Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse.

IF 3.5 3区 医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-11-01 Epub Date: 2024-06-10 DOI:10.1007/s00213-024-06631-8
Mackenzie M Spicer, Matthew A Weber, Zili Luo, Jianqi Yang, Nandakumar S Narayanan, Rory A Fisher
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Abstract

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). The neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6fl/fl; DAT-iCreER mice to determine the role of RGS6 in DA neurons on EtOH consumption, reward, and relapse behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse ventral tegmental area (VTA), and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6-/- mice. Strikingly, RGS6 loss from DA neurons before or after EtOH behavioral reward is established significantly reduced (~ 50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies identify DA neurons as the locus of RGS6 action in promoting EtOH consumption, preference, reward, and relapse. RGS6 is unique among R7 RGS proteins in promoting rather than suppressing behavioral responses to drugs of abuse and to modulate EtOH behavioral reward. This is a result of RGS6's pre-synaptic actions that we hypothesize promote VTA DA transmission by suppressing GPCR-Gαi/o-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.

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多巴胺神经元中的G蛋白信号调节器6(RGS6)可促进乙醇寻求、行为奖赏和易复发。
据信,中叶多巴胺(DA)传导在介导对包括酒精(EtOH)在内的滥用药物的奖赏反应中起着至关重要的作用。目前还不完全清楚乙醇寻求行为和依赖性的神经生物学机制,戒酒仍然是预防酒精使用障碍(AUDs)的唯一有效方法。在此,我们开发了新型 RGS6fl/fl; DAT-iCreER 小鼠,以确定 RGS6 在 DA 神经元中对 EtOH 消费、奖赏和复吸行为的作用。我们发现,RGS6在人和小鼠腹侧被盖区(VTA)的DA神经元中都有表达,而且小鼠缺失RGS6会上调VTA DA神经元突触末端的DA转运体(DAT)表达。值得注意的是,DA神经元中的RGS6缺失会显著降低EtOH的消耗量、偏好和奖赏,其方式与RGS6-/-小鼠的情况无异。令人震惊的是,在 EtOH 行为奖赏建立之前或之后,DA 神经元中 RGS6 的缺失会显著降低(约 50%)熄灭后奖赏的恢复,这表明 RGS6 在促进奖赏和 EtOH 复发易感性方面发挥着不同的作用。这些研究确定了 DA 神经元是 RGS6 促进 EtOH 消费、偏好、奖赏和复发的作用点。在 R7 RGS 蛋白中,RGS6 在促进而不是抑制对滥用药物的行为反应和调节对 EtOH 的行为奖赏方面是独一无二的。这是 RGS6 突触前作用的结果,我们假设它通过抑制 VTA DA 神经元中的 GPCR-Gαi/o-DAT 信号传导来促进 VTA DA 的传导。这些研究将 RGS6 确定为乙醇行为奖赏和复吸的潜在治疗靶点。
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来源期刊
Psychopharmacology
Psychopharmacology 医学-精神病学
CiteScore
7.10
自引率
5.90%
发文量
257
审稿时长
2-4 weeks
期刊介绍: Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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