Sex Differences in Alcohol Habit Formation in Rats: Corticostriatal Mechanisms

大鼠饮酒习惯形成的性别差异：皮质纹状体机制

• 批准号: 7528657
• 负责人: Jane R Taylor
• 金额: $ 7.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528657
• 关键词: Abstinence; Address; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Animals; Applications Grants; Behavior; Behavior Control; Behavioral; Behavioral Model; Binding; Clinical; Condition; Consumption; Corpus striatum structure; Coupled; Cues; Data; Dependence; Development; Dopamine; Dopamine Receptor; Dorsal; Early Intervention; Economic Inflation; Equilibrium; Female; Food; Foundations; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Goals; Gonadal Hormones; Habits; Health; Hormonal; Incentives; Infusion procedures; Investigation; Laboratories; Literature; Measures; Medial; Mediating; Mus; Nature; Neurobiology; Outcome; Pattern; Performance; Pharmaceutical Preparations; Prefrontal Cortex; Procedures; Process; Public Health; Rate; Rattus; Recovery; Research; Response to stimulus physiology; Rewards; Rodent; Role; Series; Sex Characteristics; Sex Chromosomes; Signal Transduction; Staging; Stimulus; Sucrose; Taste Perception; Training; Ventral Striatum; Woman; Work; alcohol behavior; alcohol cue; alcohol seeking behavior; base; deprivation; drinking; drug of abuse; experience; genetic analysis; improved; innovation; male; men; model design; neurobiological mechanism; neurotransmission; problem drinker; psychostimulant; reinforcer; research study; response; therapeutic target; transmission process

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.

描述（由申请人提供）：这项研究的目的是使用旨在调查习惯性响应的动物模型来了解酒精中毒性别差异的神经生物学基础，并与寻求强迫性酗酒和采取行为模式相关。我们提出的研究将研究涉及习惯性（即刺激反应）与目标指导（即响应结果）行为的皮质纹状体回路之间的相互作用。这些研究将重点介绍多巴胺神经传递中皮质纹状体改变的作用，这些作用可能有助于在行为的目标定向和习惯模式之间取得复杂的平衡。先前的研究表明，女性通过具有里程碑意义的阶段从初始用途到以比男性更快的依赖性进行，并且提议的一系列实验将研究我们在女啮齿动物中观察到的习惯形成速度是否更快地扩展到对酒精的习惯性反应。天然增强剂习惯形成遗传性别差异的这种发现表明，皮质纹状体回路的固有差异可能是酒精习惯形成的差异。此外，我们已经表明，对腹侧前额叶皮层的多巴胺输注可以恢复受过训练的大鼠的目标导向反应，以表达一种仪器，食物增强的习惯。这些研究共同构成了我们假设的基础，即女性大鼠将朝着寻求酒精的习惯模式迈进，并且比男性大鼠更快地采取速度，并且习惯性饮酒的发展将取决于背侧，背侧，纹状体，纹状体，曲折的多巴胺传播的增加，而不是在腹膜上的多巴胺传播，而不是腹膜上的疾病。目的，我将确定当酒精充当增强剂时，大鼠的习惯形成率是否存在性别差异。随后的实验将解决这种潜在的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将使用并行程序检查内侧前额叶皮层或背侧纹状体中的多巴胺传播是否有助于酒精习惯的性能。随后的实验将解决哪些多巴胺受体有助于区域特定的行为影响。我们认为，这种重点提供了一种创新的方法，因为以前没有研究检查药物增强剂的习惯形成性别差异或皮质纹状体多巴胺神经传递在面向目标和刺激的酒精反应组成部分中的作用。这些数据将为对酒精习惯反应的性别差异的遗传和荷尔蒙贡献进行完整分析，为酒精和与酒精相关的提示所作的性别差异提供基础。此外，获得的数据将提供前额叶皮质和背纹状体多巴胺参与习惯反应的首次直接比较。公共卫生相关性酒精中毒的特征是发展出习惯性饮酒方式，这些习惯性饮酒模式无论社会或健康后果如何。先前的工作表明，饮酒习惯的发展速度要比天然增强剂快，并且女性可能具有更快地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发展酒精习惯，并确定皮质纹状体神经环节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靶标，以通过抑制强习惯控制行为的能力来帮助酗酒者维持戒酒，并确定早期的女性酒精中毒干预措施是否可以改善康复。