This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a new project/grant examining the action of androgens on behavior and gene expression in the serotonin neural system. The serotonin system mediates impulsive behavior and aggression. It has been reasoned that androgens act on the serotonin system to reduce serotonin and thereby increase impulsivity. However, knowledge of the steroid receptor profile in serotonin neurons of male human and nonhuman primates is lacking and little is known of the actions of androgens on gene expression in serotonin neurons. We hypothesize that serotonin neurons in male primates express estrogen receptor beta (ERb) and androgen receptors (AR) and that the balance of activity at these receptors governs serotonin synthesis and neural function, which in turn, controls aggression. We will establish groups of male macaques and manipulate the activity of ERb and AR with enzyme inhibitors. Behavior and global serotonin will be assessed.We will determine whether ERb, AR, and pivotal metabolic enzymes are localized in serotonin neurons and whether they are regulated by testosterone metabolites. In addition, the regulation of serotonin-related genes TPH2, SERT, 5HT1A, MAO-A and MAO-B will be determined with in situ hybridization. Male Japanese macaques have been castrated and are currently in treatment with placebo, testosterone (T), T+ Letrozole (aromatase inhibitor) and T+Avodart (5a reductase inhibitor)(n=5/group). Serum levels of estrogen, testosterone and dihydrotestosterone are being monitored to verify the efficacy of treatment. Fenfluramine challenges to determine the global availability of serotonin are scheduled in two weeks.
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