In utero manipulation of melatonin significantly alters hippocampal gene expression and behavior in adulthood (910.8)

Abstract

Recent studies indicate that disturbances in melatonin—the neurohormone that signals darkness—have been implicated in the etiology and pathophysiology of various mental disturbances in humans. Research on developmental outcomes for fetuses of mothers receiving melatonin supplementation or drugs that reduce melatonin signaling during pregnancy is lacking. We hypothesized that administration of melatonin (5 mg/kg) or the melatonin receptor antagonist luzindole (5 mg/kg) to pregnant Sprague‐Dawley dams during days 14‐18 of gestation would elicit long‐term changes in hippocampal gene expression and behavior in adult offspring. Our results show that prenatal exposure to luzindol significantly alters adult male rat behavior in the open field test. Although treatment did not have a significant impact on time spent in the center of the arena, significant effects were observed for total distance traveled [increased; P=0.014], time inactive [increased; P=0.010], time rearing [decreased; P=0.020], time grooming [increased; P=0.007], and number of fecal boli produced [increased; P=0.022] compared to control offspring. RT‐PCR analysis of adult hippocampal gene expression revealed a significant increase in brain‐derived neurotrophic factor (BDNF) expression with a trend toward increased expression of melatonin 1A receptors (MEL1A) in melatonin‐exposed animals compared to controls. Moreover, prenatal treatment increased expression of microtubule‐associated protein 2 (MAP2), a dendritic marker, in luzindole‐treated animals compared to controls. A significant expression change was also detected in the expresson of muscle aryl hydrocarbon receptor translocator (BMAL‐1), a clock‐gene regulator, in both the melatonin‐ as well as the luzindole‐treated offspring. These data support our hypothesis that manipulation of maternal melatonin level alters brain development and leads to physiological and behavioral perturbations in adulthood.