Sex Differences in Alcohol Habit Formation in Rats: Corticostriatal Mechanisms

描述（由申请人提供）：本研究的目的是了解酒精中毒性别差异的神经生物学基础，使用动物模型来研究与强迫性酒精寻求和行为模式相关的习惯性反应的发展。我们提出的研究将调查涉及习惯（即刺激-反应）和目标导向（即反应-结果）行为的皮质纹状体回路之间的相互作用。这些研究将集中在多巴胺神经传递中皮质纹状体改变的作用，这可能有助于目标导向和习惯行为模式之间的复杂平衡。先前的研究表明，女性从最初使用到依赖的里程碑阶段的进展速度比男性更快，而拟议的一系列实验将调查我们在雌性啮齿动物中观察到的更快的习惯形成速度是否延伸到对酒精的习惯性反应。这些关于自然强化物习惯形成的遗传性别差异的发现表明，皮质纹状体回路的内在差异可能是酒精习惯形成差异的基础。此外，我们已经证明，多巴胺注入腹内侧前额叶皮层可以恢复老鼠的目标导向反应，训练它们表达一种工具性的、食物强化的习惯。这些研究共同构成了我们假设的基础，即雌性大鼠会比雄性大鼠更快地向酒精寻求和饮酒的习惯性模式发展，并且对酒精的习惯性反应的发展将取决于背外侧纹状体（而不是背内侧纹状体）多巴胺传递的增加，以及腹内侧前额叶皮层（而不是背内侧纹状体）多巴胺传递的减少。目的：我将确定当酒精作为强化物时，老鼠的习惯形成率是否存在性别差异。后续的实验将探讨这种潜在性别差异的神经生物学机制（例如性腺激素和/或性染色体基因）。Aim II将使用平行程序来检查多巴胺在内侧前额叶皮层或背纹状体中的传递是否有助于饮酒习惯的表现。后续的实验将解决哪些多巴胺受体有助于区域特定的行为效应。我们认为，这一研究重点提供了一种创新的方法，因为之前没有研究调查过药物强化剂习惯形成的性别差异，也没有研究过皮质纹状体多巴胺神经传递在酒精反应的目标导向和刺激结合成分中的作用。这些数据将为全面分析基因和激素对酒精习惯性反应的性别差异以及与酒精相关的线索的贡献提供基础。此外，获得的数据将首次直接比较前额皮质和背纹状体多巴胺参与习惯性反应。酗酒的特点是不顾社会或健康后果而形成习惯性饮酒模式。先前的研究表明，饮酒习惯的形成速度比自然强化物更快，女性可能有更快形成习惯的遗传倾向。这项研究的目的是确定女性是否比男性更快地养成饮酒习惯，并确定皮质纹状体神经回路如何调节饮酒习惯的形成。这项研究的结果将有助于确定治疗目标，通过抑制强习惯控制行为的能力来帮助酗酒者保持戒断，并将确定早期干预女性酗酒者是否可以改善恢复。

DESCRIPTION (provided by applicant): The objective of this research is to understand the neurobiological basis for sex differences in alcoholism using an animal model designed to investigate the development of habitual responding with relevance for compulsive alcohol-seeking and taking behavioral patterns. Our proposed studies will investigate the interaction between corticostriatal circuits involved in habitual (i.e., stimulus-response) and goal-directed (i.e., response-outcome) behavior. These studies will focus on the role for corticostriatal alterations in dopamine neurotransmission that likely contribute to an intricate balance between goal-directed and habitual patterns of behavior. Previous studies suggest that women progress through the landmark stages from initial use to dependence at a faster rate than men, and the proposed series of experiments will investigate whether the faster rate of habit formation that we have observed in female rodents extends to habitual responding for alcohol. Such findings of genetic sex differences in habit formation for a natural reinforcer suggest inherent differences in corticostriatal circuitry that could underlie differences in habit formation for alcohol. Additionally, we have shown that dopamine infusions into the ventromedial prefrontal cortex can restore goal-directed responding in rats trained to express an instrumental, food-reinforced, habit. Together these studies form the basis for our hypothesis that female rats will progress toward habitual patterns of alcohol-seeking and taking more rapidly than male rats and that the development of habitual responding for alcohol will depend upon increased dopamine transmission in the dorsolateral, but not dorsomedial, striatum, and on decreased dopamine transmission in the ventromedial, but not dorsomedial, prefrontal cortex. Aim I will determine whether there is a sex difference in the rate of habit formation in rats when alcohol serves as the reinforcer. Subsequent experiments will address the neurobiological mechanisms (e.g., gonadal hormones and/or sex chromosome genes) for this potential sex difference. Aim II will use parallel procedures to examine whether dopamine transmission in the medial prefrontal cortex or dorsal striatum contributes to the performance of an alcohol habit. Subsequent experiments will address which dopamine receptors contribute to regionally specific behavioral effects. We believe that this focus provides an innovative approach because no previous research has examined sex differences in habit formation for a drug reinforcer or the role of corticostriatal dopamine neurotransmission in the goal-oriented and stimulus-bound components of alcohol responding. These data will provide the foundation for the complete analysis of genetic and hormonal contributions to sex differences in habitual responding for alcohol and cues associated with alcohol. Further, the data obtained will provide the first direct comparison of prefrontal cortical and dorsal striatal dopamine involvement in habitual responding. PUBLIC HEALTH RELEVANCE Alcoholism is characterized by the development of habitual drinking patterns that occur regardless of the societal or health consequences. Previous work has indicated that habits for alcohol consumption develop faster than for natural reinforcers, and that females may have a genetic predisposition to develop habits faster. The aim of this research is to determine if females develop alcohol habits more rapidly than males, and to determine how corticostriatal neurocircuitry regulates alcohol habit formation. The results of this research will help determine therapeutic targets to help alcoholics maintain abstinence by inhibiting the ability of strong habits to control behavior, and will determine if earlier interventions for female alcoholics can improve recovery.