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Notes: The hypothalamic mechanisms which underlie the development of the fetal neuroendocrine system are unclear. However, in adult animals neuroactive amino-acids, particularly those acting at the N-methyl-D-aspartate (NMDA) receptor, have been shown to be important transmitters involved in the neuroendocrine regulation of the anterior pituitary gland. In this study we have investigated the potential role of NMDA in the neuroendocrine regulation of fetal pituitary function, by examining the ontogeny of LH and ACTH responses to NMDA during fetal development in sheep. Catheterized fetal sheep were injected with 3 intravenous doses of NMDA (1, 2 and 4 mg/kg; estimated fetal body weight) and saline vehicle on consecutive days between days 110–115, 120–125 and 135–140 gestation (term=145 days). At each gestational age fetuses also received a pituitary challenge test consisting of CRF (0.4 μg/kg), AVP (80 ng/kg) and GnRH (125 ng/kg). NMDA caused a significant dose-related increase in ACTH at day 120–125 (P〈0.02) and day 135–140 gestation (P〈0.001). NMDA had no effect on ACTH secretion at day 110–115. The ACTH response to the highest does of NMDA (4 mg/kg) increased with advancing gestational age, in contrast to the ACTH response to CRF+AVP which was the same at all ages. NMDA caused a significant increase in LH secretion at all gestational ages with the greatest response observed at the latest gestational age studied (day 135–140). A similar increase in LH response to the GnRH challenge was observed late in gestation. Pretreatment of fetuses with the competitive NMDA antagonist CGP37849 (1 mg/kg) abolished the LH and ACTH responses to an intravenous injection of NMDA (4 mg/kg) given 5 min later. These data show that activation of NMDA receptors during fetal development elicits the secretion of ACTH and LH and demonstrate that NMDA receptors are functionally coupled to the neuroendocrine pathways regulating these two hormones during fetal life. The dramatic increase in ACTH repsonse to NMDA during the final days before birth occurs at a time of high adrenocortical activity and suggests an important functional role for these receptors at this time.