Dopamine D2 and Adenosine A2A Receptors Regulate NMDA-Mediated Excitation in Accumbens Neurons Through A2A–D2 Receptor Heteromerization

Abstract

Bursting activity of striatal medium spiny neurons results from membrane potential oscillations between a down- and an upstate that could be regulated by G-protein-coupled receptors. Among these, dopamine D2 and adenosine A2A receptors are highly enriched in striatal neurons and exhibit strong interactions whose physiological significance and molecular mechanisms remain partially unclear. More particularly, respective involvements of common intracellular signaling cascades and A2A–D2 receptor heteromerization remain unknown. Here we show, by performing perforated-patch-clamp recordings on brain slices and loading competitive peptides, that D2 and A2A receptors regulate the induction by N-methyl-D-aspartate of a depolarized membrane potential plateau through mechanisms relying upon specific protein–protein interactions. Indeed, D2 receptor activation abolished transitions between a hyperpolarized resting potential and a depolarized plateau potential by regulating the CaV1.3a calcium channel activity through interactions with scaffold proteins Shankl/3. Noticeably, A2A receptor activation had no effect per se but fully reversed the effects of D2 receptor activation through a mechanism in which A2A–D2 receptors heteromerization is strictly mandatory, demonstrating therefore a first direct physiological relevance of these heteromers. Our results show that membrane potential transitions and firing patterns in striatal neurons are tightly controlled by D2 and A2A receptors through specific protein–protein interactions including A2A–D2 receptors heteromerization.

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

“…We also show here that the A 2A receptor agonist, CGS21680, did not cause any pharmacological effect on the firing rate or pattern of dopamine neurons, confirming the lack of pharmacologically accessible A 2A receptors on dopamine neurons, which is in agreement with a low level of A 2A receptor expression in the VTA (Rosin et al, 1998;Rosin et al, 2003). CGS21680 also failed to acutely alter D 2 receptor function in the VTA, indicating a lack of direct pharmacological interaction between D 2 and A 2A receptors in the VTA, like those in the striatum (Azdad et al, 2009).…”

“…Via different G-protein coupling and second messenger systems, the activation of the adenosine A 2A receptors increases cAMP levels and cellular excitability, while the activation of the dopamine D2 receptors decreases cAMP levels and cellular excitability. Antagonistic interactions between the two receptor systems are also manifested by direct receptor-receptor cross-talk in the form of heterodimers, where stimulation of the adenosine A 2A receptors causes a reduction in the affinity of dopamine D 2 receptor agonists and vice versa (Ferre et al, 1991;Kull et al, 1999;Azdad et al, 2009). The functional interactions between adenosine A 2A receptors and dopamine D 2 receptors are thought to underlie the involvement of adenosine A 2A receptors in the control of several behavioral functions (Sebastiao & Ribeiro, 1996;Fredholm et al, 2005).…”

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…It has been further suggested that an imbalance in adenosine signaling, a neurotransmitter which modulates both dopamine and glutamate transmission, may be a central factor in the susceptibility to develop schizophrenia (Boison et al, 2012). In support of this hypothesis, it has been repeatedly shown that enhancing NMDA receptor function improves the negative and cognitive symptoms of schizophrenia (Coyle, 2012), and interestingly, heteromerization of the D2R with the A2R negatively regulated D2R-induced suppression of NMDA-mediated depolarization plateau potential (Azdad et al, 2009).…”

Differential Effects of Presynaptic versus Postsynaptic Adenosine A2AReceptor Blockade on Δ9-Tetrahydrocannabinol (THC) Self-Administration in Squirrel Monkeys

“…We showed previously that presynaptic and postsynaptic effects of A 2A receptor antagonists depend on the differential affinity of ligands for different A 2A receptor heteromers, which are differentially localized in different striatal neuronal elements. Thus, postsynaptic A 2A receptors are mostly localized in striatal medium spiny neurons (MSNs) that project to the external segment of the globus pallidus, in which they form heteromers with dopamine D 2 receptors, which modulate neuronal excitability (Azdad et al, 2009). Blockade of postsynaptic A 2A receptors mediates the locomotor activating effects of A 2A receptor antagonists and is also involved in the locomotor activating effects of the nonselective adenosine receptor antagonist caffeine (Ferré et al, 2008;Orru et al, 2011).…”

“…Experimental chambers and other apparatus, as well as the general self-administration procedure, were as described previously (Justinová et al, 2003). Monkeys were surgically prepared with chronic indwelling venous catheters (polyvinyl chloride;Goldberg 1973). At the start of the session, a white house light was turned off, green stimulus lights were turned on, and monkeys were required to make 10 responses on a lever [10-response, fixed-ratio schedule of reinforcement (FR10)], which turned off the green lights and produced an intravenous injection of 4 g/kg THC (0.2 s, 0.2 ml) paired with a 2 s amber light.…”