Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets

Abstract

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

“…Although not yet tested, one can speculate that A 2A AR NAM could potentially counteract in a spatial-selective manner the tumor-increased adenosine immunosuppressive action. In the CNS, blockade of A 2A ARs is indicated, with varying degrees of preclinical and clinical evidence, as a promising therapeutic strategy for Parkinson's disease, supported by the recent approval of the antagonist istradefylline as add-on therapy (Chen and Cunha, 2020), but also for Alzheimer's disease (Merighi et al, 2022), acute brain dysfunction (Cunha, 2016), and some neuropsychiatric disorders such as fragile X syndrome, depression, and anxiety (Domenici et al, 2019).…”

“…In addition to the several physiological effects of adenosine, its receptor-mediated signaling has many documented effects on the progression of countless pathological states ( Karmouty-Quintana et al, 2013 ). Among the main ones, modulation of adenosine receptors has been indicated as a promising therapeutic strategy in pathological states such as cancer ( Vijayan et al, 2017 ; Allard et al, 2020 ), cardiovascular diseases ( Reiss et al, 2019 ), pain ( Vincenzi et al, 2020a ), neurological/neurodegenerative diseases ( Blum et al, 2018 ; Sebastião et al, 2018 ; Jenner et al, 2021 ; Merighi et al, 2021 ), neuropsychiatric disorders ( Pasquini et al, 2022 ), inflammatory diseases ( Pasquini et al, 2021 ; Antonioli et al, 2022 ), respiratory diseases ( Caruso et al, 2013 ), ocular diseases ( Spinozzi et al, 2021 ), diabetes, and other metabolic disorders ( Antonioli et al, 2015 ; Sanni and Terre’Blanche, 2021 ). Despite this encouraging profusion of experimental evidence, relatively few adenosinergic system-based drugs have so far achieved clinical approval.…”

The Purinergic System as a Target for the Development of Treatments for Bipolar Disorder

“…− indicates lower levels compared to healthy controls, = indicates equal levels compared to healthy controls, + indicates a subtle increase in levels compared to healthy controls, ++ indicates a moderate increase in levels compared to healthy controls, +++ indicates a high increase in levels compared to healthy controls, DA dopamine, ENT equilibrative nucleoside transporter, MDD major depressive disorder, NT5E ecto-5′-nucleotidase, PNP purine nucleoside phosphorylase, XO xanthine oxidase. Figure created with BioRender.com relevant hypothesis for psychiatric disorders [51][52][53], especially BD and schizophrenia [54][55][56].…”

Astrocytic Abnormalities in Schizophrenia

“…Excess shedding of ATP into the intercellular area from induced/injured nerve cells or abnormal purinergic signaling induces the nod-like receptor proteins (NLRPs) of inflammasomes in astrocytes/microglia [84]. A new review article details the involvement of aberrant purinergic signaling in the pathogenesis of SCZ, in addition to other neuropsychiatric disorders such as major depressive disorder, bipolar disorder, autism, anxiety, and attention-deficit/ hyperactivity disorders (ADHDs) [88]. Each of these conditions could be attributed to abnormalities in signaling from P1 and P2 receptors along with enzymes processing the metabolism of purinergic mediators.…”