Behavioral control by striatal adenosine A 2A -dopamine D 2 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 D ₂ receptors (D ₂ R) predominantly form A _2A R-D ₂ 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 D ₂ R within the frame of such a predominant striatal heteromeric population. First, in order to avoid possible strain-related differences, a new D ₂ 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 D ₂ R knock-out mice, with and without the concomitant administration of either the D ₂ R agonist sumanirole or the A _2A R antagonist SCH442416. SCH442416-mediated locomotor effects were demonstrated to be dependent on D ₂ 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-D ₂ R heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders.
(© 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)