Effects of Neonatal Dopamine Depletion and Neuroleptic Treatment of Dopamine D2 Receptor Systems

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Rochester
Investigators Name
Gelbard, Harris, MD, PhD

Haloperidol and other neuroleptic agents such as pimozide are first-line pharmacotherapy of Tourette’s Syndrome (TS), a developmental disorder that usually occurs in the first decade of life. These drugs block the effect of the neurotransmitter dopamine at its D2 receptor. This may be a critical mechanism in the amelioration of symptoms of TS. In support of this hypothesis, drugs that increase the amount of dopamine in the brain such as amphetamine may exacerbate the symptoms of TS. The observations suggest that damage to developing dopaminergic pathways in the striatum, a brain region with high concentrations of dopamine, may result in abnormally high levels of the D2 receptor subtype for dopamine. The neurotoxin 6-hydroxydopamine (6-OHDA) has been used in rats to deplete stores of brain dopamine by destroying dopaminergic nerve terminals. In contrast to adult rats, neonatal rats treated with 6-OHDA exhibit attention deficits and cognitive impairments (children with TS have an increased incidence of attention deficit disorders relative to other children without TS). In addition, neonatal rats treated with 6-OHDA exhibit self-mutilating behavior, increased motor activity and abnormal facial-oral movements when treated with drugs that act like dopamine. Our laboratory has shown that neonatal dopamine depletion results in altered levels of dopamine receptor subtypes in the striatum. The purpose of this project is to study neonatal dopamine depletion and subsequent treatment with drugs that selectively block D2 receptors in the striatum. The questions to be answered include whether these experimental manipulations change neuronal gene expression of the rat D2 receptor or its metabolism in the cell or both. Results from these studies will provide important information about compensatory pathologic changes that take place after damage to developing dopaminergic pathways. This in turn may provide important insights into how drugs used to treat symptoms of TS modify D2 receptor systems. Harris A. Gelbard, M.D., Ph.D. University of Rochester School of Medicine, Rochester, NY Award $25,000 Tourette Association of America Inc. – Research Grant Award 1991