Chapter Fifteen - Involvement of Adenosine A2A Receptors in Depression and Anxiety
Introduction
In this stressful contemporary society, the number of patients suffering from psychiatric disorders grows with each passing year. As a result, mental illness has become one of the biggest problems in advanced nations because of the misery of the patients and the large economic burden associated with it (Olesen et al., 2012, Wittchen et al., 2011). Although there are some therapeutic drugs for mental illnesses, it is difficult to say that we can manage these conditions adequately. Therefore, alternative therapeutic options must be developed. Meanwhile, the literature on neuropsychopharmacology increasingly suggests a relationship between mental illness and the modulation of adenosinergic signal transductions in the central nervous system. In particular, depression and anxiety seem to be connected to this modulation, but, up until recently, there have been no agonists or antagonists of adenosine receptors in the brain to serve as potential therapeutic agents.
In 2013, istradefylline was approved as the antiparkinsonian agent in Japan. This is the first therapeutic agent targeting adenosine A2A receptors in the central nervous system, and other candidates for A2A antagonists have emerged in clinical studies. Therefore, in this review, the adenosine receptor-mediated effects on anxiety and depression are summarized, with a focus on the A2A subtype, in order to evaluate whether adenosinergic agents might have therapeutic risks and benefits in the treatment of these disorders.
Section snippets
Effects of coffee
The molecular targets of caffeine (1,3,7-trimethylxanthine) at physiological concentrations (i.e., by daily coffee drinking) are considered to be the adenosine A1 and A2A receptors, where caffeine acts as a competitive antagonist, although the agent is also known as a nonselective phosphodiesterase inhibitor at concentrations higher than the physiological conditions (Ferré, 2008). Consequently, caffeine use can provide valuable insights into the effects of adenosine and its possible modulation
Effect of caffeine
From the epidemiological point of view, it remains unclear whether the habit of drinking coffee or caffeine-intake affects depression-like conditions. An analysis of medical histories of 3600 adult twins failed to show significant associations between lifelong consumption and lifetime histories of various psychiatric disorders including major depression (Kendler, Myers, & Gardner, 2006). In hospitalized adult psychiatric patients, high caffeine consumers tended to have higher scores on some
Sites of the actions
Adenosine A2A receptors are abundantly expressed in striatum of the basal ganglia (Rosin et al., 1998, Svenningsson et al., 1999). By blocking receptors in this brain region, A2A receptor antagonists are expected to improve the motor symptoms in patients with Parkinson's disease (Mori & Shindou, 2003). Depression model rats, which were subjected to unpredictable chronic mild stress for 40 days, presented an increase in A2A receptor binding in the striatum (Crema et al., 2013). Therefore, the
Conclusion
Recently, istradefylline became the first therapeutic agent targeting adenosine A2A receptors, and other compounds with a similar mechanism will be available in near future. Therefore, it is important to investigate the effects of the A2A receptor's modulation on anxiety and depression, given their high complication rate with Parkinson's disease (Reijnders, Ehrt, Weber, Aarsland, & Leentjens, 2008). Further studies using animal models would clarify the potential risks and benefits of A2A
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