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Dissecting the Role of GABA Neurons in the VTA versus SNr in Opioid Reward
Journal of Neuroscience ( IF 5.3 ) Pub Date : 2020-11-11 , DOI: 10.1523/jneurosci.0988-20.2020
Ewa Galaj , Xiao Han , Hui Shen , Chloe J. Jordan , Yi He , Bree Humburg , Guo-Hua Bi , Zheng-Xiong Xi

Opioid reward has traditionally been thought to be mediated by GABA-induced disinhibition of dopamine (DA) neurons in the VTA. However, direct behavioral evidence supporting this hypothesis is still lacking. In this study, we found that the μ opioid receptor (MOR) gene, Oprm1, is highly expressed in GABA neurons, with ~50% of GABA neurons in the substantia nigra pars reticulata (SNr), ~30% in the VTA, and ~70% in the tail of the VTA (also called the rostromedial tegmental nucleus) in male rats. No Oprm1 mRNA was detected in midbrain DA neurons. We then found that optogenetic inhibition of VTA DA neurons reduced intravenous heroin self-administration, whereas activation of these neurons produced robust optical intracranial self-stimulation in DAT-Cre mice, supporting an important role of DA neurons in opioid reward. Unexpectedly, pharmacological blockade of MORs in the SNr was more effective than in the VTA in reducing heroin reward. Optogenetic activation of VTA GABA neurons caused place aversion and inhibited cocaine, but not heroin, self-administration, whereas optogenetic activation of SNr GABA neurons caused a robust increase in heroin self-administration with an extinction pattern, suggesting a compensatory response in drug intake due to reduced heroin reward. In addition, activation of SNr GABA neurons attenuated heroin-primed, but not cue-induced, reinstatement of drug-seeking behavior, whereas inhibition of SNr GABA neurons produced optical intracranial self-stimulation and place preference. Together, these findings suggest that MORs on GABA neurons in the SNr play more important roles in opioid reward and relapse than MORs on VTA GABA neurons.

SIGNIFICANCE STATEMENT Opioid reward has long been believed to be mediated by inhibition of GABA interneurons in the VTA that subsequently leads to disinhibition of DA neurons. In this study, we found that more μ opioid receptors (MORs) are expressed in GABA neurons in the neighboring SNr than in the VTA, and that pharmacological blockade of MORs in the SNr is more effective in reducing heroin reward than blockade of MORs in the VTA. Furthermore, optogenetic activation of VTA GABA neurons inhibited cocaine, but not heroin, self-administration, whereas activation of SNr GABA neurons inhibited heroin reward and relapse. These findings suggest that opioid reward is more likely mediated by stimulation of MORs in GABA afferents from other brain regions than in VTA GABA neurons.



中文翻译:

剖析GABA神经元在VTA中与SNr在阿片类药物奖励中的作用

传统上认为阿片样物质的奖励是由GABA诱导的VTA中多巴胺(DA)神经元的去抑制作用介导的。但是,仍然缺乏支持该假设的直接行为证据。在这项研究中,我们发现μ阿片受体(MOR)基因Oprm1在GABA神经元中高表达,其中约50%的GABA神经元在黑质网(SNr)中,约30%在VTA中,并且雄性大鼠的VTA尾巴中也有约70%(也称为罗氏弓被盖核)。无操作1在中脑DA神经元中检测到mRNA。然后,我们发现对VTA DA神经元的光遗传学抑制作用减少了静脉注射海洛因的自我给药,而这些神经元的激活在DAT-Cre小鼠中产生了强大的光学颅内自我刺激,支持了DA神经元在阿片样物质奖励中的重要作用。出乎意料的是,在SNr中对MOR的药理阻断作用比在VTA中对降低海洛因奖赏的作用更有效。VTA GABA神经元的光遗传激活会引起地方厌恶并抑制可卡因,但不是海洛因的自我给药,而SNr GABA神经元的光遗传激活会导致海洛因自我给药的强烈增加且具有灭绝模式,这表明由于摄入毒品而产生的补偿性反应减少海洛因报酬。此外,SNr GABA神经元的激活会减弱海洛因引发的,而不是提示诱导的药物寻找行为的恢复,而SNr GABA神经元的抑制则产生了颅内光学刺激和位置偏好。总之,这些发现表明,与VTA GABA神经元上的MORs相比,SNr中GABA神经元上的MORs在阿片样物质的奖励和复发中起着更重要的作用。

意义声明长期以来,人们一直认为阿片样物质奖励是通过抑制VTA中的GABA中间神经元介导的,随后会导致DA神经元的去抑制。在这项研究中,我们发现邻近SNr的GABA神经元中表达的μ阿片受体(MOR)比VTA中的要多,并且在SNr中对MORs的药理阻断作用比在snr中的MORs阻断更有效VTA。此外,VTA GABA神经元的光遗传学激活抑制了可卡因,但海洛因的自我给药却没有,而SNr GABA神经元的激活抑制了海洛因的奖励和复发。这些发现表明,与其他VTA GABA神经元相比,来自其他大脑区域的GABA传入的阿片样物质奖励更有可能是通过刺激MORs介导的。

更新日期:2020-11-12
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