STEROID AND COCAINE INTERACTIONS WITH CATECHOLAMINE SYSTEMS

类固醇和可卡因与儿茶酚胺系统的相互作用

• 批准号: 6450698
• 负责人: VANYA QUINONES-JENAB
• 金额: $ 5.95万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450698
• 关键词: autoradiography; behavioral /social science research tag; behavioral habituation /sensitization; catecholamines; chordate locomotion; cocaine; drug addiction; drug habituation; drug interactions; estrogens; gender difference; high performance liquid chromatography; hormone regulation /control mechanism; in situ hybridization; laboratory rat; mesencephalon; microdialysis; neurochemistry; neurotoxicology; neurotransmitter receptor; neurotransmitter transport; nucleus accumbens; polymerase chain reaction; progesterone

Addiction is a complex disease which combines psychological and physiological adaptations that result in social consequences. Drug dependence gradually develops by neuronal adaptations caused by repeated exposure to the abused drug. It is critical to understand the temporal components of adaptations that occur at the neuronal circuits in the presence of a drug which, in turn, alter the CNS to a dependent state. Functional interactions between estrogen, progesterone, and the catecholamine systems may play critical roles in cocaine's reinforcing actions and behavioral alterations including locomotor and stereotypic behaviors. The identification of the roles of steroid hormones in cocaine- induced CNS alterations are behavioral and molecular levels is essential for understanding sex differences in drug abuse. The following Specific Aims are propose: (1) To utilize SCORE funding to establish myself as an independent and productive scientist in the field of neuroscience. By the termination of the funding period of this proposal, I expect to apply and obtain an independent award. This aim will be accomplished by learning new and relevant techniques, such as HPLC analysis (through the collaboration with senior members, Drs. Luine and Harding, of the Behavioral Neuroscience Group of SCORE at Hunter). Our laboratory will be more competitive by expanding the current research to neurochemical studies, an area of cocaine and steroids which differentially affect behavioral responses to cocaine. Effects of cocaine alone and in combination with hormones will be assessed on behavioral sensitization (3) To test the hypothesis that there are interactions between cocaine and steroids which differentially affects basal extracellular dopamine, serotonin, and norepinephrine concentration in the nucleus accumbens and raphe nucleus which may be the basis for sex differences in sensitization and behavioral responses to cocaine. Extracellular monoamine concentrations will be measured by quantitative microdialysis and correlated with locomoter and stereotypic activity. (4) To test the hypothesis that there are interactions between cocaine and steroids with affects the levels of mRNA and number of dopamine and serotonin receptors and transporter in the mesocorticolimbic and nigrostriatal pathways. Receptor and transporter sites will be measured by quantitative autoradiography. mRNA levels will be measured by RT-PCR and in situ hybridization and will be correlated with locomoter activity and stereotypic behaviors. The identification of which of the cocaine- induced CNS alterations at the behavioral, neurochemical and molecular levels are affected by ovarian hormones is essential for understanding the mechanism affecting sex differences. Furthermore, the correlation of behavioral endpoints (such as stereotype and locomotive activity) and neurotransmitter levels in conjunction with molecular endpoints (dopamine and serotonin transporters or receptors mRNA levels) should provide some insight into the functional significance of alterations in the CNS to cocaine.

成瘾是一种复杂的疾病，结合了心理和生理适应，从而导致社会后果。药物依赖性通过反复接触滥用药物引起的神经元适应逐渐发展。在存在药物的情况下，了解在神经元电路处发生的适应性的时间成分至关重要，这反过来又将CNS改变为依赖性状态。雌激素，孕酮和儿茶酚胺系统之间的功能相互作用可能在可卡因的加强作用和行为改变（包括运动和刻板印象行为）中起关键作用。类固醇激素在可卡因诱导的中枢神经系统改变中的作用是行为和分子水平对于理解药物滥用性别差异至关重要。 提出了以下具体目标：（1）利用得分资金来确立自己是神经科学领域的独立和生产性科学家。通过终止本提案的资金期限，我希望申请并获得独立裁决。这个目标将通过学习新的和相关的技术，例如HPLC分析（通过与Hunter行为神经科学分数的高级成员Luine和Harding博士的合作）。我们的实验室将通过将当前的研究扩展到神经化学研究，这是可卡因和类固醇区域，从而差异地影响对可卡因的行为反应。可卡因单独和与激素结合的影响将在行为敏化（3）上进行评估，以检验以下假说，即可卡因和类固醇之间存在相互作用，这些假说会差异地影响基础细胞外多巴胺，5-羟色胺，血清素和去甲肾上腺素的浓度，在核和raphe核中的作用可能是差异的，这可能是对cace的反应和cace的反应。细胞外单胺浓度将通过定量微透析测量，并与运动和刻板印象活性相关。 （4）测试可卡因与类固醇之间存在相互作用的假设，会影响中皮质糖和尼格拉斯术途径中多巴胺和5-羟色胺受体的数量，多巴胺和5-羟色胺受体的数量以及转运蛋白。受体和转运蛋白部位将通过定量放射自显影测量。 mRNA水平将通过RT-PCR和原位杂交测量，并将与运动活性和刻板印象相关。在行为，神经化学和分子水平上可卡因诱导的中枢神经系统改变的鉴定受卵巢激素的影响对于理解影响性别差异的机制至关重要。此外，行为终点（例如刻板印象和机车活性）和神经递质水平与分子终点（多巴胺和5-羟色胺转运蛋白或受体mRNA水平）的相关性应提供一些洞察力的见解。