The Role of Adenosine Receptors in Psychostimulant Addiction

Abstract

Adenosine receptors (AR) are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3 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, A1 and A3 receptors inhibit adenylyl cyclase (AC), through Gi/o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors 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 A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1 and 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 A1 agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2 heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A2A 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 A1 and A2A receptors constitute promising tools to counteract psychostimulants addiction.

The intertwined roles of circadian rhythmsand neuronal metabolism fueling drug reward and addiction

“…Adenosine activates P1 receptors (A1, A2A, A2B, and A3), which are primarily located on presynaptic terminals. Several of these receptors have been implicated in addiction [106], such as the A2AR, which is highly expressed in the striatum [107]. During withdrawal from cocaine, A2ARs are upregulated in both hippocampus and striatum of the rat [108–111], although these receptors seem to differentially modulate the behavioral effects of repeated cocaine administration.…”

“…Indeed, deletion of A2ARs in striatal neurons enhanced cocaine sensitization, while deletion of the receptors in cortical and hippocampal neurons attenuated locomotor sensitization [112,113]. These receptors are involved in many other drug reward related behaviors [106]. …”

Therapeutic Perspectives of Adenosine Deaminase Inhibition in Cardiovascular Diseases

“…All subtypes of AR are characterized by seven transmembrane domains connected by three intracellular and extracellular domains. At the extracellular level, the N-terminus presents specific glycosylation sites, while at the intracellular side, the C-terminus contains phosphorylation and palmitoylation sites, important for receptor desensitization [ 23 ]. Each AR has unique cell and tissue distribution, secondary signaling transductors, affinity for adenosine, and physiological effects.…”

Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity

“…However, a second study reported that either increasing or decreasing the activity at A2AR was found to prevent the aversive motivational response to withdrawal from chronic, but not acute nicotine administration [ 114 ]. It is relevant here to note that A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, while A2A receptors are localized mainly in the striatum and olfactory bulb (A2B and A3 receptors are found at low levels of expression) [ 115 ]. A2A receptors are found in receptor clusters with dopamine and glutamate receptors [ 116 ] and A2A-D2-mGlu5 receptor mosaics have been discovered [ 117 ].…”