Addiction Propensity After Prenatal Ethanol Exposure

产前乙醇暴露后的成瘾倾向

• 批准号: 8577118
• 负责人: ROH-YU SHEN
• 金额: $ 34.59万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-05 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577118
• 关键词: AMPA Receptors; Addictive Behavior; Adult; Amphetamines; Animals; Area; Behavioral; Brain; CNR1 gene; Clinical; Clinical Research; Complex; Cues; Data; Development; Dose; Down-Regulation; Drug Addiction; Electron Microscopy; Endocannabinoids; Ethanol; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Glutamates; Goals; In Vitro; Individual; Late Effects; Lead; Learning; Life; Long-Term Depression; Mediating; Molecular; Pharmaceutical Preparations; Phenotype; Play; Prevention; Prevention strategy; Problem behavior; Rattus; Risk; Role; Self Administration; Signal Transduction; Stress; Substance abuse problem; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic; Time; Ventral Tegmental Area; addiction; alcohol exposure; design; dopamine system; dopaminergic neuron; insight; interdisciplinary approach; male; neurotransmission; patch clamp; preference; prenatal; presynaptic; psychostimulant; public health relevance; receptor; receptor expression; response; transmission process; treatment strategy

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.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）的临床研究证据表明，产前接触乙醇可能导致成瘾倾向增加。动物研究的结果还表明，产前接触乙醇会导致与成瘾倾向增加和对药物线索的学习增强相关的行为表型。我们发现产前乙醇暴露会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会导致 AMPA 受体介导的电流纠正，表明缺乏 AMPA 受体的高电导 GluR2 亚基的表达增加。我们还观察到内源性大麻素（eCB）介导的长期抑郁症（LTD）的阻断。 LTD 在突触强度的减弱中起着至关重要的作用。在产前乙醇暴露的动物中观察到的 LTD 阻断和缺乏 GluR2 的 AMPA 受体的增加可能会导致 VTA DA 神经元中谷氨酸突触传递的持续增加，从而导致成瘾倾向增加。 在拟议的研究中，我们将采用多学科方法来进一步表征产前乙醇暴露对 VTA DA 神经元谷氨酸突触传递增加的影响。具体来说，我们将寻求确认产前乙醇暴露是否会导致缺乏 GluR2 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 阻断的详细机制。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的成瘾倾向增加。拟议研究的结果将在以下领域产生重要影响。首先，它们将有助于更好地理解介导产前乙醇暴露引起的成瘾倾向增加的细胞/分子机制。研究结果将为 FASD 行为问题的更好治疗策略提供重要见解。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 信号传导机制。尽管已经提出了 eCB 信号传导在 DA 系统功能和成瘾中的关键作用，但详细的细胞机制尚未得到表征。拟议研究的结果可能会填补这一空白。第三，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，从而增加了一种常见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会为介导成瘾倾向增加和总体预防成瘾的大脑机制提供见解。