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，产前乙醇暴露会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）神经元的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。具体来说，我们观察到产前乙醇暴露导致AMPA受体介导的电流纠正，这表明高电导GluR2亚基缺失的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（LTD）的阻断。LTD在突触强度减弱中起关键作用。在产前乙醇暴露的动物中观察到的LTD的阻断和glur2缺失的AMPA受体的增加可能有助于VTA DA神经元中谷氨酸突触传递的持续增加，从而导致成瘾倾向的增加。在拟议的研究中，我们将采用多学科方法进一步表征产前乙醇暴露对VTA DA神经元中谷氨酸突触传递增加的影响。具体来说，我们将试图确认产前乙醇暴露是否会导致glur2缺失的AMPA受体表达增加。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，我们将研究上述两种细胞机制在VTA - DA神经元中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的成瘾倾向增加。建议研究的结果将对以下领域产生重要影响：首先，他们将导致更好地理解细胞/分子机制介导产前乙醇暴露诱导的成瘾倾向的增加。该结果将为FASD行为问题的更好治疗策略提供重要见解。其次，研究结果还将有助于阐明中边缘/中皮层DA系统中复杂的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FASD以外的广泛影响。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，从而提高了一种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大脑机制调解增加的成瘾倾向和一般的成瘾预防提供见解。

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.