Abstract
Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor–receptor interactions within A2AR/D2R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson’s disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A2AR/D2R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.
Highlights
Adenosine, a purine nucleoside, plays several behavioral and physiological roles throughout the central nervous system (CNS)
As A2A receptors are known to be located mainly in the striatum, in postsynaptic locations on dendrites and dendritic spines [21,22] and, to a lesser extent (25%), on nerve endings [23,24]. These findings suggest the existence of postsynaptic interactions between adenosine and dopamine receptors, probably the A2A and D2 subtypes
TM5 peptide, completely counteracted the inhibitory effect of CGS21680 on cocaine intake [203]. In contrast to this striking impact of a TM5 peptide, microinjections of a TM2 peptide did not counteract the effect of CGS21680 on cocaine self-administration [204]. These results suggest that the beneficial actions of CGS21680 in animal models of cocaine abuse are mediated by the triggering of an allosteric inhibition of D2 protomer signaling in A2A R-D2 R
Summary
Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging. Dierckx 1,2 and Aren van Waarde 1, *.
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