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bioRxiv · 10.64898/2026.01.05.697635

Differential Effects of 5-HT7 Receptor Signaling in the Noradrenergic System in a Rat Model of Treatment-Resistant Depression

Bruzos-Cidon, C.·Llamosas, N.·Bengoetxea, H.·Lafuente, J. V.·Ugedo, L.·Torrecilla, M.
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Abstract

IntroductionTreatment-resistant depression (TRD) is a major clinical challenge, and its neurobiological basis remains unclear. The locus coeruleus (LC), a key noradrenergic hub, shows altered activity in TRD models, and serotonergic 5-HT7 receptors have emerged as potential modulators of this circuit. MethodsWe assessed the impact of 5-HT7 receptor activation on LC function in Wistar Kyoto rats, an established TRD model, using in vivo extracellular recordings, in vitro patch-clamp assays, and receptor expression analysis. ResultsSystemic administration of AS19, a selective 5-HT7 receptor agonist, increased LC neuronal firing in both strains, with a significantly greater effect in Wistar Kyoto rats. This response was prevented by a 5-HT7 antagonist confirming receptor specificity. Glutamatergic blockade altered AS19 effects in a strain-dependent manner, whereas in vitro assays revealed no differential postsynaptic modulation and similar presynaptic inhibition across groups. Western blot analysis showed elevated 5-HT7 receptor expression in the LC, ventral hippocampus, and amygdala of Wistar Kyoto rats, alongside reduced expression in the prefrontal cortex. ConclusionThese findings indicate that 5-HT7 receptor activation exerts complex, circuit-dependent modulation of LC activity, influenced by glutamatergic and serotonergic inputs. Enhanced receptor expression in limbic regions and altered LC responsiveness may contribute to TRD pathophysiology and highlight 5-HT7 signaling as a promising target for novel therapeutic strategies.

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Bruzos-Cidon, C., Llamosas, N., Bengoetxea, H., Lafuente, J. V., Ugedo, L., Torrecilla, M.. 2026-01-05. Differential Effects of 5-HT7 Receptor Signaling in the Noradrenergic System in a Rat Model of Treatment-Resistant Depression. https://doi.org/10.64898/2026.01.05.697635

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