Noradrenergic Regulation in the BNST

摘要/摘要： 复发是治疗成瘾的障碍，而压力是一种急促的刺激。α2-肾上腺素能受体(AR) 激动剂可以阻止应激诱导的动物模型药物寻找的恢复，特别是通过它们的 大脑终纹床核(BNST)区域的活动。然而，在 在之前的资金支持期间，我们发现了这些受体意外的促恢复作用，这可能会限制 α-2-AR激动剂的临床疗效此外，支持恢复的α2a-ARs的发现提供了一个 潜在的方法来确定控制恢复的神经元回路。我们还发现BNST中的α2a-Ars 诱导一种意想不到的神经兴奋形式，尽管偶联到“抑制性”的胃肠道异源三聚体G蛋白， 这种兴奋可能参与诱导与药物相关的行为的恢复。因此，我们 假设BNST神经元集合被α2-AR激动剂Ganfacine兴奋以驱动恢复 与毒品有关的行为。我们建议在这一应用中进行实验以1)确定功能电路 在通过这个过程激活的BNST细胞中，2)检验这种兴奋是通过减少 环AMP信号改变超极化激活的环核苷酸门控通道的功能 这些细胞，以及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有助于治疗方法的理性选择 可能会减少因压力而导致的寻药行为。

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.