Adenosine Signaling: Convergent Mechanisms for Rapid Antidepressants. (IMAGE)
Caption
Adenosine Signaling: Convergent Mechanisms for Rapid Antidepressants. Three distinct interventions—ketamine (pharmacological), electroconvulsive therapy/ECT (electrical), and acute intermittent hypoxia/aIH (physiological)—converge on a common mechanism: adenosine surges in the medial prefrontal cortex (mPFC). Ketamine triggers adenosine release through metabolic modulation (decreased ATP/ADP ratio) and ENT1/2-mediated efflux, without causing neuronal hyperactivity. ECT produces adenosine surges via neuronal hyperactivity and rapid metabolic demand. aIH generates adenosine through controlled hypoxia in a non-invasive manner. All three interventions activate A1 and A2A adenosine receptors in the mPFC, detected in real-time using fiber photometrywith genetically encoded sensors (GRABAdo1.0). This adenosine signaling triggers downstream synaptic plasticitymechanisms (BDNF upregulation,mTOR activation, neuroplasticity), resulting in rapid antidepressant effects with onset in hours and duration lasting days. Clinical Considerations: The adenosine mechanism raises important questions about caffeine consumption patterns. Tonic signaling (chronic/baseline coffee consumption) appears protective against depression and may help prevent depressive episodes. Phasic signaling (acute pre-treatment coffee) raises mechanistic concerns about potential interference with the adenosine surge during ketamine/ECT administration, though this remains speculative and requires clinical validation. The dual nature of caffeine’s effects—protective chronically, potentially interfering acutely—reflects the distinction between tonic baseline adenosine receptor modulation and phasic adenosine surge responses to rapid-acting treatments.
Credit
Julio Licinio
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License
CC BY