There is evidence that adenosine/dopamine antagonism in the central nervous system may involve an adenosine/dopamine receptor-receptor interaction. There also is an anatomical basis for the existence of functional interactions between adenosine A 1 receptors (A 1 Rs) and dopamine D 1 receptors (D 1 Rs) and between adenosine A 2A (A 2A Rs) and dopamine D 2 (D 2 Rs) receptors in the same neurons. Selective A 1 R agonists negatively affect the high-affinity binding of D 1 Rs. Activation of A 2A Rs leads to a decrease in receptor affinity for dopamine agonists acting on D 2 Rs, especially with regard to the high-affinity state. All these findings suggest receptor subtype-specific interactions between adenosine and dopamine receptors that may be achieved by molecular interactions, for example, receptor heterodimers. There exists evidence that A 1 Rs form homodimers in membranes and also form high-order molecular structures containing heterotrimeric G proteins and adenosine deaminase. In view of the occurrence of homodimers of adenosine and of dopamine receptors, it was speculated that heteromers between these receptors, belonging to two different families of G protein-coupled receptors, can be formed. Evidence that A 1 /D 1 receptors can form heterodimers in co-transfected cells and in primary cultures of neurons, in fact, has been obtained. These intramembrane interactions may constitute a major molecular basis to explain the behavioral effects of adenosine-related drugs in health and disease. There is also evidence that intramembrane dopamine/ adenosine receptor antagonism not only is mediated by direct receptor/receptor interaction (heteromers) but also involves other interacting proteins. In fact, adenosine deaminase absolutely is required for adenosine/dopamine antagonism. In the central nervous system, functional modules in which receptors for neurotransmitters or neuromodulators interact with each other and with other interacting proteins are crucial to understanding the physiology of the neuron and higher neural functions, such as learning and memory. Refined knowledge of the molecular mechanism of these interactions would be beneficial, to improve our therapeutic arsenal against neurological and neuropsychiatric diseases.
