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(1), A(2A), A(2B), and A(3) 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(1) and A(3) receptors inhibit adenylyl cyclase (AC), through G(i/o) proteins, while A(2A) and A(2B) receptors stimulate it through G(s) proteins. In the CNS, A(1) receptors are widely distributed in the cortex, hippocampus, and cerebellum, A(2A) receptors are localized mainly in the striatum and olfactory bulb, while A(2B) and A(3) receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A(1)/A(2A)), as well as with other subtypes (e.g., A(2A)/D(2)), opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A(1) and A(2A) receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A(1) receptors colocalized in heteromeric complexes with D(1) receptors, and A(2A) receptors with D(2) receptors. This review documents the present state of knowledge of the contribution of AR, particularly A(1) and A(2A), 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(1) agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A(2A)/D(2) heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A(2A) 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(1) and A(2A) receptors constitute promising tools to counteract psychostimulants addiction.