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.
Highlights
Drug addiction is a complex chronic cognitive disorder characterized by drug seeking and compulsive use, which is difficult to control despite its harmful consequences
A series of experiments to increase our understanding of the role of A1 and A2A receptors in METH-induced behavior were designed by Kavanagh et al (2015), reporting that the initial METH-mediated rewarding effects may be tempered by A1 or A2A receptor activation in a model of rat selfadministration. They found that in Sprague-Dawley rats, the stimulation of A1 receptors using CPA reduced METH self-administration, and that the stimulation of both A1 and A2A receptors reduced METH-induced place preference (Kavanagh et al, 2015). These results suggest that, taking into account the antagonism of A1/D1 and A2A/D2 heteromers, both A1 and A2A agonists will be useful to reduce METH-induced behaviors during the initial exposures to METH but, when METH exposures are more prolonged, the modulation of Adenosine receptors (AR) renders only the A1 agonist powerful enough to counteract the rewarding properties of METH
This evidence, and the experiments reported in this review, will make A1 receptor signaling an important target for the development of novel pharmacological treatments for the common anxietylike disorders reported during the process of drug-seeking and withdrawal, and as such will produce lasting changes in relapse susceptibility
Summary
Drug addiction is a complex chronic cognitive disorder characterized by drug seeking and compulsive use, which is difficult to control despite its harmful consequences. According to DSM-5 (American Psychiatric Association, 2013), which is used to define mental disorders in epidemiologic studies, it is accepted that the criteria used to clinically define the terms abuse and dependence should be combined to form a new category known as Substance use disorders, including craving as a new criterion to increase diagnostic accuracy (Hasin et al, 2013). Drug addiction is currently a global health problem, as can be deduced from comparison of data obtained from the Global Burden of Diseases Study between 1990 and 2015. Psychostimulants are a broad class of drugs whose effects include increases in arousal, wakefulness, cardiovascular stimulation, vigilance, and attention, and which constitute one of the most abused classes of prohibited drugs in the world, including as representative examples cocaine and amphetaminelike molecules (Chesworth et al, 2016). According to the 2017 report of the European Monitoring Centre for Drugs and Drug Addiction (European Monitoring Centre for Drugs and Drug Addiction, 2017), it was estimated that in the year 2016, the global annual prevalence among Europeans aged 15 or over was 3.5 million users of cocaine, 2.7 million users of MDMA and 1.8 million users of amphetamines which corresponds to 1.0, 0.8, and 0.5% of the European adults, respectively, which occasional consumed mentioned psychostimulants during 2016
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