Characterization of Dopamine receptor Function in the Striatum of Dopamine Transporter Knock-Out Mice: Relevance for Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
Duke University
Investigators Name
Gainetdinov, Raul, MD, PhD

Our hypothesis is based on the idea that while Tourette Syndrome (TS) is unequivocally an inherited condition, the severity of symptoms may be related to prenatal levels of dopamine (DA) in the brain. We have evidence that prenatal events known to cause elevated DA do correlate with more severe TS symptoms. Specifically, we will test whether prenatal exposure to elevated DA levels leads to long-lasting postsynaptic DA receptor supersensitivity system activity, which in turn could cause increased random motor activity. Our laboratory is uniquely positioned to explore the adaptive changes which could result from a hyperdopaminergic tone in the central nervous system. Recently, a strain of mice (where the gene encoding the dopamine transporter [DAT] has been disrupted by means of in vivo homologous recombination) has been produced in our laboratory. The DAT knock-out mice gain weight more slowly than normal mice. Preliminary behavioral studies on these mice showed extreme spontaneous hyperlocomotion and movements especially in stressful situations. The overactivity of central dopamin¬ergic transmission was confirmed by cyclic voltammetry experiments in mouse brain slices, which showed a 300-fold increase in the amount of time dopamine lingers in the extracellular space in the DAT knock-out mice. In summary, we believe that the genetically engineered DAT knock-out mice (which do not express the DAT, and thus present generalized behavioral and biochemical overactive dopaminergic states) might be considered an excellent non-pharmacologically manipulated animal model to examine alterations in the function of DA receptors by persistent hyperdopaminergic tone. While it is reasonable to speculate the DAT knock-out mice have properties reminiscent of some aspects of TS, a much better characterization of the fundamental neurobiological properties of these mice needs to be performed to determine whether they are a potential model for TS. These studies are relevant for Tourette Syndrome for the following reasons: First, understanding the mechanisms of long-lasting alterations in DA receptor sensitivity is particularly important as this information might yield some new insights into the root causes of Tourette Syndrome. Second, elucidation of the adaptive processes in striatal dopa¬minergic transmission in DAT knock-out mice induced by persistent hyperdopaminergic tone (i.e. in utero during critical periods of development) might be of importance in understanding the role of developmental factors on the phenotypic expression of TS. Third, the potential characterization of DAT knock-out mice as a TS animal model will give us test subjects to validate hypotheses about the pathophysiology of the disorder, as well as to test the effectiveness of novel pharmacological interventions. Raul R. Gainetdinov, M.D., Ph.D. Duke University Medical Center Durham, NC Award: $25,000 Tourette Association of America Inc. – Research Grant Award 1997