Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

摘要 酒精使用障碍(AUD)是一种慢性复发性障碍，29%的美国人一生中都会受到这种疾病的困扰。 致残2，并增加死亡率3。需要新的药物靶点和对AUD的神经生物学洞察。 强迫性饮酒可能涉及到对饮酒的背侧(与腹侧)纹状体控制的转变，以及 支持适应性行为选择的间接途径MSN(IMSN)的相对活性低下 过度活跃的直接途径MSN(DMSN)，驱动饮酒行为。强迫性饮酒还涉及到 酒精相关纹状体控制从腹内侧(伏隔核)移至背侧(尾壳核) 行为。在新的初步数据的指导下，这个多学科项目检验了总体假设 间接介质刺神经元中背侧纹状体磷酸二酯酶10A(PDE10A)2型活性降低 (MSN)减少强迫性饮酒。在4个具体目标中，我们寻求填补分子、电路、药理学、 在我们对PDE10A亚型激活的作用的理解中的行为和人类遗传差距 明显的纹状体MSN通路和强迫性饮酒。目标1寻求确定可翻译的PDE10A 减少强迫性酒精自我给药的抑制剂，考虑到酶的脱落率， 亲脂性效率和对不同MSN回路的神经激活作用。目标2将与Adora2a-Cre相交 将经过验证的PDE10A shRNA表达到击倒背侧IMSN PDE10A的大鼠，以便 确定尾壳核PDE10A在iMSN中的作用 行政管理。目的3试图确定纹状体受限的、膜相关的 强迫性酒精摄入中的PDE10A2亚型。最后，Aim 4寻找PDE10A基因变种 与有问题的酒精使用以及他们的功能、表达和精神遗传有关 相互关联。我们集结的多学科协作团队的集体工作将揭示 PDE10A亚型在不同纹状体环路和强迫性饮酒中的神经生物学和遗传学作用 治疗AUD的新型可翻译PDE10A抑制剂的行为和潜在影响。

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.