Gonadal Hormone Effects on Amine Systems of Rat Cortex

EXCEED THE SPACE PROVIDED. This proposal expores novel hypotheses about the nature, mechanisms and consequences of gonadal hormone influence on extracellular dopamine levels in the prefrontal cortices of adult male rats. Both basal and stimulated extracellular dopamine levels are pivotal and in many ways unique to dopamine's modulation of the cells, curicuts and complex cognitive, mnemonic and motivational functions of the prefrontal cortices. Driven by the importance of these measures for prefrontal cortical dopamine neurotransmission and by our own preliminary data suggesting their hormone senstivity, the hypothesis guiding this proposal is that circulating gonadal hormones influence the function and perhaps the dysfunction of the prefrontal cortex in diseases including schizophrenia and ADHD by affecting amine levels within these cortical fields. Founded in previous studies in this lab and in others show ing remarkably selective effects of androgens in particular on an array of biological and behavioral endpoints associated with the mesoprefrontal dopamine system, the proposed quantitative in vivo, hostological, biochemical and behavioral studies will include assessment the androgen vs. estrogen sensitivity of glutamatergic regulation of prefrontal dopamine release, of the clearance of dopamine from the extracellular space via the dopamine and norepinephrine transporters, and of dopamine catabolism via catechol-O-methyltransferase. The focus on these and other endpoints aligns these studies with contemporary functional views of the mesoprefrontal dopamne system and with current etiological theories and/or candidate genes in schizophrenia and ADHD-two dopamine related disorders where prefrontal cortical functions are at risk, and where androgen influence is suspected in their disproportionate occurrence in males. While relevant to broad issues including the functional and phsyiological differences that separate major forebrain projecting dopamine systems, e.g.,mesolimbic, mesostriatal, and adult cortical plasticity, the focus of this propsoal on the hormone sensitivity of decidedly functional measures of the prefrontal dopamine system and the use of in vivo and behavioral methods of assessment to explore them should enable strides to be made toward mapping biology onto behavior in the context of a complex cognitive system. PERFORMANCE SITE ========================================Section End===========================================