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

Grant Type
Basic
Grant Year
1997
Institution Location
VA
Institution Organization Name
University of Virginia
Investigators Name
Rosin, Diane, PhD

One strategy for better understanding neurological conditions such as Tourette Syndrome (TS) is to study the role of neurotransmitters, i.e. the chemical messengers used by the brain’s cells (neurons) for communication. Alteration of the function of specific neurotransmitters in the brain using carefully developed medications has been an important approach to treatment. Haloperidol has been one of the drugs used effectively in reducing some of the tic symptoms of TS, but its use is frequently limited by the development of 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 of the brain that plays an important role in coordinating movement and one that may function abnormally in people with TS. Along with the 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 last 10 years, various 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 dopamine 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 with TS. The goal of our research project 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 (the messages that encode the synthesis of proteins) 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. We will use immunohistochemical techniques, methods that allow us to visualize the location of a protein in the brain, to examine the combined cellular localization of adenosine A2A receptors and dopamine D2 receptors in rat brain by light and electron microscopy. Our findings and those of others have shown by immunohistochemistry that both A1 and A2A adenosine receptors are found in the striatum, but there is little known of the role of A1 adenosine receptors in modulating dopamine function. Further, some studies point to a dopamine D1/ adenosine A2A interaction, but the anatomical basis for this observation has not been examined. To investigate other potentially important sites involved in adenosine-dopamine interactions, our studies will also focus on the combined immunohistochemical localization of 1) adenosine A2A receptors and dopamine D1 receptors and 2) adenosine A1 and A2A receptors in the striatum. 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 treating Tourette Syndrome. Diane L. Rosin, Ph.D. University of Virginia Charlottesville, VA Award: $39,000 Tourette Association of America Inc. – Research Grant Award 1997