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，导致社会后果。由于反复接触滥用药物而引起神经元适应，药物依赖性逐渐​​发展。了解药物存在下神经元回路中发生的适应的时间成分至关重要，这反过来又将中枢神经系统改变为依赖状态。雌激素、孕激素和儿茶酚胺系统之间的功能相互作用可能在可卡因的强化作用和行为改变（包括运动和刻板行为）中发挥关键作用。确定类固醇激素在可卡因诱导的中枢神经系统行为和分子水平改变中的作用对于了解药物滥用的性别差异至关重要。 提出以下具体目标： (1) 利用 SCORE 资金使自己成为神经科学领域独立且富有成效的科学家。在本提案的资助期结束时，我希望申请并获得独立奖项。这一目标将通过学习新的相关技术来实现，例如 HPLC 分析（通过与 Hunter SCORE 行为神经科学小组的高级成员 Luine 和 Harding 博士合作）。通过将当前的研究扩展到神经化学研究，我们的实验室将更具竞争力，神经化学研究是可卡因和类固醇的领域，它们对可卡因的行为反应有不同的影响。将评估单独可卡因和与激素联合使用对行为致敏的影响 (3) 检验可卡因和类固醇之间存在相互作用的假设，这种相互作用对伏隔核和中缝核中的基础细胞外多巴胺、血清素和去甲肾上腺素浓度产生不同影响，这可能是对可卡因致敏和行为反应的性别差异的基础。细胞外单胺浓度将通过定量微透析测量并与运动和定型活性相关。 (4) 检验可卡因和类固醇之间存在相互作用并影响中皮质边缘和黑质纹状体通路中的 mRNA 水平以及多巴胺和血清素受体和转运蛋白数量的假设。受体和转运位点将通过定量放射自显影来测量。 mRNA 水平将通过 RT-PCR 和原位杂交进行测量，并将与运动活性和刻板行为相关联。确定哪些可卡因诱导的中枢神经系统在行为、神经化学和分子水平上的改变受到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（例如刻板印象和运动活动）和神经递质水平与分子终点（多巴胺和血清素转运蛋白或受体 mRNA 水平）的相关性应该有助于了解中枢神经系统对可卡因的改变的功能意义。