Addiction Propensity After Prenatal Ethanol Exposure

描述（由申请人提供）：来自胎儿酒精谱系障碍（FASD）临床研究的证据表明，产前乙醇暴露可能导致成瘾倾向增加。动物研究的结果也表明，产前乙醇暴露导致与成瘾倾向增加和药物线索学习增强相关的行为表型。我们发现产前乙醇暴露导致位于腹侧被盖区（VTA）的多巴胺（DA）神经元中谷氨酸突触传递持续增加，这种效应被认为是成瘾的关键细胞机制。具体而言，我们观察到，产前乙醇暴露导致AMPA受体介导的电流整流，这表明高电导GluR 2亚基缺乏AMPA受体的表达增加。我们还观察到内源性大麻素（eCB）介导的长期抑郁症（LTD）的阻滞。LTD在突触强度的减弱中起关键作用。在产前乙醇暴露的动物中观察到的LTD的阻断和GluR 2缺乏的AMPA受体的增加都可能导致腹侧被盖区DA神经元中谷氨酸突触传递的持续增加，这反过来又导致成瘾倾向的增加。 在拟议的研究中，我们将使用多学科的方法，以进一步表征产前乙醇暴露对腹侧被盖区DA神经元谷氨酸突触传递增加的影响。具体来说，我们将寻求确认是否产前乙醇暴露导致GluR 2缺乏AMPA受体的表达增加。我们还将研究导致产前乙醇暴露诱导的eCB依赖性LTD阻滞的详细机制。最后，我们将研究VTA DA神经元中上述两种细胞机制引起的谷氨酸突触传递增加是否确实导致产前乙醇暴露动物成瘾倾向增加。拟议研究产生的结果将在以下领域产生重要影响。首先，他们将导致更好地了解在细胞/分子机制介导的产前乙醇成瘾倾向的增加。研究结果将为FASD行为问题的治疗策略提供重要的参考。其次，结果还将有助于阐明中边缘/中皮质DA系统内复杂的eCB信号机制。虽然已经提出了eCB信号在DA系统功能和成瘾中的关键作用，但详细的细胞机制尚未被表征。拟议研究的结果可能会填补这一空白。第三，研究结果可能会产生超越FASD的广泛影响。导致成瘾倾向增加的其他条件（例如精神兴奋剂或压力暴露）也会改变DA系统功能，从而提高了共同的大脑机制介导药物滥用倾向增加的可能性。拟议研究的结果可能为介导成瘾倾向增加和预防成瘾的大脑机制提供见解。 公共卫生相关性：产前乙醇暴露会导致许多不良影响，其中包括增加成瘾的风险。在拟议的研究中，我们将调查大脑多巴胺神经元的特定细胞变化是否是产前乙醇暴露后成瘾风险增加的原因。研究结果将有助于更好地理解介导成瘾行为的大脑机制，并有助于制定预防和治疗胎儿酒精谱系障碍和其他高度脆弱个体成瘾的策略。

DESCRIPTION (provided by applicant): Evidence from clinical studies of fetal alcohol spectrum disorders (FASD) has shown that prenatal ethanol exposure could lead to increased propensity of addiction. Results from animal studies also show prenatal ethanol exposure leads to behavioral phenotypes associated with increased addiction propensity and enhanced learning of drug cues. We have found prenatal ethanol exposure results in a persistent increase in glutamate synaptic transmission in dopamine (DA) neurons located in the ventral tegmental area (VTA), an effect thought to be a critical cellular mechanism for addiction. Specifically, we observe that prenatal ethanol exposure leads to a rectification of AMPA receptor-mediated current, suggesting an increased expression of high conductance GluR2 subunit-lacking AMPA receptors. We also observe a blockade of endocannabinoid (eCB)-mediated long-term depression (LTD). LTD plays a critical role in the weakening of synaptic strength. Both the blockade of LTD and increase in GluR2-lacking AMPA receptors observed in prenatal ethanol exposed animals are likely to contribute to a persistent increase in glutamate synaptic transmission in VTA DA neurons, which in turn leads to increased addiction propensity. In the proposed studies, we will use a multidisciplinary approach to further characterize the effects of prenatal ethanol exposure on increased glutamate synaptic transmission in VTA DA neurons. Specifically, we will seek to confirm whether prenatal ethanol exposure leads to an increased expression of GluR2-lacking AMPA receptors. We will also investigate the detailed mechanism leading to prenatal ethanol exposure- induced blockade of eCB-dependent LTD. Lastly, we will investigate if increased glutamate synaptic transmission caused by above two cellular mechanisms in VTA DA neurons indeed leads to increased addiction propensity in prenatal ethanol exposed animals. The results generated from the proposed studies will have important implications in the following areas. First, they will lead to a better understanding in the cellular/molecular mechanisms mediating prenatal ethanol exposure-induced increase in addiction propensity. The results, will provide important insights to better therapeutic strategies for behavioral problems of FASD. Second, the results will also help clarify the complex eCB signaling mechanisms within the mesolimbic/mesocortical DA systems. Although a critical role of eCB signaling in DA system function and addiction has been proposed, the detailed cellular mechanisms are not - characterized. The results from the proposed studies are likely to fill this gap. Third, the results may have broad impact beyond FASD. Other conditions leading to increased addiction propensity (e.g. psychostimulant or stress exposure) also alter DA system function, raising the possibility that a common brain mechanism mediates increased substance abuse propensity. The results from the proposed studies may provide insights to brain mechanisms mediating increased addiction propensity and the prevention of addiction in general. PUBLIC HEALTH RELEVANCE: Prenatal ethanol exposure leads to many adverse effects later in life which include increased risk of addiction. In the proposed studies, we will investigate if specific cellular changes in brain dopamine neurons are responsible for increased risk of addiction after prenatal ethanol exposure. The results will lead to better understanding in brain mechanisms mediating addictive behaviors and contribute to the development of preventive and treatment strategies for addiction in individuals with fetal alcohol spectrum disorders and other highly vulnerable individuals.