Potential Therapeutic Interest of Adenosine A2A Receptors in Psychiatric Disorders

Rodrigo   A.   Cunha; Sergi      Ferre; Jean-Marie      Vaugeois; Jiang-Fan      Chen

Abstract

The interest on targeting adenosine A2A receptors in the realm of psychiatric diseases first arose based on their tight physical and functional interaction with dopamine D2 receptors. However, the role of central A2A receptors is now viewed as much broader than just controlling D2 receptor function. Thus, there is currently a major interest in the ability of A2A receptors to control synaptic plasticity at glutamatergic synapses. This is due to a combined ability of A2A receptors to facilitate the release of glutamate and the activation of NMDA receptors. Therefore, A2A 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 A2A receptors particularly attractive targets to manage psychiatric disorders since adenosine may act as go-between glutamate and dopamine, two of the key players in mood processing. Furthermore, A2A receptors also control glia function and brain metabolic adaptation, two other emerging mechanisms to understand abnormal processing of mood, and A2A receptors are important players 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 A2A receptors, based on the effects of caffeine (an antagonist of both A1 and A2A receptors) in psychiatric disorders. However, the introduction of A2A receptors antagonists in clinics as anti-parkinsonian agents is hoped to bolster our knowledge on the role of A2A receptors in mood disorders in the near future.

Keywords: Adenosine, A2A receptor, caffeine, mood disorders, psychiatric diseases, anxiety, depression, schizophrenia, attention deficit hyperactivity disorder, ADHD