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

作者：Jiang‐Fan Chen, Rosario Moratalla, Francesco Impagnatiello, David K. Grandy, Beatriz Cuéllar, Marcelo Rubinstein, Mark A. Beilstein, Elizabeth Hackett, J. Stephen Fink, Malcolm James Low, Ennio Ongini, Michael A. Schwarzschild · 发表于：Proceedings of the National Academy of Sciences · 年份：2001 · DOI：10.1073/pnas.98.4.1970 · 被引用次数：257 · 研究领域：Adenosine and Purinergic Signaling、Neurotransmitter Receptor Influence on Behavior、Receptor Mechanisms and Signaling

The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A(2A)R antagonizes D(2)R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A(2A)R-D(2)R interaction. However, whether the D(2)R is required for the A(2A)R to exert its neural function 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 knockout (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral analysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D(2) KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D(2)R, although the stimulation was significantly attenuated. At the cellular level, A(2A)R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D(2)R deficiency. Consistent with the D(2) KO phenotype, A(2A)R inactivation partially reversed both acute D(2)R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A(2A)Rs elicit behavioral and cellular responses despite either the genetic deficienc...