Abstract
The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson’s disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.
Highlights
One of the most noticeable functions of adenosine in the brain is the ability to impose a brake on the central dopaminergic system
We propose a functional model for the A2A receptor (A2AR)-D2R heterotetramerAC5 complex in the striatopallidal neuron, a complex formed by one A2AR homodimer coupled to a Golf protein, a D2R homodimer coupled to a Gi protein and its signaling molecule adenylyl cyclase subtype 5 (AC5)
We present new results of the effect of the A2AR antagonist SCH 442416 in radioligand binding, locomotor activation and optogenetic experiments in mice, which reconcile previous studies with the same compound that were apparently incompatible with our hypothesis of a predominant population of striatal A2AR-D2R heteromers that modulate striatopallidal neuronal function
Summary
One of the most noticeable functions of adenosine in the brain is the ability to impose a brake on the central dopaminergic system. Unilateral optogenetic stimulation led to significant ipsilateral rotational behavior, while bilateral optogenetic stimulation led to a significant decrease in locomotor activity (Kravitz et al, 2010; Freeze et al, 2013; Zwilling et al, 2014) (Figure 2A) These results were opposite to those obtained by the selective ablation of a large proportion of dorsal and ventral striatopallidal neurons in BAC transgenic A2AR-Cre mice by Cre-mediated expression of a diphtheria toxin receptor and diphtheria toxin injection, which led to hyperlocomotion (Durieux et al, 2009).
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