Abstract:Background: Insomnia is associated with psychiatric illnesses such as bipolar disorder or schizophrenia. Treating insomnia improves psychotic symptoms severity, quality of life, and functional outcomes. Patients with psychiatric disorders are often dissatisfied with the available therapeutic options for their insomnia. In contrast, positive allosteric modulation of adenosine A2A receptors (A2ARs) leads to slow-wave sleep without cardiovascular side effects in contrast to A2AR agonists.Methods: We investigated … Show more
“…We did not analyze other behaviors after photoactivation of the A 2A RPAM-1 in the NAc because A 2A RPAM-1, likely due to its sleep-inducing properties, strongly suppresses behaviors such as risk-taking in an open field test in WT as well as in microtubule-associated protein 6 (MAP6) KO mice (Supplementary Fig. 9 , unpaired Mann-Whitney test), a genetic mouse model of schizophrenia/psychosis 10 , 27 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Male C57BL/6, A 2A R KO 53 , vesicular γ-aminobutyric acid transporter-Cre 54 , and MAP6 KO 10 mice (10–15 weeks of age, 24–30 g) used in the experiments were maintained at the International Institute for Integrative Sleep Medicine and housed in insulated sound-proof chambers maintained at an ambient temperature of 23 ± 0.5 °C with 50 ± 5% humidity on a 12-h light/dark cycle (lights on at 8:00, illumination intensity ≈ 100 lux). Food and water were provided ad libitum .…”
Section: Methodsmentioning
confidence: 99%
“…The development of adenosine analogs as A 2A R agonists for treating CNS disorders is impeded, however, by poor to non-existent drug transport across the BBB and peripheral side effects such as cardiovascular impairment 8 . We previously developed a positive allosteric modulator (PAM) of A 2A Rs (A 2A RPAM-1) that induces slow-wave sleep (SWS) without affecting cardiovascular function, unlike classic A 2A R agonists 9 , 10 . The nucleus accumbens (NAc) is a novel region for SWS regulation that integrates motivational stimuli 11 .…”
Optochemistry, an emerging pharmacologic approach in which light is used to selectively activate or deactivate molecules, has the potential to alleviate symptoms, cure diseases, and improve quality of life while preventing uncontrolled drug effects. The development of in-vivo applications for optochemistry to render brain cells photoresponsive without relying on genetic engineering has been progressing slowly. The nucleus accumbens (NAc) is a region for the regulation of slow-wave sleep (SWS) through the integration of motivational stimuli. Adenosine emerges as a promising candidate molecule for activating indirect pathway neurons of the NAc expressing adenosine A2A receptors (A2ARs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A2ARs (A2AR PAM) that can be rapidly photoactivated with visible light (λ > 400 nm) and used it optoallosterically to induce SWS in the NAc of freely behaving male mice by increasing the activity of extracellular adenosine derived from astrocytic and neuronal activity.
“…We did not analyze other behaviors after photoactivation of the A 2A RPAM-1 in the NAc because A 2A RPAM-1, likely due to its sleep-inducing properties, strongly suppresses behaviors such as risk-taking in an open field test in WT as well as in microtubule-associated protein 6 (MAP6) KO mice (Supplementary Fig. 9 , unpaired Mann-Whitney test), a genetic mouse model of schizophrenia/psychosis 10 , 27 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Male C57BL/6, A 2A R KO 53 , vesicular γ-aminobutyric acid transporter-Cre 54 , and MAP6 KO 10 mice (10–15 weeks of age, 24–30 g) used in the experiments were maintained at the International Institute for Integrative Sleep Medicine and housed in insulated sound-proof chambers maintained at an ambient temperature of 23 ± 0.5 °C with 50 ± 5% humidity on a 12-h light/dark cycle (lights on at 8:00, illumination intensity ≈ 100 lux). Food and water were provided ad libitum .…”
Section: Methodsmentioning
confidence: 99%
“…The development of adenosine analogs as A 2A R agonists for treating CNS disorders is impeded, however, by poor to non-existent drug transport across the BBB and peripheral side effects such as cardiovascular impairment 8 . We previously developed a positive allosteric modulator (PAM) of A 2A Rs (A 2A RPAM-1) that induces slow-wave sleep (SWS) without affecting cardiovascular function, unlike classic A 2A R agonists 9 , 10 . The nucleus accumbens (NAc) is a novel region for SWS regulation that integrates motivational stimuli 11 .…”
Optochemistry, an emerging pharmacologic approach in which light is used to selectively activate or deactivate molecules, has the potential to alleviate symptoms, cure diseases, and improve quality of life while preventing uncontrolled drug effects. The development of in-vivo applications for optochemistry to render brain cells photoresponsive without relying on genetic engineering has been progressing slowly. The nucleus accumbens (NAc) is a region for the regulation of slow-wave sleep (SWS) through the integration of motivational stimuli. Adenosine emerges as a promising candidate molecule for activating indirect pathway neurons of the NAc expressing adenosine A2A receptors (A2ARs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A2ARs (A2AR PAM) that can be rapidly photoactivated with visible light (λ > 400 nm) and used it optoallosterically to induce SWS in the NAc of freely behaving male mice by increasing the activity of extracellular adenosine derived from astrocytic and neuronal activity.
“…The compound, named A 2A RPAM-1, was found to effectively alleviate insomnia linked to mania- or schizophrenia-like behaviors in mice. Unlike diazepam, it did not lead to abnormal sleep patterns [ 95 ]. Furthermore, activating A 2A ARs in the olfactory tubercle promoted NREM sleep [ 96 ].…”
Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets.
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