Citalopram-induced decrease of CLOCK-ir and BMAL1-ir kisspeptin neurons in the anteroventral periventricular nucleus...

A complex network exists between the reproductive, circadian and the serotonergic system. Modulation of brain serotonin levels triggers sexual irregularities and alters circadian behaviour. This study investigated the presence of an endogeneous clock within kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC); and their modulation by a serotonin reuptake inhibitor, citalopram (CIT), in adult male mice. Treatment consisted of daily (chronic) intra-peritoneal administration of CIT (10 mg/kg) or saline for 4 weeks in adult male mice. Gene expression study using RT-PCR was conducted at two timepoints during the dark phase (ZT14) and the light phase (ZT4). Higher expression of Kiss1, Per1 and Per2 mRNA was observed at ZT14, anti-phase to Bmal1 mRNA showing higher expression at ZT4 in the AVPV. Morphological analysis confined to ZT14 showed the presence of CLOCK and BMAL1 proteins in kisspeptin neurons. Chronic CIT-treatment did not induce any change in Kiss1 mRNA expression in the AVPV. However, a significant reduction in CLOCK-ir and BMAL1-ir kisspeptin neurons was observed in CIT-treated male mice at ZT14 in the AVPV using double immunohistochemistry. In brief, a time-dependent expression of Per1, Per2 and Bmal1 exists in the AVPV and chronic CIT orchestrates a decrease in CLOCK-ir and BMAL1-ir kisspeptin neurons. These data suggests rhythmic imbalances in kisspeptin neurons as a potential mediator of reproductive irregularities.