The role of adenosine receptors in psychostimulant addiction

Adenosine receptors (AR) are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3receptors, 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, A1and A3receptors inhibit adenylyl cyclase (AC), through Gi/oproteins, while A2Aand A2Breceptors stimulate it through Gs proteins. In the CNS, A1receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2Areceptors are localized mainly in the striatum and olfactory bulb, while A2Band A3receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A1/A2A), as well as with other subtypes (e.g., A2A/D2), opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A1and A2Areceptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1receptors colocalized in heteromeric complexes with D1receptors, and A2Areceptors with D2receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1and A2A, 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 A1agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A2Areceptor 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 A1and A2Areceptors constitute promising tools to counteract psychostimulants addiction.