Recent evidence from a variety of sources indicates that components of the 'extended amygdala' are importantly involved in opiate withdrawal (OW). This application seeks to extend our previous work on the noradrenergic locus coeruleus (LC) and OW by characterizing the role in OW of norepinephrine (NE) inputs to a key component of the extended amygdala, the bed nucleus of the stria terminalis (BNST). The BNST is the focus of this application because (I) it receives a very dense NE innervation, (ii) it is a key element of the extended amygdala that has been overlooked in studies of OW, and (iii) our recent data reveal that neurons in the BNST, and its NE afferents, are strongly responsive to OW. A set of coordinate anatomical and electrophysiological experiments are proposed that will characterize basic neurobiological attributes of NE in the BNST. Anatomical experiments will characterize the NE innervation of the medial and lateral subdivisions of the BNST, specifying innervation patterns and fiber morphologies. Using tract-tracing combined with immunohistochemistry, the sources of NE input to the different BNST subdivisions will also be identified. Electrophysiological studies will then confirm and characterize the inputs identified anatomically. The influence of the different NE afferents on BNST impulse activity will be determined, and the adrenoceptors involved in mediating responses will be identified. These studies will be some of the first to systematically investigate basic attributes of this dense noradrenergic projection to the extended amygdala. The role of this NE target area in OW will also be examined from the cellular to the behavioral level. We will determine the electrophysiological response of BNST neurons to OW; preliminary evidence for this application indicates that these cells will be strongly activated. The role of NE inputs from the different source cell groups in this OW response will be determined, and the adrenoceptor involved will be identified. Finally, in behavioral experiments the contribution of the NE-BNST synapse to somatic and aversive responses to OW will be determined. In particular, we will explore the role of the NE input to the BNST in conditioned withdrawal responses, a critical element in continued drug abuse and relapse. Together, the above experiments represent a comprehensive analysis of cellular substrates, and physiological and behavioral consequences, of the dense NE input to the BNST. These studies will provide much needed basic and withdrawal-related information on an important but neglected NE target in the extended amygdala.
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