Adenosine-dopamine interactions revealed in knockout mice.

Neurochemical and pharmacological evidence obtained over the past 30 yr has indicated that adenosine and dopamine interact functionally in the basal ganglia and that such interactions have pathophysiological and therapeutic implications. The receptors implicated are adenosine A1 and A2A, and dopamine D1 and D2. There is evidence that dopamine D2 receptor activation in vivo antagonizes tonic activation of adenosine A2A receptors. Thus, acute blockade of dopamine D2 receptors, or disruption of dopamine transmission, unmasks strong adenosine A2A activation. Effects of dopamine D2 blockade are different after adenosine A2A blockade or in A2A knockout mice. Possibly as an adaptation to this increase in adenosine A2A signaling, there is a decreased coupling of A2A receptors to biological effects in dopamine D2 knockout mice. Compared to wild-type mice, adenosine A2A knockout mice show decreased neurodegeneration after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and show improved motor performance in models of Parkinson's disease Adenosine A1 receptors are not specifically located with any dopamine receptor, as is the A2A receptor with D2 receptors. Many A1 receptors are located presynaptically, where they regulate transmitter release. In A1 knockout mice, glutamatergic and dopaminergic transmission is therefore modified.