Potential Therapeutic Interest of Adenosine A2A Receptors in Psychiatric Disorders

Abstract

The interest on targeting adenosine A 2A receptors in the realm of psychiatric diseases first arose based on its tight physical and functional interaction with dopamine D 2 receptors. However, the role of central A 2A receptors is now viewed as much broader than just controlling D 2 receptor function. Thus, there is currently a major interest in the ability of A 2A receptors to control synaptic plasticity at glutamatergic synapses. This is due to a combined ability of A 2A receptors to facilitate the release of glutamate and the activation of NMDA. Therefore, A 2A receptors are now conceived as a normalizing device promoting adequate adaptive responses in neuronal circuits, a role similar to that fulfilled, in essence, by dopamine. This makes A 2A receptors a particularly attractive target to manage psychiatric disorders since adenosine may act as go-between glutamate and dopamine, two of the key players in mood processing. Furthermore, A 2A receptors also control glia function and brain metabolic adaptation, two other emerging mechanisms to understand abnormal processing of mood, and A 2A receptors are an important player in controlling the demise of neurodegeneration, considered an amplificatory loop in psychiatric disorders. Current data only provide an indirect confirmation of this putative role of A 2A receptors, based on the effects of caffeine (an antagonist of both A 1 and A 2A receptors) in psychiatric disorders. However, the introduction of A 2A receptors in clinics as antiparkinsonian agents is hoped to bolster our knowledge on the role of A 2A receptors in mood disorders in the near future.

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

“…The adenosinergic system can affect the efficiency of synaptic transmission and neurotransmitter release through a combined activation of inhibitory adenosine A 1 receptors and facilitatory adenosine A 2A receptors in neuronal circuits [28,29]. There is a growing body of evidence suggesting that these adenosine receptors could be promising therapeutic targets in a wide range of conditions, including neurodegenerative and psychiatric disorders such as major depression [30][31][32][33][34].…”

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

“…Both receptors have a role in miscellaneous biological processes, particularly the cAMPprotein kinase A signaling cascade and the fine-tuning of glutamatergic information flow (Schiffmann et al, 2007;van Calker and Biber, 2005). They are considered to be modulators of glial function, neuronal communication and neuronal activity, and to be involved in sleep and arousal, and cognition, as well as different psychiatric disorders, including anxiety and other mood disorders (Ribeiro et al, 2003;Cunha et al, 2008;Freitag et al, 2010). In mice, genetic knockout of adenosine A 1 or A 2A receptors has been linked to increased anxiety (Ledent et al, 1997;Johansson et al, 2001), implicating the corresponding genes or, more precisely, polymorphisms within these genes, as promising candidates for increased anxiety reactions.…”

Synthesis and hypoglycemic activity of some new theophylline derivatives

“…These compounds proved to be the most active members in our study. 16,17,22,23,26, 29 and 30 showed 20-37% reduction in serum glucose level. Structureactivity correlation among this series showed that the type of phthalimide and/or benzamide functionality is crucial for activity as presented by compound 24 (theophylline-diimide 56%) Figure 1.…”

“…Fundamental signs of diabetes mellitus such as hyperglycemia, loss of body weight, polyphagia and polydipsia were induced in rats by injection of streptozotocin [17][18][19] . Subsequently, animals were treated with the compounds under test and glibenclamide as a positive control.…”

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