Fortin Samantha M, Roitman Mitchell F
Graduate Program in Neuroscience, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.
Graduate Program in Neuroscience, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA; Department of Psychology, University of Illinois at Chicago, 1007 W Harrison St, Chicago, IL 60607, USA.
Physiol Behav. 2017 Jul 1;176:17-25. doi: 10.1016/j.physbeh.2017.03.019. Epub 2017 Mar 16.
Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.
滥用药物会增加终末区域短暂（1 - 3秒）、高浓度（时相性）多巴胺释放事件的频率和幅度。这些被认为是药物强化以及最终成瘾发展的关键部分。最近，包括饱腹感信号胰高血糖素样肽 - 1（GLP - 1）在内的代谢调节肽已被证明可调节可卡因给药后奖励驱动行为和持续多巴胺水平。在此，我们使用快速扫描循环伏安法（FSCV）来探究可卡因给药期间伏隔核（NAc）中GLP - 1受体（GLP - 1R）对动态多巴胺释放的调节作用。我们分析了NAc壳部和核心区域的多巴胺释放事件，因为这两个亚区域受可卡因的影响不同，且对动机行为有独特贡献。我们发现，向中枢递送GLP - 1R激动剂艾塞那肽 - 4可抑制静脉注射可卡因诱导的时相性多巴胺释放事件。这种效应在NAc核心区域的多巴胺信号传导方面具有选择性。艾塞那肽 - 4对核心区域时相信号的抑制作用不能归因于其干扰可卡因与其主要底物之一多巴胺转运体的结合，因为可卡因诱导的再摄取增加未受影响。结果表明，相反，GLP - 1R激活通过改变多巴胺释放发挥其抑制作用——可能是通过抑制多巴胺神经元的兴奋性。鉴于NAc核心区域多巴胺在基于联想学习的条件反应产生中的作用，GLP - 1R激动作用对该亚区域可卡因诱导的多巴胺信号传导的抑制可能会降低可卡因的强化特性。因此，GLP - 1R仍然是治疗和预防可卡因寻求、使用及复发的可行靶点。
