The objective of this research project is to characterize the neurochemical mechanisms involved in the therapeutic effects of 5-?-reductase (5AR) inhibitors in Tourette syndrome (TS). We have shown that the potent 5AR inhibitor finasteride (FIN) reduces tic severity in several male adult TS patients. Moreover, FIN counters the disruption of the prepulse inhibition (PPI) of the startle and the stereotyped behavior induced by the dopamine (DA) receptor agonist apomorphine, two well-validated animal models of TS. Unfortunately, FIN cannot be used in children. Thus, the elucidation of the role of 5AR in TS is critical to develop alternative therapies. Over the previous funding period, we discovered that, in rat models of TS, FIN’s effects are mediated by the nucleus accumbens (nAC) and medial prefrontal cortex (mPFC). These effects appear to be unparalleled by alterations of DA release, suggesting a post-synaptic mechanism of action of FIN. We hypothesize that FIN exerts its therapeutic actions by decreasing 5AR products and increasing 5AR substrates. With this funding we will determine what 5AR substrates and products are responsible for the antipsychotic-like effects of FIN. To this end, we will test the antipsychotic-like effects of FIN in PPI, in combination with systemic and local treatments aimed at reducing the levels of 5AR endogenous steroid precursors or restoring the content of their 5-alpha reduced metabolites. The identification of the specific role of 5AR substrates and metabolites in the behavioral effects of FIN will provide critical information to understand FIN’s mechanism of action in TS. Furthermore, these findings will help elucidate the role of steroids in the pathophysiology of TS, and may help in the development of novel therapeutic strategies with higher specificity and limited side effects. Marco Bortolato, M.D., Ph.D., Paola Devoto, Ph.D. University of Cagliari, Monserrato, Italy Award: $72,990 (2nd Year) Commentary: We have shown that finasteride, a medication that blocks the function of male hormones, can lead to a reduction in tic severity and compulsive symptoms in adult males with TS. Unfortunately this medication cannot be used to treat children with TS because it interferes with sexual development. Our long-term goal is to understand how this medication works in the brain so that we can develop novel, effective pharmacological strategies to treat children and adolescents with TS. We anticipate that this work will identify critical targets in the brain that may lead to the development of novel therapies for Tourette syndrome. Tourette Association of America Inc. – Research Grant Award 2010-2011