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, A_2A, A_2B, 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 G_i/o proteins, while A_2A and A_2B receptors stimulate it through G_s proteins. In the CNS, A₁ 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 A₃ receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A₁/A_2A), as well as with other subtypes (e.g., A_2A/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 A_2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A₁ receptors colocalized in heteromeric complexes with D₁ receptors, and A_2A receptors with D₂ receptors. This review documents the present state of knowledge of the contribution of AR, particularly A₁ 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 A₁ agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A_2A/D₂ 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 A₁ and A_2A receptors constitute promising tools to counteract psychostimulants addiction.

Keywords: Adenosine A1 receptors; Adenosine A2A receptors; amphetamines; behavioral effects; cocaine; dopamine; psychostimulants; striatum.

FIGURE 1

Schematic representation of pathways involved in intoxication, withdrawal and craving stages of addiction. Release of dopamine in the nucleus accumbens is a common feature of psychostimulants reinforcement at initial stages of psychostimulants intake (dots in black are regions directly involved in binge and intoxication). The negative emotional stage of withdrawal appears to be related to the activation of amygdala (dots in white are regions directly involved in negative emotional stage) and, finally, the latter stage of psychostimulant addiction, craving, depends on prefrontal cortex, amygdala and hippocampal activities (dots in gray). In blue, glutamatergic pathways; in green, dopaminergic pathways; in red, GABAergic connections. NAc, Nucleus Accumbens; Amy, Amygdala; dStr, dorsal Striatum; Hipp, Hippocampus; PFC, Prefrontal Cortex; SN/VTA, Substantia Nigra and Ventral Tegmental Area; Thal, Thalamus.

FIGURE 2

Integrative scheme of reward circuit in striatum with focus on adenosine and dopamine receptors and their interactions. A₁ and A_2A receptors are located pre- and post-synaptically forming homo-, heterodimers and oligomers in the dendritic spines of medium spiny neurons in striatum (MSN). Glutamatergic input from cortex and dopaminergic input from ventral tegmental area project to both MSNs expressing D₁-like and MSNs expressing D₂-like dopamine receptors. A_2A, adenosine 2A receptors; CB₁, endocannabinoid CB₁ receptors; DAT, dopamine active transporters; D₁, dopamine D₁ receptors; D₂, dopamine D₂ receptors; mGlu₅, metabotropic glutamate subtype 5 receptors; 5HTRs, serotonin receptors.