The role of the D2 dopamine receptor (D2R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D-2 receptor knockout mice

The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the st riatum where it modulates dopaminergic activity. Activation of the A(2A)R a ntagonizes D2R-mediated behavioral and neurochemical effects in the basal g anglia through a mechanism that may involve direct A(2A)R-D2R interaction. However, whether the D2R is required for the A(2A)R to exert its neural fun ction is an open question. In this study, we examined the role of D(2)Rs in A(2A)R-induced behavioral and cellular responses, by using genetic knockou t (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral ana lysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)henethylamino-5'-N- ethylcarbox-amidoadenosine reduced spontaneous as well as amphetamine-induc ed locomotion in both D-2 KO and wild-type mice. Conversely, the nonselecti ve adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyry l)caffeine produced motor stimulation in mice lacking the DIR, although the stimulation was significantly attentuated. At the cellular level, A(2A)R i nactivation counteracted the increase in enkephalin expression in striatopa llidal neurons caused by D2R deficiency. Consistent with the D-2 KO phenoty pe, A(2A)R inactivation partially reversed both acute D2R antagonist (halop eridol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA e xpression. Together, these results demonstrate that A(2A)Rs elicit behavior al and cellular responses despite either the genetic deficiency or pharmaco logical blockade of D(2)Rs. Thus, A(2A)R-mediated neural functions are part ially independent of D(2)Rs. Moreover, endogenous adenosine acting at stria tal A(2A)Rs may be most accurately viewed as a facilitative modulator of st riatal neuronal activity rather than simply as an inhibitory modulator of D 2R neurotransmission.