伏隔核GABA能MSNs在丙泊酚精神依赖性中的作用及其与VTA、VP间环路的调控机制

As the most widely used intravenous anaesthetics, propofol has potential of psychological dependence. Propofol abuse has severe outcome with high mortality. But the underlying mechanism of propofol dependence is still clouded. In our previous studies, we found dopamine D1 receptor and the extracellular signal-regulated kinase (ERK) singnaling pathway in nucleus accumbens (NAc) involve in propofol reward effect; GABAA and GABAB receptors in ventral tegmental area (VTA) mediate propofol self-administration. Accumulated evidence indicate that GABAergic medium spiny neurons (MSNs) in NAc mediate drug psychic dependence, and the underlying regulating mechanism of NAc and its downstream brain region, VTA and ventral pallidum (VP). Therefore, we hypothesis that GABAergic MSNs in NAc play certain role in propofol reward effect, which is regulated by NAc and its projection to downstream brain region (VTA, VP) circuit. To explore the hypotheses, optogenetics technique and behavioral tests will be applied. And we will utilize micro-dialysis and ultra performance liquid chromatography (UPLC) to verify the effect of GABA on propofol reward. Accomplishment of this project will shed light upon the mechanisms of propofol addiction, necessary supplement of drug addiction and provide novel supporting data.

丙泊酚是最常用的静脉麻醉药，有明显精神依赖性。滥用时易致死，危害严重，但具体成瘾机制尚未完全清楚。申请人前期发现伏隔核(NAc)D1受体及其介导的ERK信号转导通路参与了丙泊酚的奖赏作用；腹侧被盖区(VTA)GABAA/B受体有调节丙泊酚奖赏的作用。文献提示NAc-VTA/腹侧苍白球(VP)的GABA能投射对药物奖赏有调控作用。因此，我们推测伏隔核GABA能中间多棘型神经元(MSNs)介导了丙泊酚的奖赏作用，并且NAc-VTA/VP环路对丙泊酚奖赏具有调控作用。本项目采用丙泊酚自身给药模型，结合光遗传学方法验证伏隔核GABA能MSNs在丙泊酚依赖中的作用；探索NAc-VTA/VP的GABA能投射对丙泊酚依赖的调控机制。使用微透析、超高效液相等手段明确GABA在丙泊酚奖赏效应中的作用。该课题的完成有助于查明丙泊酚的成瘾机制，是药物成瘾的必要补充，为药物成瘾治疗和预防提供理论依据。

丙泊酚是一种常用的静脉麻醉药，具有明显的精神依赖性。丙泊酚已成为一种新型毒品，滥用日益严重，危害不容忽视。申请人前期发现伏隔核(NAc)D1受体及其介导的ERK信号转导通路参与了丙泊酚的奖赏作用；腹侧被盖区(VTA)GABA受体有调节丙泊酚奖赏的作用。文献提示NAc-VTA/腹侧苍白球(VP)的GABA能投射对药物奖赏有调控作用。因此，我们推测伏隔核GABA能中间多棘型神经元(MSNs)介导了丙泊酚的奖赏作用，并且NAc-VTA/VP环路对丙泊酚奖赏具有调控作用。.本项目采用大鼠丙泊酚自身给药模型，利用电生理技术，化学遗传学，光遗传学结合药理学实验来验证假设。首选我们对SD大鼠NAc进行定位，显微注射病毒并用免疫组化技术进行验证。验证了光遗传实验和化学遗传实验对大鼠的活动能力和丙泊酚自身给药行为不产生影响。发现了丙泊酚依赖大鼠NAc内的神经元兴奋性明显增高；光刺激兴奋NAc内GABA能神经元，丙泊酚依赖大鼠的觅药行为明显加强；而且化学遗传抑制NAc内GABA能神经元则抑制大鼠的觅药行为。光刺激兴奋NAc-VTA和NAc-VP环路的GABA能投射，增强了丙泊酚依赖大鼠的觅药行为。另外，我们还发现VTA注射GABAA受体拮抗剂荷包牡丹碱明显抑制光刺激兴奋NAc-VTA环路GABA能投射引起的觅药行为。.该课题的完成有助于查明丙泊酚的成瘾机制，是药物成瘾的必要补充，为药物成瘾治疗和预防提供理论依据。