Many people with Tourette Syndrome (TS) also have obsessive-compulsive symptoms (OCS). Recent clinical studies have demonstrated that the OCS improve following treatment with fluoxetine (Prozac), a drug which affects the actions of the neurotransmitter serotonin (5-HT) in the brain. Interestingly, injecting 5-HT into the striatum, an area of the brain which functions abnormally in TS, produces compulsive oral behaviors in awake rats. At present, little is known about the actions of 5-HT in the striatum, or why drugs like fluoxetine are helpful in the treatment of the compulsive symptoms of TS. The overall purpose of these studies is to determine the role of serotonin in the striatum to control compulsive oral behaviors in rats. Anatomical studies will tell us how 5-HTsensitive cells in the striatum are connected to other functionally-relevant areas of the basal ganglia. Molecular studies will further reveal how these striatal cells produce messenger RNA which code for a specific type of 5-HT receptor. Behavioral studies using rats will reveal specific drugs which are effective in stimulating or blocking the 5-HT receptors potentially involved in controlling the compulsive oral behaviors. Finally, rats will be chronically injected with fluoxetine to mimic the clinically-effective treatment regimen. These behavioral studies will, therefore, determine whether chronic injection of fluoxetine reduces 5-HTstimulated compulsive behaviors in rats. Taken together, these studies provide an important foundation for the development of improved drug treatment strategies for TS. Serotonergic drugs are effective in the treatment of TS and have relatively low incidence of neuroleptic-associated side effects such as tardive dyskinesia. Thus, drugs which act on serotonergic systems have an important therapeutic advantage over the dopaminergic drugs (i.e. haloperidol) traditionally used to treat TS. The oral stereotypies produced in rats by injecting 5-HT directly into the striatum may provide a useful animal model to predict new drug treatment strategies potentially useful in the treatment of TS and other related basal ganglia-mediated disorders. Kim Eberle-Wang, Ph. D. University of Pennsylvania School of Medicine, Philadelphia, PA Award $20,000 Tourette Association of America Inc. – Research Grant Award 1993