The Role of Adenosine Receptors in Psychostimulant Addiction.

Adenosine receptors (AR) are a family of G-protein coupled receptors, comprised of four members, named A, A, A, and A receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS), adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A and A receptors inhibit adenylyl cyclase (AC), through G proteins, while A and A receptors stimulate it through G proteins. In the CNS, A receptors are widely distributed in the cortex, hippocampus, and cerebellum, A receptors are localized mainly in the striatum and olfactory bulb, while A and A receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A/A), as well as with other subtypes (e.g., A/D), opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A and A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A receptors colocalized in heteromeric complexes with D receptors, and A receptors with D receptors. This review documents the present state of knowledge of the contribution of AR, particularly A and A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A/D heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A receptor is proposed as a potential therapeutic target for the treatment of drug addiction. The overall analysis of presented data provide evidence that excitatory modulation of A and A receptors constitute promising tools to counteract psychostimulants addiction.