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1.
Nat Commun ; 14(1): 1880, 2023 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-37019936

RESUMEN

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.


Asunto(s)
Trastorno Depresivo Mayor , Habénula , Ratones , Animales , Masculino , Habénula/fisiología , Adenosina/farmacología , Neuronas/metabolismo , Hipotálamo/metabolismo , Receptor de Adenosina A2A/metabolismo
2.
Neuropharmacology ; 144: 122-132, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30336152

RESUMEN

Insomnia is one of the most common sleep problems with an estimated prevalence of 10%-15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.


Asunto(s)
Agonistas del Receptor de Adenosina A2/farmacología , Hipnóticos y Sedantes/farmacología , Sueño de Onda Lenta/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/síntesis química , Regulación Alostérica , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Temperatura Corporal/efectos de los fármacos , Células CHO , Cricetulus , Evaluación Preclínica de Medicamentos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fenetilaminas/farmacología , Distribución Aleatoria , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/metabolismo , Transducción de Señal/efectos de los fármacos , Sueño de Onda Lenta/fisiología , Vigilia/efectos de los fármacos , Vigilia/fisiología
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