Objective: Recent studies have identified a novel heterodimer involving the ghrelin receptor (GHS-R1A) and the 5-HT2C receptor, a subtype of serotonin receptors. Whether or not interactions between GHS-R1A and the 5-HT2C receptor exist and how they are modulated by photoperiod and nutritional status in seasonally animals remains unknown. The aims of this study were to determine the effects of ghrelin and a 5-HT2B/2C serotonin receptor agonist, 1-(3-chlorophenyl) piperazine hydrochloride (m-CPP), on GH and PRL secretion under the influence of nutritional status and photoperiod.Methods: Normally fed (n=12) or fasted (n=12) ewes were assigned to one of 4 groups and treatments: 1) control (saline); 2) ghrelin (2.5 μg/kg); 3) m-CPP (2.5 mg/kg); 4) ghrelin followed by m-CPP were infused once at the beginning of the study for groups 1, 2 and 3; in group 4, ghrelin was administered at 15 min, and m-CPP at 30 min. Blood samples were collected at 15-min intervals for 3 h during the short day (SD) and long day (LD) season.Results: Ghrelin and m-CPP enhanced (p<0.05) GH secretion in fasted ewes during LD. The m-CPP significantly decreased GH concentrations in fasted ewes during SD. Prolactin concentrations were lower (p<0.01) in normally fed ewes after the ghrelin + m-CPP treatment compared to treatment with m-CPP alone. Conclusion:There were interactions among ghrelin, serotonin, photoperiod and metabolic status that influenced GH and PRL secretion in ewes. Using an ovine model, our work provides a basis for future studies of the pathogenesis of metabolic disorders associated with alterations in nutritional status and day length.