Agomelatine normalizes region-specific, diurnal mGluR5 dysregulation in a chronic mild stress rat model of depression

Desynchronization of circadian rhythms is a hallmark of major depressive disorder (MDD). Agomelatine is an atypical antidepressant that acts as a melatonin receptor agonist and serotonin receptor antagonist. It has shown efficacy in alleviating symptoms of MDD with a favorable side effect profile. In the brain, agomelatine also modulates the glutamatergic system and in the present study, we investigated the effects of chronic mild stress (CMS) and agomelatine treatment on metabotropic glutamate receptor 5 (mGluR5) and synaptic vesicle glycoprotein 2 A (SV2A) binding in the medial prefrontal cortex (mPFC) and hippocampus (HP) in postmortem brain tissue derived from male rats using autoradiography. To account for diurnal influences, assessments were conducted at two time points: light-on (ZT6) and light-off (ZT18). The sucrose consumption test classified animals into four groups: Control, anhedonic-like, agomelatine responders, and non-responders. CMS increased mGluR5 binding in the prelimbic cortex of the mPFC during the light-on phase, an effect that was normalized by agomelatine treatment in responder rats. Agomelatine also reduced mGluR5 binding in the infralimbic cortex of the mPFC. No changes in mGluR5 binding were detected during the light-off phase or in the HP at either time point. Presynaptic density, assessed by SV2A levels, remained unchanged across all groups and time points. These findings reveal significant region-specific and diurnal alterations in mGluR5, emphasizing the role of time-of-day dependent timing in regulating mGluR5 and its association with depressive-like behaviors. Furthermore, the selective normalization of mGluR5 by agomelatine in responders reinforces its potential as a targeted therapeutic approach for MDD.