Interactions of Adenosine and Dopamine in Basal Ganglia: Potential Substrates for Novel Therapeutic Strategies in TS

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Virginia
Investigators Name
Rosin, Diane, PhD

One strategy for achieving a better understanding of neurological disorders such as Tourette Syndrome (TS) is to study the role of neurotransmitters. Alteration of the function of specific neurotransmitters in the brain using developed medications has been an important approach to treatment. Haloperidol has been one of the drugs used effectively in reducing some of the symptoms of TS (particularly motor tics), but its use is frequently limited by unwanted side effects. Dopamine antagonists, such as haloperidol, bind to dopamine receptors and block the effects of the neurotransmitter dopamine in several areas of the brain including the striatum—an area that plays an important role in coordinating movement and one that may function abnormally in TS. In combination with other scientific evidence, the effectiveness of haloperidol in inhibiting dopamine function suggests that one of the causes of TS may be an abnormality in the brain that leads to an overactive dopamine system. Over the past decade, several research groups have discovered that adenosine (another neurochemical found in the brain) can oppose the actions of dopamine in the striatum. More specifically, stimulation of adenosine A2A receptors opposes the action of dopamine at D2 receptors. Given this interaction of adenosine and dopamine, development of drugs that alter adenosine function may prove to be effective new therapies for treatment of some people with TS. Our goal is to study the interaction of dopamine and adenosine-containing neurons at the anatomical level in the striatum to better understand how they might modulate each others’ activity. Prior studies have shown that mRNAs for adenosine A2A receptors and dopamine D2 receptors are colocalized in the medium spiny, GABAergic striatopallidal neurons, part of a neuronal circuit in the brain that is important in integrating motor function. Using techniques that allow us to visualize the location of a protein in the brain during our first year of TSA funding, we examined the combined cellular localization of adenosine A2A receptors and markers of dopamine neurons in rat brain by light and electron microscopy. During this second year of funding, we will further define the cellular mechanisms by which A2A receptors modulate the outflow of information from the striatum by (1) determining the ultrastructural substrate for adenosine A2A receptor’s role in modulating GABAergic neurons in the striatum, (2) evaluating the cellular basis of A2A receptor modulation of acetylcholine release in striatum, and (3) investigating the cellular basis for reported interactions of adenosine A2A and dopamine D1 receptors. New information gained from our studies will contribute to our understanding of dopamine and adenosine function in the brain and may reveal anatomical targets that could be used to therapeutic advantage in controlling TS symptoms. Diane L. Rosin, Ph.D. University of Virginia, Charlottesville, VA Award: $40,000 Tourette Association of America Inc. – Research Grant Award 1998