JPP 2008, 60: 1409–1430 ß 2008 The Authors Received February 19, 2008 Accepted June 11, 2008 DOI 10.1211/jpp/60.11.0001 ISSN 0022-3573 Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, 3052, Australia Robyn M. Brown, Jennifer L. Short Correspondence: J. L. Short, Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, 3052, Australia. E-mail: jennifer.short@vcp.monash.edu.au Review Adenosine A 2A receptors and their role in drug addiction Robyn M. Brown and Jennifer L. Short Abstract The specific events between initial presumably manageable drug intake and the development of a drug- addicted state are not yet known. Drugs of abuse have varying mechanisms of action that create a complex pattern of behaviour related to drug consumption, drug-seeking, withdrawal and relapse. The neuromodulator adenosine has been shown to play a role in reward-related behaviour, both as an independent mediator and via interactions of adenosine receptors with other receptors. Adenosine levels are elevated upon exposure to drugs of abuse and adenosine A 2A receptors are enriched in brain nuclei known for their involvement in the processing of drug-related reinforcement processing. A 2A receptors are found in receptor clusters with dopamine and glutamate receptors. A 2A receptors are thus ideally situated to influence the signalling of neurotransmitters relevant in the neuronal responses and plasticity that underlie the development of drug taking and drug-seeking behaviour. In this review, we present evidence for the role of adenosine and A 2A receptors in drug addiction, thereby providing support for current efforts aimed at developing drug therapies to combat substance abuse that target adenosine signalling via A 2A receptors. Introduction Adenosine and drug reinforcement The role of adenosine in the mediation of withdrawal and the consequences of abstinence following drug taking has been known for over 30 years. Adenosine is ubiquitous, being found throughout the central nervous system (CNS), and is responsible for mediating a myriad of often subtle but influential effects. Early research discounted the role of adenosine, other than as a metabolite of adenosine triphosphate (ATP) and cyclic adenosine monophosphate (cAMP); however, the importance of adenosine as a modulator of neurotransmission and complex behaviour is now beyond doubt. In this review, we focus upon the role of adenosine, the A 2A receptor and A 2A receptor interactions in the positive aspects of drug-seeking and consumptive behaviour modelled in mice and rats, and we will be restricting our discussion to ethanol, opiates and psychostimulants. Drugs of abuse and neuronal reward mechanisms Worldwide, the consequences of drug addiction are substantial. Substance abuse (alcohol, tobacco and illicit drugs) was estimated to account for 12.4% of deaths in 2000 (WHO 2008). Drug abuse has a significant impact on society, with reduced economic, health and social outcomes, but the concept of drug addiction as a treatable brain disease is progressing (Volkow & Li 2005). The World Health Organization estimates that for every dollar spent on drug treatment across the world, 7 dollars are saved. While some currently available therapies have experienced moderate success, there are issues, such as the development of tolerance, limited efficacy in some individuals, inconvenient formulation and dosing regimes, abuse liability and adverse side effects, that make these therapies less than ideal. The drawbacks of existing therapies impact upon completion rates or restrict the use of these interventions to specific subpopulations of drug-addicted individuals. Continuing research is therefore required to identify new therapeutic targets that have the potential to overcome these drawbacks. Drugs of abuse appropriate the neuronal mechanisms that evolved to reinforce conventional reinforcers such as food and water intake and sexual and maternal behaviour (Nestler & Landsman 2001). Accepted theories differ with respect to the processes mediated via the mesolimbic dopaminergic system, although most investigators are in agreement regarding the 1409 Downloaded from https://academic.oup.com/jpp/article/60/11/1409/6141785 by guest on 25 June 2022