Many patients with Tourette Syndrome (TS) have obsessive-compulsive symptoms. Recent clinical studies have demonstrated that the obsessive-compulsive symptoms of patients with TS improve following treatment with fluoxetine (Prozac), a drug which affects the actions of the neurotransmitter serotonin in the brain. The subthalamic nucleus (STh) plays a critical role in controlling hyperactive movements via the basal ganglia, an area of the brain which functions abnormally in TS. Clinical information indicates that there may be changes in the actions of serotonin and the STh in brains of patients with TS. Injecting serotonin directly into the STh produces compulsive oral behavior in awake rats – but little is known about how this occurs or why drugs like Prozac are helpful in treating the compulsive symptoms of TS. Determining the chemical mechanisms involved in producing the abnormal movements in rats is especially important because this type of information aids in the design of more effective medications with fewer side-effects. The purpose of these studies is to learn more about how serotonin acts on cells in the STh to produce abnormal oral-facial movements in rats. Anatomical studies will demonstrate which cells in the STh and related areas express messenger RNA for a specific serotonin receptor (5-HT2c). Behavioral studies will reveal what type of experimental drugs block the abnormal oral movements produced by the STh. Also, rats will be injected chronically with Prozac (to mimic the clinically-effective treatment regimen) to determine whether sustained treatment with Prozac reduces serotonin-stimulated compulsive behaviors in rats. These studies provide an important foundation for the development of improved drug treatment strategies for TS. Serotonergic drugs are effective in the treatment of obsessive compulsive behaviors in TS and have a relatively low incidence of neuroleptic-associated side effects such as tardive dyskinesia. Thus, medications that act on serotonergic systems have an important therapeutic advantage over the dopaminergic drugs (i.e. haloperidol) traditionally used to treat TS. The abnormal oral-facial movements produced by serotonin within the STh 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., Department of Pharmacology University of Pennsylvania, Philadelphia, PA Award $20,000 Tourette Association of America Inc. – Research Grant Award 1994