Noradrenergic Regulation in the BNST

摘要/总结： 复吸是成瘾治疗的障碍，而压力是一种突发性刺激。α2-肾上腺素能受体（AR） 在动物模型中，激动剂可以阻断应激诱导的药物寻求恢复，特别是通过其 大脑中一个被称为终纹床核（BNST）的区域的活动。但在 在上一个资助期，我们发现这些受体的意外促恢复作用可能会限制 α2-AR激动剂的临床有效性。此外，存在促恢复α 2a-AR的发现提供了一个新的证据。 确定控制恢复的神经元回路的潜在方法。我们还发现BNST中的α 2a-AR 尽管与“抑制性”Gi异源三聚体G蛋白偶联， 并且这种兴奋可能参与诱导药物相关行为的恢复。因此我们 假设BNST神经元系综被α2-AR激动剂胍法辛激发以驱动恢复 与毒品有关的行为我们在此应用中提出实验以1）确定功能电路 的BNST细胞激活通过这一过程，2）测试的假设，这种兴奋发生减少 环AMP信号转导改变超极化激活的环核苷酸门控通道的功能， 这些细胞，和3）直接测试这些细胞驱动药物相关的恢复的假设， 行为。这些研究的成功完成将促进有关治疗的合理选择 可能会减少压力引起的药物寻求行为。

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.