Sex Differences in Alcohol Habit Formation in Rats: Corticostriatal Mechanisms

描述（由申请人提供）：本研究的目的是使用动物模型来了解酒精中毒性别差异的神经生物学基础，该动物模型旨在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参与习惯性（即，刺激反应）和目标导向（即，反应-结果）行为。这些研究将集中在皮质纹状体改变在多巴胺神经传递中的作用，这可能有助于目标导向和习惯行为模式之间的复杂平衡。以前的研究表明，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，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习惯形成的更快速度是否延伸到对酒精的习惯性反应。这种自然饮酒者习惯形成的遗传性别差异的发现表明，皮质纹状体回路的固有差异可能是酒精习惯形成差异的基础。此外，我们已经证明，多巴胺注入到腹内侧前额叶皮层可以恢复大鼠训练表达工具，食物强化，习惯的目标导向反应。这些研究共同构成了我们假设的基础，即雌性大鼠将比雄性大鼠更快地朝着酒精寻求和服用的习惯性模式发展，并且对酒精的习惯性反应的发展将取决于背外侧而不是背内侧纹状体中多巴胺传输的增加，以及腹内侧而不是背内侧前额叶皮质中多巴胺传输的减少。目的探讨以酒精为刺激剂时，大鼠习惯形成的速度是否存在性别差异。随后的实验将解决神经生物学机制（例如，性腺激素和/或性染色体基因）对这种潜在的性别差异起作用。目的二将使用平行的程序，以检查是否在内侧前额叶皮层或背侧纹状体的多巴胺传输有助于酒精习惯的表现。随后的实验将解决哪些多巴胺受体有助于区域特异性行为效应。我们认为，这一重点提供了一个创新的方法，因为没有以前的研究已经检查了药物成瘾习惯形成的性别差异或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相关成分中的作用。这些数据将为完整分析遗传和激素对酒精习惯性反应和与酒精相关的线索的性别差异的贡献提供基础。此外，获得的数据将提供第一个直接比较前额叶皮层和背侧纹状体多巴胺参与习惯性反应。公共卫生相关性酒精中毒的特征是形成习惯性饮酒模式，而不考虑社会或健康后果。先前的研究表明，饮酒习惯的养成速度比自然饮酒快，女性可能具有更快养成习惯的遗传倾向。这项研究的目的是确定女性是否比男性更快地养成酒精习惯，并确定皮质纹状体神经回路如何调节酒精习惯的形成。这项研究的结果将有助于确定治疗目标，通过抑制强烈习惯控制行为的能力来帮助酗酒者保持戒酒，并将确定对女性酗酒者的早期干预是否可以改善恢复。

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.