Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making
Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making
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DOI：
10.1523/jneurosci.4394-15.2016
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发表时间：
2016-03-30
影响因子：
5.3
通讯作者：
Clark, Jeremy J.
中科院分区：
文献类型：
--
作者：
Schindler, Abigail G.;Soden, Marta E.;Clark, Jeremy J.
酒精是青少年中最常滥用的物质，它会促使青少年患上药物使用障碍，并损害成年后的决策能力。我们以前已经证明，在啮齿动物的临床前模型，青少年饮酒导致成人冒险行为，积极相关的阶段性多巴胺传输响应风险的选择，但其潜在的机制仍然未知。在这里，我们表明，青少年饮酒可能会产生适应不良的决策，通过破坏多巴胺网络动力学通过增加GABA能传递腹侧被盖区（VTA）。事实上，我们发现青少年饮酒后增加的阶段性多巴胺信号传导归因于中脑回路，包括从脚桥被盖到腹侧被盖的输入。此外，我们证明，成年大鼠的腹侧被盖区多巴胺神经元表现出增强的IPSC青少年酒精暴露后，相应的基础多巴胺水平下降，在成年期，负相关的冒险。基于这些发现，我们开发了一个模型，其中多巴胺神经元上的抑制性张力增加导致紧张性多巴胺水平的持续降低，并导致刺激诱发的阶段性多巴胺释放的增强，这可能会驱动风险选择行为。基于这一模型，我们采取药理学方法，通过正常化多巴胺传递的这种模式来逆转冒险行为。这些结果分离了酒精诱导的适应不良决策的潜在电路，并确定了一种新的治疗靶点。
Alcohol is the most commonly abused substance among adolescents, promoting the development of substance use disorders and compromised decision-making in adulthood. We have previously demonstrated, with a preclinical model in rodents, that adolescent alcohol use results in adult risk-taking behavior that positively correlates with phasic dopamine transmission in response to risky options, but the underlying mechanisms remain unknown. Here, we show that adolescent alcohol use may produce maladaptive decision-making through a disruption in dopamine network dynamics via increased GABAergic transmission within the ventral tegmental area (VTA). Indeed, we find that increased phasic dopamine signaling after adolescent alcohol use is attributable to a midbrain circuit, including the input from the pedunculopontine tegmentum to the VTA. Moreover, we demonstrate that VTA dopamine neurons from adult rats exhibit enhanced IPSCs after adolescent alcohol exposure corresponding to decreased basal dopamine levels in adulthood that negatively correlate with risk-taking. Building on these findings, we develop a model where increased inhibitory tone on dopamine neurons leads to a persistent decrease in tonic dopamine levels and results in a potentiation of stimulus-evoked phasic dopamine release that may drive risky choice behavior. Based on this model, we take a pharmacological approach to the reversal of risk-taking behavior through normalization of this pattern in dopamine transmission. These results isolate the underlying circuitry involved in alcohol-induced maladaptive decision-making and identify a novel therapeutic target.