Tourette Syndrome (TS) is a relatively common neurobiological disorder that is characterized by motor and phonic tics that can include sudden repetitive movements, gestures, or utterances. In some cases, TS is also associated with other behavioral problems, including attention deficit disorder and obsessive-compulsive traits. At present, few pharmacological treatments are available that are highly effective in the treatment of TS symptoms. However, in recent years there have been major advances in our understanding of the pathological changes that underlie TS. These advances provide a unique opportunity to develop new therapeutic strategies for treatment of this disorder. Several lines of evidence suggest that a primary factor contributing to the symptoms of TS is a pathological change in a group of brain structures that involve movement control—collectively termed the basal ganglia. According to current models, TS is associated with an imbalance in the basal ganglia motor system that ultimately leads to a large increase in the activity of a group of neurons that employ the inhibitory neurotransmitter GABA for cell to cell communication. According to a current model of TS, over-activity of these inhibitory GABA-containing neurons produces an unusually large inhibition of neurons that would normally prevent the occurrence of motor tics. Excessive release of GABA and inhibition of these neurons is believed to underlie the tics commonly observed in TS patients. Therefore, decreasing the excessive GABA release might be effective in reducing the symptoms of TS, and thus provide an alternative to current treatments that produce a variety of side effects. Release of the inhibitory amino acid neurotransmitter GABA is often controlled by a specific GABA receptor termed the GABAB subclass of GABA receptor. Drugs that activate GABAB receptors have been shown to reduce the release of GABA at various inhibitory synapses. Recently, we and others have found that GABAB agonists have this effect at the basal ganglia synapses considered important for causing tics. Furthermore, recent studies suggest that there are multiple types of GABAB receptors. This raises the exciting possibility that it may be possible to develop selective agonists of GABAB receptors that modulate GABA release at the basal ganglia synapses. Such drugs hold great promise as potential therapeutic agents for treatment of TS since they could reduce GABA release at these synapses without having widespread effects in other regions of the brain. In an attempt to define potential new drug targets for the treatment of TS, we will perform a series of studies that will elucidate the roles and pharmacological properties of GABAB receptors in the basal ganglia. This effort could pave the way for future studies in which these compounds are evaluated for efficacy in the treatment of TS patients. P. Jeffrey Conn, Ph.D. Emory University School of Medicine, Atlanta, GA Award $40,000* * This investigation was funded through a generous contribution from Evelyn and Frank Bloom, Harrisburg, PA Tourette Association of America Inc. – Research Grant Award 2000-2001