Behavioral control by striatal adenosine A_2A -dopamine D₂ receptor heteromers

G protein-coupled receptors (GPCR) exhibit the ability to form receptor complexes that include molecularly different GPCR (ie, GPCR heteromers), which endow them with singular functional and pharmacological characteristics. The relative expression of GPCR heteromers remains a matter of intense debate. Recent studies support that adenosine A_2A receptors (A_2A R) and dopamine D₂ receptors (D₂ R) predominantly form A_2A R-D₂ R heteromers in the striatum. The aim of the present study was evaluating the behavioral effects of pharmacological manipulation and genetic blockade of A_2A R and D₂ R within the frame of such a predominant striatal heteromeric population. First, in order to avoid possible strain-related differences, a new D₂ R-deficient mouse with the same genetic background (CD-1) than the A_2A R knock-out mouse was generated. Locomotor activity, pre-pulse inhibition (PPI) and drug-induced catalepsy were then evaluated in wild-type, A_2A R and D₂ R knock-out mice, with and without the concomitant administration of either the D₂ R agonist sumanirole or the A_2A R antagonist SCH442416. SCH442416-mediated locomotor effects were demonstrated to be dependent on D₂ R signaling. Similarly, a significant dependence on A_2A R signaling was observed for PPI and for haloperidol-induced catalepsy. The results could be explained by the existence of one main population of striatal postsynaptic A_2A R-D₂ R heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders.