Habit Formation after Random Interval Training Is Associated with Increased Adenosine A2A Receptor and Dopamine D2 Receptor Heterodimers in the Striatum

Abstract

Striatal adenosine A2A receptors (A2ARs) modulate striatal synaptic plasticity and instrumental learning, possibly by functional interaction with the dopamine D2 receptors (D2Rs) and metabotropic glutamate receptors 5 (mGluR5) through receptor-receptor heterodimers, but in vivo evidence for these interactions is lacking. Using in situ proximity ligation assay (PLA), we studied the subregional distribution of the A2AR-D2R and A2AR-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 A2AR-D2R heterodimers with the A2AR knockout and D2R knockout mice, we detected a heterogeneous distribution of the A2AR-D2R 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 A2AR-D2R 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 A2AR-D2R heterodimer complexes. In contrast to the A2AR-D2R heterodimers, the A2AR-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 A2AR-D2R heterodimer protein complexes which may lead to reduced dependence on D2R signaling in the striatum.

G protein-coupled receptor heteromers are key players in substance use disorder

“…In the striatum of C57BL6/J mice, A 2a -D 2 heteromers were more abundant in the dorsolateral than in the dorsomedial striatum in basal conditions (He et al, 2016;Trifilieff et al, 2011). However, in situ PLA revealed higher signal in the dorsomedial and dorsolateral striatum in a paradigm of habit formation (random interval training) whereas it remained unchanged in a paradigm of goal directed behavior (random ratio training) (He et al, 2016). This suggests that A 2a -D 2 heteromers participate in the negative regulation of D 2 signaling in the striatum and contribute to the control of abnormal habit formation taking place during drug addiction especially during relapse.…”

“…This transition is facilitated by D 1 receptor activation and inhibited by D 2 receptors. In the striatum of C57BL6/J mice, A 2a -D 2 heteromers were more abundant in the dorsolateral than in the dorsomedial striatum in basal conditions (He et al, 2016;Trifilieff et al, 2011). However, in situ PLA revealed higher signal in the dorsomedial and dorsolateral striatum in a paradigm of habit formation (random interval training) whereas it remained unchanged in a paradigm of goal directed behavior (random ratio training) (He et al, 2016).…”

“…Heteromerization of adenosine A 2a and dopamine D 2 receptors has been extensively studied in native tissue. Close physical proximity of A 2a and D 2 receptors was detected by in situ PLA in the striatum of C57BL6/J mice (He et al, 2016;Trifilieff et al, 2011) and confirmed in rats by electron microscopy and time-resolved fluorescence resonance energy transfer (FRET) (Fernandez-Duenas et al, 2015). Co-internalization was detected upon activation by D 2 or A 2 agonists in SHSY5Y neuroblastoma and in primary striatal neurons (Hillion et al, 2002;Huang et al, 2013).…”

The D2 Dopamine Receptor Interferes With the Protective Effect of the A2A Adenosine Receptor on TDP-43 Mislocalization in Experimental Models of Motor Neuron Degeneration

“…Functional interactions between D 2 R and A 2A R in the striatum have been extensively investigated in the past few decades (Ongini and Fredholm, 1996 ; Svenningsson et al, 2000 ). These D 2 R/A 2A R complexes not only exist in vivo but can also be regulated by pathophysiological activities and stresses (e.g., levodopa-induced dyskinesia, cocaine self-administration, and habit formation; He et al, 2016 ; Borroto-Escuela et al, 2017 ; Zhou et al, 2017 ), as well as appear to modulate the pharmacological characters and signaling pathways of both D 2 R and A 2A R (Fernández-Dueñas et al, 2012 , 2013 ). In the present study, our findings demonstrate that D 2 R and A 2A R are co-localized in mouse and human motor neurons and functionally interact at the cAMP/PKA level (Figures 1 – 3 ; Table 1 ).…”

Pharmacological Blockade of Adenosine A2A but Not A1 Receptors Enhances Goal-Directed Valuation in Satiety-Based Instrumental Behavior

“…Also, loss of striatal endocannabinoid-mediated long-term depression selectively in DLS striatopallidal neurons prevent the transition from goal-directed seeking to habitual responding behavior but did not interfere lever-press performance in the acquisition phase ( Gremel et al, 2016 ). Given the documented antagonistic interaction of the A 2A R-D 2 R and the A 2A R-CB 1 R in the striatum by possibly the A 2A R-D 2 R heterodimers ( He et al, 2016 ) and A 2A R-CB 1 R heterodimers ( Moreno et al, 2017 ), these findings suggest that A 2A R may selectively influence coding of the current value of the outcome (but not the contingency association) by the A 2A R interaction with the D 2 R and CB 1 R functions in the striatum.…”