Neonatal SSRI Exposure Programs a Hypermetabolic State in Adult Mice

Abstract

Background. Selective serotonin reuptake inhibitor (SSRI) therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods. C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d) from P1–P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2) expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX). Metabolic rate was determined by indirect calorimetry. Results. In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions. SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome.