Adenosine as a biomarker of Huntington Disease

Results from genetic studies and from experiments with animal models have suggested the involvement of adenosine A2a receptor (A2aR) in the pathogenesis of Huntington Disease (HD). An A2aR gene polymorphism has been found to be significantly associated with a decrease in the age at onset in HD and some controversial abnormalities of A2aR expression or function have been found in transgenic mouse HD models. We recently reported a complete insensitivity of the A2aR antagonist, KW-6002, at inducing locomotor activity in a transgenic HD rat models. When trying to discover a possible A2aR abnormality, we found no evidence for differences in the striatal density of A2aR (with saturation experiments with the A2aR antagonist [3H]ZM-2413851, or in the ability of the A2aR agonist CGS 21680 to produce locomotor depression. Significantly, transgenic rats did not respond to the locomotor activating effects of the adenosine A1 receptor (A1R) antagoníst CPT either. Again no evidence for differences were seen in the striatal density of A1R (with saturation experiments with the A2aR antagonist f [3H]DPCPX or in the ability of the A1R agonist CPA to produce locomotor depression. The results therefore indicate the existence of a decreased striatal adenosinergic tone, which was confirmed with in vivo microdialysis experiments, with a significantly lower extracellular concentration of adenosine in transgenic HD rats compared to controls. These results support a switch in the focus of research in the pathogenesis of HD from the receptor (A2aR) to the neurotransmitter (adenosine) and from the neuron to the astrocyte.