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bioRxiv · 10.64898/2026.04.30.721903

Alcohol and Opioids Modulate Excitatory Inputs to the SCN

Purvines, W. W.·Vierkant, V. V. M.·Westbo, P.·Wang, X.·Jones, J.·Earnest, D.·Wang, J.
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Abstract

BackgroundDisturbance of circadian rhythms is a hallmark of substance use disorders, with depressant drugs often causing soporific effects such as reduced sleep latency. The suprachiasmatic nucleus (SCN) of the hypothalamus is the central circadian pacemaker in mammals, regulating daily rhythms in physiology and behavior. However, the cellular mechanisms through which depressants alter SCN function remain poorly defined. MethodsWe used whole-cell patch clamp electrophysiology in acute brain slices to examine how alcohol and opioids modulate excitatory glutamatergic transmission onto SCN neurons. Ethanol effects were examined both acutely and following chronic exposure paradigms. Optogenetic stimulation was used to activate either RHT input or -opioid receptor-expressing (MOR) terminals, and MOR agonists were used to assess opioid-mediated effects on synaptic transmission. ResultsWe show that acute application of ethanol paradoxically enhances SCN firing rates. In contrast, chronic alcohol exposure reduces glutamatergic drive. We also found that activating MOR+ terminals produced bidirectional modulation of SCN firing and that MOR+ inputs formed functional glutamatergic synapses onto SCN neurons. Notably, this transmission could be suppressed by the MOR agonists DAMGO and fentanyl. ConclusionsTogether, these findings reveal that both alcohol and opioids modulate glutamatergic input to the SCN. This work establishes the SCN as a novel target of depressant substances and highlights glutamatergic transmission as a key point of vulnerability in circadian dysregulation associated with substance use.

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Purvines, W. W., Vierkant, V. V. M., Westbo, P., Wang, X., Jones, J., Earnest, D., Wang, J.. 2026-05-04. Alcohol and Opioids Modulate Excitatory Inputs to the SCN. https://doi.org/10.64898/2026.04.30.721903

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