Habit Formation after Random Interval Training Is Associated with Increased Adenosine A Receptor and Dopamine D Receptor Heterodimers in the Striatum.

Striatal adenosine A receptors (ARs) modulate striatal synaptic plasticity and instrumental learning, possibly by functional interaction with the dopamine D receptors (DRs) and metabotropic glutamate receptors 5 (mGluR5) through receptor-receptor heterodimers, but evidence for these interactions is lacking. Using proximity ligation assay (PLA), we studied the subregional distribution of the AR-DR and AR-mGluR5 heterodimer complexes in the striatum and their adaptive changes over the random interval and random ratio training of instrumental learning. After confirming the specificity of the PLA detection of the AR-DR heterodimers with the AR knockout and DR knockout mice, we detected a heterogeneous distribution of the AR-DR heterodimer complexes in the striatum, being more abundant in the dorsolateral than the dorsomedial striatum. Importantly, habit formation after the random interval training was associated with the increased formation of the AR-DR heterodimer complexes, with prominant increase in the dorsomedial striatum. Conversely, goal-directed behavior after the random ratio schedule was not associated with the adaptive change in the AR-DR heterodimer complexes. In contrast to the AR-DR heterodimers, the AR-mGluR5 heterodimers showed neither subregional variation in the striatum nor adaptive changes over either the random ratio (RR) or random interval (RI) training of instrumental learning. These findings suggest that development of habit formation is associated with increased formation of the AR-DR heterodimer protein complexes which may lead to reduced dependence on DR signaling in the striatum.