Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

摘要 酒精使用障碍（AUD）是一种慢性、复发性疾病，29%的美国人在一生中受到折磨1，2， 正在使人丧失能力并增加死亡率。需要新的药物靶点和对AUD的神经生物学见解。 强迫性饮酒性惊厥涉及到背侧（与腹侧）纹状体控制饮酒的过渡， 间接途径MSN（iMSN）的相对活性不足，使适应性行为选择与 过度活跃的直接途径MSN（dMSN）驱动饮酒行为。强迫性饮酒还包括 乙醇相关的纹状体控制从腹内侧核（延髓核）转移到背侧核（尾壳核） 行为在新的初步数据的指导下，这个多学科项目测试了总体假设， 降低间接中型棘神经元中背侧纹状体磷酸二酯酶10A（PDE 10A）2型活性 (MSN)减少强迫性饮酒。在4个具体目标，我们寻求填补分子，电路，药理学， 行为和人类遗传的差距，我们的理解的作用，PDE 10A亚型的激活， 明显的纹状体MSN通路和强迫性饮酒目标1旨在确定可翻译的PDE 10A 考虑到酶解离速率， 亲脂效率和对不同MSN回路的神经激活作用。目标2将与Adora 2a-Cre相交 表达floxed、验证的PDE 10A shRNA以敲低背侧iMSN PDE 10A的大鼠， 确定尾壳核PDE 10A在iMSN中的作用，在升级和厌恶抵抗的自我- 局目的3旨在确定纹状体限制性，膜相关性 PDE 10A 2亚型在强迫性乙醇摄入中的作用最后，Aim 4寻找PDE 10A基因变体， 与有问题的酒精使用以及他们的功能，表达和精神遗传 相互关联我们集合的多学科协作团队的集体工作将阐明 PDE 10A亚型在不同纹状体回路和强迫性饮酒中的神经生物学和遗传学作用 行为以及新型可翻译PDE 10A抑制剂治疗AUD的潜在影响。

ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disorder that afflicts 29% of Americans in their lifetime1,2, is disabling2 and increases mortality3. New drug targets and neurobiological insight for AUD are needed. Compulsive drinking putatively involves a transition to dorsal (vs. ventral) striatal control over drinking and a relative underactivity of indirect pathway MSNs (iMSNs) that enable adaptive behavioral selection in contrast to overactive direct pathway MSNs (dMSNs) that drive drinking behaviors. Compulsive drinking also involves a shift to dorsal (caudate-putamen) from ventromedial (nucleus accumbens) striatal control of ethanol-related behavior. Guided by novel preliminary data, this multidisciplinary project tests the overarching hypothesis that decreasing dorsal striatal phosphodiesterase 10A (PDE10A) type 2 activity in indirect medium spiny neurons (MSN) reduces compulsive drinking. In 4 Specific Aims, we seek to fill molecular, circuitry, pharmacological, behavioral and human genetic gaps in our understanding of the role of PDE10A isoforms in activation of distinct striatal MSN pathways and compulsive drinking. Aim 1 seeks to identify translatable PDE10A inhibitors that reduce compulsive-like ethanol self-administration, with consideration of enzyme off-rate, lipophilic efficiency and neuroactivational effects on distinct MSN circuits. Aim 2 will intersect Adora2a-Cre rats with expression of a floxed, validiated PDE10A shRNA to knockdown dorsal iMSN PDE10A in order to determine this the role of caudate-putamen PDE10A in iMSNs in escalated and aversion-resistant self- administration. Aim 3 seeks to determine the causal role of the striatal-restricted, membrane-associated PDE10A2 isoform in compulsive-like ethanol intake. Finally, Aim 4 seeks PDE10A gene variants that associate with problematic alcohol use as well as their functional, expression, and psychiatric genetic correlates. The collective work of our assembled, multidisciplinary collaborative team will shed light on the neurobiological and genetic role of PDE10A isoforms in distinct striatal circuits and compulsive drinking behaviors as well as the potential impact of novel translatable PDE10A inhibitors to treat AUD.