Behavioral control by striatal adenosine A2A -dopamine D2 receptor heteromers

Abstract

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 A2A receptors (A2A R) and dopamine D2 receptors (D2 R) predominantly form A2A 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 A2A 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 A2A R knock-out mouse was generated. Locomotor activity, pre-pulse inhibition (PPI) and drug-induced catalepsy were then evaluated in wild-type, A2A R and D2 R knock-out mice, with and without the concomitant administration of either the D2 R agonist sumanirole or the A2A R antagonist SCH442416. SCH442416-mediated locomotor effects were demonstrated to be dependent on D2 R signaling. Similarly, a significant dependence on A2A 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 A2A R-D2 R heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders.

Keywords: GPCR heteromers; SCH442416; adenosine A2A receptor; catalepsy; dopamine D2 receptor; locomotor activity; pre-pulse inhibition; sumanirole.

© 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.