The role of the D₂ dopamine receptor (D₂R) in A_2A adenosine receptor (A_2AR)-mediated behavioral and cellular responses as revealed by A_2A and D₂ receptor knockout mice

The A_2AR is largely coexpressed with D₂Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A_2AR antagonizes D₂R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A_2AR-D₂R interaction. However, whether the D₂R is required for the A_2AR to exert its neural function is an open question. In this study, we examined the role of D₂Rs in A_2AR-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A_2ARs or D₂Rs or both). Behavioral analysis shows that the A_2AR agonist 2-4-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D₂ KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A_2AR antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D₂R, although the stimulation was significantly attentuated. At the cellular level, A_2AR inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D₂R deficiency. Consistent with the D₂ KO phenotype, A_2AR inactivation partially reversed both acute D₂R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A_2ARs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D₂Rs. Thus, A_2AR-mediated neural functions are partially independent of D₂Rs. Moreover, endogenous adenosine acting at striatal A_2ARs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D₂R neurotransmission.