Budygin Evgeny A, Bass Caroline E, Grinevich Valentina P, Deal Alex L, Bonin Keith D, Weiner Jeff L
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
iScience. 2020 Mar 27;23(3):100877. doi: 10.1016/j.isci.2020.100877. Epub 2020 Jan 31.
Despite many years of work on dopaminergic mechanisms of alcohol addiction, much of the evidence remains mostly correlative in nature. Fortunately, recent technological advances have provided the opportunity to explore the causal role of alterations in neurotransmission within circuits involved in addictive behaviors. Here, we address this critical gap in our knowledge by integrating an optogenetic approach and an operant alcohol self-administration paradigm to assess directly how accumbal dopamine (DA) release dynamics influences the appetitive (seeking) component of alcohol-drinking behavior. We show that appetitive reward-seeking behavior in rats trained to self-administer alcohol can be shaped causally by ventral tegmental area-nucleus accumbens (VTA-NAc) DA neurotransmission. Our findings reveal that phasic patterns of DA release within this circuit enhance a discrete measure of alcohol seeking, whereas tonic patterns of stimulation inhibit this behavior. Moreover, we provide mechanistic evidence that tonic-phasic interplay within the VTA-NAc DA circuit underlies these seemingly paradoxical effects.
尽管在酒精成瘾的多巴胺能机制方面已经进行了多年研究，但许多证据在本质上大多仍只是相关性的。幸运的是，最近的技术进步为探索参与成瘾行为的神经回路中神经传递改变的因果作用提供了机会。在这里，我们通过整合光遗传学方法和操作性酒精自我给药范式，直接评估伏隔核多巴胺（DA）释放动态如何影响饮酒行为的欲望（寻求）成分，从而填补我们在这一知识领域的关键空白。我们表明，经过训练自我给药酒精的大鼠的欲望性奖赏寻求行为可由腹侧被盖区 - 伏隔核（VTA - NAc）多巴胺神经传递因果性地塑造。我们的研究结果表明，该回路内多巴胺释放的相位模式增强了对酒精寻求的离散测量，而持续性刺激模式则抑制这种行为。此外，我们提供了机制证据，表明VTA - NAc多巴胺回路内的持续性 - 相位相互作用是这些看似矛盾的效应的基础。
