels. Thus altering the level of output of the BNST would be predicted to have a dramatic impact on behavioral responses to drugs of abuse. We have identified two adrenergic receptors that play opposing roles in regulating inputs to the BNST. Here we will test the hypothesis that this regulation is altered in the periadolescent compared to the adult BNST. We will also determine whether psychostimulants, which indirectly target these receptors through altering endogenous catecholamine levels, produce similar effects on transmission. Finally, we will assess the impact of alterations in the relative levels of the receptors on both regulation of transmission and basal anxiety levels by screening recombinant inbred strains of mice (BxDs) with varying levels of receptor expression. ? ?
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