This proposal explores 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, circuits 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 sensitivity, the guiding hypothesis 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 others showing 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, histological and biochemical/molecular studies include assessment of the androgen and/or estrogen sensitivity of basal and glutamate stimulated 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. These foci align our studies with contemporary views of the mesoprefrontal dopamine system and with current etiological theories for schizophrenia and ADHD-two of several dopamine related disorders where prefrontal functions are at risk and where androgen influence is suspected in a disproportionate occurrence in males. While relevant to broad issues including the functional and physiological differences that separate major forebrain dopamine systems and the innate capacity for adult cortical plasticity, the focus of this proposal on the hormone sensitivity of decidedly functional measures of the prefrontal dopamine system should enable strides to be made toward mapping biology onto behavior in the context of a complex cognitive system;these studies should also provide insights into the roles that the deficiencies in the hormonal milieu that are seen in clinical conditions ranging from schizophrenia to hypogonadalism to androgen deprivation treatment of prostrate cancer may play in producing the deficits in highest order information processing that are also seen in these disorders.
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