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

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.