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The discovery of receptor-receptor interactions in the early 1980s, together with a more accurate focusing of allosteric mechanisms in proteins, expanded the knowledge on the G protein-coupled receptor (GPCR)-mediated signaling processes. GPCRs were seen to operate not only as monomers, but also as quaternary structures shaped by allosteric interactions. These integrative mechanisms can change the function of the GPCRs involved, leading to a sophisticated dynamic of the receptor assembly in terms of modulation of recognition and signaling. In this context, the heterodimeric complex formed by the adenosine A2A and the dopamine D2 receptors likely represents a prototypical example. The pharmacological evidence obtained, together with the tissue distribution of the A2A-D2 heteromeric complexes, suggested they could represent a target for new therapeutic strategies addressing significant disorders of the central nervous system. The research findings and the perspectives they offer from the therapeutic standpoint are the focus of the here presented discussion.

The mammalian brain contains a myriad of receptors localized on neuronal axon terminals (presynaptic receptors) the function of which is to modulate neurotransmitter release. Similarly to postsynaptic receptors, presynaptic receptors exist as pharmacologically distinct types and subtypes. Inasmuch as modulation of release is the functional response that follows their activation, transmitter release represents an excellent model to investigate receptors in general as well as to test potentially novel and more selective drugs. Types and subtypes of presynaptic receptors regulating the release of various transmitters will be described and their potential involvement in different pathophysiological conditions will be discussed.

The mechanisms by which the synthesis of dopamine (DA) is controlled have been only in part elucidated. End-product inhibition and autoreceptor activation have been proposed as negative feedback regulatory processes. We here present evidence against the existence of DA autoreceptors controlling DA formation and propose a model in which DA reuptake plays a key role in the end-product inhibition of DA synthesis. In striatal synaptosomes incubated with 14 C-tyrosine, DA or ADTN decreased 14 CO 2 evolution. Their effect was not counteracted by DA receptor antagonists, but was prevented by DA carrier blockers, suggesting that the DA agonists do not activate autoreceptors on the external synaptic membrane. The DA uptake inhibitors nomifensine, cocaine and benztropine were found to increase 14 CO 2 evolution from striatal synaptosomes. Depolarizing concentrations of KCl also stimulated DA synthesis and this effect was greatly potentiated when DA reuptake was prevented. DA reuptake blockers largely counteracted the decrease of DA synthesis caused by MAO inhibitors or by L-DOPA. These data indicate that DA synthesis is under the inhibitory control of the amine recaptured following release.