DOPAMINE SENSITIZATION BY MOTIVATED BEHAVIORS

动机行为引起的多巴胺敏化

• 批准号: 6256392
• 负责人: Robert L Meisel
• 金额: $ 21.94万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6256392
• 关键词: adenylate cyclase; amphetamines; autoradiography; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; cyclic AMP; dopamine; dopamine receptor; dopamine transporter; drug abuse; enzyme induction /repression; hamsters; limbic system; long term potentiation; microdialysis; molecular psychobiology; motivation; neuroanatomy; neurons; neurotransmitter transport; nucleus accumbens; ovariectomy; psychopharmacology; receptor expression; sex behavior

DESCRIPTION: (Adapted from the Investigator's Abstract) Long-term changes in the cellular properties of neurons (i.e., sensitization) has been thought to be one mechanism mediating both continued drug abuse and relapse in individuals who have been abstinent from drug use. However, this leaves the question of what leads to the initiation and maintenance of drug use prior to the induction of sensitization following repeated use of drugs. Like drugs of abuse, sexual behavior will activate the mesoaccumbens dopamine pathway in female hamsters. Prior sexual experience will sensitize the dopamine response to sexual interactions and produce behavioral sensitization to the initial presentation of amphetamine (i.e., cross-sensitization) in otherwise drug-naive animals. The long-term goal of this project will be to compare at the anatomical and cellular levels the degree to which motivated behaviors and drugs of abuse have common mechanisms of sensitization of dopamine pathways. There are 4 specific aims of this project. The first two aims will analyze the properties of sensitization produced by sexual experience using microdialysis measurements of extracellular dopamine concentrations and postsynaptic activation using c-Fos immunocytochemistry. The persistence of sensitization of extracellular dopamine responses in the nucleus accumbens, responsivity to a novel environment, cross-sensitization to amphetamine treatment will be studied. The third aim is to examine presynaptic mechanisms mediating the sensitized dopamine response in microdialysis studies. Potential long-term effects of sexual experience on autoreceptor function and the dopamine transporter will be explored in this aim. The fourth aim will determine whether there are enduring postsynaptic changes following sexual experience. One experiment will test whether there is a decrease in dopamine D1 receptor internalization in sexually-experienced females. A second experiment will assess responsivity of cAMP accumulation to activation of D1 receptors as a function of prior sexual experience. A final aim will examine possible long-term changes in dopamine D1 and D2 receptors following sexual experience. Together, these experiments will pave the way for future studies comparing neural changes produced by behaviors relevant to the natural history of animals with those induced by repeated exposure to drugs of abuse.

描述：（改编自研究者的摘要）长期变化 神经元的细胞特性（即敏化）被认为是 一种介导个体持续药物滥用和复发的机制 已戒毒的人。然而，这留下了一个问题 诱导前开始和维持药物使用的原因是什么 重复使用药物后致敏。比如滥用药物、性行为 行为会激活雌性仓鼠的中伏隔多巴胺通路。 先前的性经历会使多巴胺对性的反应敏感 互动并对初始演示产生行为敏感性 安非他明（即交叉致敏）在其他未曾接受过药物治疗的动物中的作用。这 该项目的长期目标是比较解剖学和 细胞水平 动机行为和滥用药物的程度 多巴胺通路致敏的常见机制。具体有4个 该项目的目标。前两个目标将分析 使用微透析测量性经验产生的敏化 使用 c-Fos 测量细胞外多巴胺浓度和突触后激活 免疫细胞化学。细胞外多巴胺致敏的持续性 伏隔核的反应，对新环境的反应， 将研究对安非他明治疗的交叉过敏。第三个目标是 检查介导敏感多巴胺反应的突触前机制 微透析研究。性经历对性经历的潜在长期影响 本研究将探讨自身受体功能和多巴胺转运蛋白 目的。第四个目标将确定是否存在持久的突触后 性经历后的变化。一项实验将检验是否存在 有性经验的人多巴胺 D1 受体内化减少 女性。第二个实验将评估 cAMP 积累对 D1 受体的激活是先前性经历的函数。决赛 目标将检查多巴胺 D1 和 D2 受体可能的长期变化 性经历之后。总之，这些实验将为 未来的研究将比较与相关行为产生的神经变化 动物的自然史与反复接触药物引起的自然史 虐待。