STEROID AND COCAINE INTERACTIONS WITH CATECHOLAMINE SYSTEMS

成瘾是一种复杂的疾病，它结合了心理和生理适应，导致社会后果。药物依赖是由反复接触滥用药物引起的神经元适应逐渐发展而来的。理解在药物作用下发生在神经元回路上的适应的时间成分是至关重要的，而药物反过来又使中枢神经系统改变为依赖状态。雌激素、黄体酮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）中起关键作用。在行为和分子水平上鉴定类固醇激素在可卡因诱导的中枢神经系统改变中的作用对于理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基金使自己成为神经科学领域的独立和富有成效的科学家。在本次提案的资助期结束后，我希望能够申请并获得一个独立的奖项。这一目标将通过学习新的和相关的技术来实现，例如高效液相色谱分析（通过与高级成员，博士合作）。亨特大学行为神经科学小组的Luine和Harding说。通过将目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，这是一个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。(3)为了验证可卡因和类固醇之间的相互作用对伏隔核和中隔核细胞外多巴胺、血清素和去甲肾上腺素浓度的不同影响，这可能是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，并与运动和刻板印象活动相关。(4)验证可卡因和类固醇相互作用对中脑皮质边缘和黑质纹状体通路中多巴胺和血清素受体及转运体mRNA水平和数量的影响。受体和转运体位点将通过定量放射自显影术测量。mRNA水平将通过RT-PCR和原位杂交来测量，并将与运动活动和刻板行为相关。卵巢激素在行为、神经化学和分子水平上影响可卡因诱导的中枢神经系统改变，这对于理解影响性别差异的机制至关重要。此外，行为终点（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体或受体mRNA水平）的相关性应该为中枢神经系统对可卡因改变的功能意义提供一些见解。

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.