Adenosine A_2A receptors modulate the dopamine D₂ receptor‐mediated inhibition of synaptic transmission in the mouse prefrontal cortex

Abstract

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D - and D -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A receptors (A R) also control PFC-related responses and A R antagonists are potential anti-psychotic drugs. As tight antagonistic A R-D R and synergistic A R-D R interactions occur in other brain regions, we now investigated the crosstalk between A R and D /D R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D R-like antagonist sulpiride but not by the D R antagonist SCH23390 and was mimicked by the D R agonist sumanirole, but not by the agonists of either D R (A-412997) or D R (PD128907). Dopamine inhibition was prevented by the A R antagonist, SCH58261, and attenuated in A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A R and D R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A R-D R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A R antagonists.

A specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction

“…All these genes encode G-protein-coupled receptors and are known to be involved in the neurobiological pathways recruited in addiction 40 . D 2 R and A 2A R, encoded by Drd2 and Adora2A, respectively, are colocalized in the mPFC glutamatergic neurons projecting from the L2/3 to L5 at presynaptic terminals 41 . Here, receptor activation synergistically inhibit synaptic glutamatergic transmission 41 .…”

“…D 2 R and A 2A R, encoded by Drd2 and Adora2A, respectively, are colocalized in the mPFC glutamatergic neurons projecting from the L2/3 to L5 at presynaptic terminals 41 . Here, receptor activation synergistically inhibit synaptic glutamatergic transmission 41 . This is contrary to the well stablished postsynaptic antagonistic interaction in the GABAergic MSNs of the striatum 42 .…”

“…Once the evoked fPSP were stabilized, at least 50 consecutive responses were recorded. Synaptic facilitation was estimated as the ratio among second response (P2) respect the first response (P1) 41 . Electrical stimulus (0.06 Hz) was the 50% of the intensity needed to evoke the maximal fPSP.…”

Adenosine A2A Receptors in the Rat Prelimbic Medial Prefrontal Cortex Control Delay-Based Cost-Benefit Decision Making

“…We have recently reported that A 2A R in the PLmPFC control long-term plasticity of excitatory synaptic transmission onto fast spiking interneurons (Kerkhofs et al, 2018) and that they are necessary for dopamine-induced decrease in population activity (Real et al, 2018). Thus, we anticipated a role for PFC A 2A R in the control of PFC-dependent behaviors, which include anxiety-like behavior (Calhoon and Tye, 2015; Tovote et al, 2015), cost-benefit decision-making (Bailey et al, 2016) and working memory (Goldman-Rakic, 1999; Fuster, 2001).…”

Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model

“…To directly test the possibility that therapeutic effect of trifluoperazine is mediated through its activity against dopamine receptors, we used other known D1 and D2 receptor (D1R and D2R) antagonists. At concentrations that affect dopamine receptor function [36][37][38] , neither the D1R antagonist SCH23390 nor the D2R antagonist raclopride inhibited pAkt in neurons (Supplementary Fig. 10a, b).…”