Chapter Fifteen - Involvement of Adenosine A2A Receptors in Depression and Anxiety

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Abstract

When administered to normal healthy patients, a nonselective adenosine A1/A2A antagonist, caffeine, tended to improve anxiety and depression at low doses and to exacerbate anxiety at high doses. Caffeine also appears to enhance anxiety-related symptoms in patients with panic disorder, and A2A receptor-deficient mice have been reported to exhibit higher anxiety-like behaviors, as well as a lower incidence of depression-like behaviors. Some selective A2A antagonists were reported to ameliorate anxiety-like behaviors in rodents, while others did not affect these behaviors. In addition, most A2A antagonists showed inhibitory effects on depression-like behaviors. The mechanisms underlying the relationship between A2A receptor antagonists and anxiety and depression remain unclear at the present time, although many studies have produced hypotheses. Given that a selective A2A receptor antagonist has recently become available for use in humans, research on the role of A2A receptors in the treatment of mental illness should progress in the near future.

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

References (106)

  • M.P. Kaster et al.

    Pharmacological evidence for the involvement of the opioid system in the antidepressant-like effect of adenosine in the mouse forced swimming test

    European Journal of Pharmacology

    (2007)
  • M.P. Kaster et al.

    Adenosine administration produces an antidepressant-like effect in mice: Evidence for the involvement of A1 and A2A receptors

    Neuroscience Letters

    (2004)
  • M.P. Kaster et al.

    Involvement of 5-HT1A receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test

    Brain Research Bulletin

    (2005)
  • A.L. Klatsky et al.

    Coffee, tea, and mortality

    Annals of Epidemiology

    (1993)
  • K. Koga et al.

    Adenosine A2A receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats

    European Journal of Pharmacology

    (2000)
  • P. Lam et al.

    Association study of A2a adenosine receptor genetic polymorphism in panic disorder

    Neuroscience Letters

    (2005)
  • U.E. Lang et al.

    Emotional instability but intact spatial cognition in adenosine receptor 1 knock out mice

    Behavioural Brain Research

    (2003)
  • W.H. Loke

    Effects of caffeine on mood and memory

    Physiology & Behavior

    (1988)
  • T. Maemoto et al.

    Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors

    Journal of Pharmacological Sciences

    (2004)
  • J.L. Moreau et al.

    Central adenosine A2A receptors: An overview

    Brain Research. Brain Research Reviews

    (1999)
  • E. Ongini et al.

    Pharmacology of adenosine A2A receptors

    Trends in Pharmacological Sciences

    (1996)
  • C.M. Pariante et al.

    The HPA axis in major depression: Classical theories and new developments

    Trends in Neurosciences

    (2008)
  • C.M. Pariante et al.

    Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment

    Biological Psychiatry

    (2001)
  • R.D. Prediger et al.

    Adenosine A1 receptors modulate the anxiolytic-like effect of ethanol in the elevated plus-maze in mice

    European Journal of Pharmacology

    (2004)
  • N. Rebola et al.

    Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses

    Neuron

    (2008)
  • J.D. Salamone et al.

    Differential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism

    Behavioural Brain Research

    (2009)
  • S.N. Schiffmann et al.

    Adenosine A2A receptors and basal ganglia physiology

    Progress in Neurobiology

    (2007)
  • A.D. Sherman et al.

    Specificity of the learned helplessness model of depression

    Pharmacology, Biochemistry, and Behavior

    (1982)
  • P. Svenningsson et al.

    Distribution, biochemistry and function of striatal adenosine A2A receptors

    Progress in Neurobiology

    (1999)
  • C.J. Wei et al.

    Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain

    Biological Psychiatry

    (2014)
  • H.U. Wittchen et al.

    The size and burden of mental disorders and other disorders of the brain in Europe 2010

    European Neuropsychopharmacology

    (2011)
  • K. Alsene et al.

    Association between A2a receptor gene polymorphisms and caffeine-Induced anxiety

    Neuropsychopharmacology

    (2003)
  • P. Barone

    Treatment of depressive symptoms in Parkinson's disease

    European Journal of Neurology

    (2011)
  • S.K. Bhattacharya et al.

    Anxiogenic action of caffeine: An experimental study in rats

    Journal of Psychopharmacology

    (1997)
  • J.P. Boulenger et al.

    Increased sensitivity to caffeine in patients with panic disorders. Preliminary evidence

    Archives of General Psychiatry

    (1984)
  • M.S. Bruce

    The anxiogenic effects of caffeine

    Postgraduate Medical Journal

    (1990)
  • D.S. Charney et al.

    Increased anxiogenic effects of caffeine in panic disorders

    Archives of General Psychiatry

    (1985)
  • J.F. Chen et al.

    A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice

    The Journal of Neuroscience

    (1999)
  • J. Chen et al.

    The type 1 equilibrative nucleoside transporter regulates anxiety-like behavior in mice

    Genes, Brain, and Behavior

    (2007)
  • A.R. Costenla et al.

    Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing

    European Journal of Neuroscience

    (2011)
  • J. Deckert et al.

    Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease

    Molecular Psychiatry

    (1998)
  • M.J. Diogenes et al.

    Activation of adenosine A2A receptor facilitates brain-derived neurotrophic factor modulation of synaptic transmission in hippocampal slices

    The Journal of Neuroscience

    (2004)
  • A.K. Dixon et al.

    Tissue distribution of adenosine receptor mRNAs in the rat

    British Journal of Pharmacology

    (1996)
  • R. Duster et al.

    Purinergic signaling and hippocampal long-term potentiation

    Current Neuropharmacology

    (2014)
  • M. El Yacoubi et al.

    Adenosine A2A receptors and depression

    Neurology

    (2003)
  • M. El Yacoubi et al.

    Adenosine A2A receptor antagonists are potential antidepressants: Evidence based on pharmacology and A2A receptor knockout mice

    British Journal of Pharmacology

    (2001)
  • M. El Yacoubi et al.

    The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A2A adenosine receptor antagonists

    Psychopharmacology

    (2000)
  • A.M. Farrar et al.

    Adenosine A2A receptor antagonism reverses the effects of dopamine receptor antagonism on instrumental output and effort-related choice in the rat: Implications for studies of psychomotor slowing

    Psychopharmacology

    (2007)
  • S. Ferré

    An update on the mechanisms of the psychostimulant effects of caffeine

    Journal of Neurochemistry

    (2008)
  • B.H. Flores et al.

    Clinical and biological effects of mifepristone treatment for psychotic depression

    Neuropsychopharmacology

    (2006)
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