Noradrenergic Regulation in the BNST

Abstract/Summary: Relapse is a barrier in addiction treatment, and stress is a precipitating stimulus. α2-adrenergic receptor (AR) agonists can block stress-induced reinstatement of drug-seeking in animal models, particularly through their actions in a region of the brain known as the bed nucleus of the stria terminalis (BNST). However, in the previous funding period we found unexpected pro-reinstatement actions of these receptors which may limit the clinical effectiveness of α2-AR agonists. Moreover, the finding that pro-reinstatement α2a-ARs exist provides a potential way to determine neuronal circuits controlling reinstatement. We also found that α2a-ARs in the BNST induce an unexpected form of neuronal excitation despite coupling to “inhibitory” Gi heterotrimeric G-proteins, and that this excitation may participate in inducing reinstatement of drug-associated behaviors. Thus, we hypothesize that a BNST neuronal ensemble is excited by the α2-AR agonist guanfacine to drive reinstatement of drug-associated behavior. We propose experiments in this application to 1) determine the functional circuitry of BNST cells activated through this process, 2) test the hypothesis that this excitation occurs by decreased cyclic AMP signaling to alter the function of hyperpolarization-activated cyclic nucleotide gated channels in these cells, and 3) directly test the hypothesis that these cells drive reinstatement of drug-associated behaviors. The successful completion of these studies will facilitate rational choices regarding therapeutics likely to reduce stress-induced drug seeking behavior.