The interaction of serotonin and dopamine in the neostriatum is an important line of investigation since both Tourette Syndrome (TS) (treated with drugs affecting dopamine) and obsessive compulsive disorder (treated with drugs affecting serotonin) occur in some families. To address this issue we have asked two questions: Do serotonin levels alter the synthesis of striatal neurotransmitters? Are the effects of serotonin direct or are they mediated through the dopamine system? We have found that permanent or transient decreases of serotonergic input to the striatum of the rat decrease the synthesis of substance P as well as a second striatal neurotransmitter, acetylcholine. In this project two drugs reported to increase serotonergic neurotransmission, the serotonin uptake blocker zimelidine and the MAO inhibitor clorgyline, will be tested for their effect on the synthesis of acetylcholine and substance P. Of the two categories of drugs, only serotonin uptake blockers have a therapeutic effect in the treatment of obsessive compulsive behavior. Therefore, differences between the two on the synthesis of substance P or acetylcholine might be related to their ability to treat obsessive compulsive behavior. In our studies, serotonin may exert its effect on the striatum in two ways — directly, or through the dopamine neurons of the substantia nigra. In the second part of this study, the dopaminergic ceurotoxin, 6-OH-dopamine, will be used to destroy dopaminergic neurons in adult rats. After recovery, these rats will be treated with zimelidine and clorgyline to increase serotonergic transmission. If an intact dopaminergic neurotransmitter system is required for the changes in substance P seen with zimelidine or clorgyline, lesioning of the animals with 6-OH-dopamine should abolish the effect. Interactions between serotonin and dopamine in the striatum are important not only for the understanding of combined Tourette Syndrome and obsessive compulsive disorder, but for those cases of TS that are exacerbated by the type of drugs used to treat obsessive compulsive disorder. Leigh A. Riley, M.D. Rutgers University, Newark, NJ Award $20,000 Tourette Association of America Inc. – Research Grant Award 1990