STEROID AND COCAINE INTERACTIONS WITH CATECHOLAMINE SYSTEMS

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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.