Levels of lactogenic hormones, prolactin from the maternal anterior pituitary and/or the closely related placental lactogen, are elevated during pregnancy and lactation. While these hormones are well established to have an critical role in mammary development and lactogenesis, they also exert important actions in the brain. Prolactin receptors are expressed in the choroid plexus and in several hypothalamic nuclei, and we have shown that levels of expression increase during pregnancy and lactation. Prolactin is known to influence a variety of hypothalamic functions, including regulation tuberoinfundibular dopamine (TIDA) neurons, stress responses, appetite and food intake, and fertility (1). Many of these prolactin-sensitive functions appear to change during pregnancy in a manner consistent with the influence of prolactin. Two specific examples have been examined to evaluate the role of prolactin in mediating neuroendocrine adaptation in the maternal brain: a) Decreased sensitivity of TIDA neurons to prolactin, leading to decreased secretion of dopamine and subsequent hyperprolactinaemia. b) Increased food intake and the development of leptin-resistance during pregnancy. Both changes are important maternal adaptations to pregnancy, providing high prolactin for mammary development and maternal behaviou, and increased energy storage to meet the metabolic demands of lactation, respectively. Prolactin acts directly on prolactin receptors on TIDA neurons inducing phosphorylation of STAT5b and activation of tyrosine hydroxylase (TH, the rate limiting enzyme responsible for dopamine synthesis) and an increase in TH mRNA expression. We have measured mRNA for the long form of the prolactin receptor on TIDA neurons by in situ hybridisation and this does not change during pregnancy or lactation (2), although there is an increase in expression of met-enkephalin in prolactin-responsive TIDA neurons. Prolactin-induced phosphorylation of STAT5b in TIDA neurons is suppressed during lactation, associated with a prolactin- or suckling-dependent increase in mRNA for several endogenous inhibitors of STAT pathways (CIS, SOCS1 and SOCS3) (3). The data suggest that prolactin signal transduction in TIDA neurons is specifically altered during late pregnancy and lactation. Prolactin loses the ability to induce STAT5b phosphorylation, probably due to an upregulation of SOCS proteins. Consequently, TH activity and TH mRNA levels fall, resulting in decreased dopamine release into the portal blood and increased prolactin secretion. TIDA neurons continue to express prolactin receptors, however, and may respond to the elevated prolactin with an increase in met-enkephalin expression, which could result in further suppression of dopamine secretion. Appetite and food intake is increased during pregnancy, resulting in increased fat deposition and elevated leptin secretion. Despite high leptin levels, the increased food intake is maintained during pregnancy, suggesting leptin resistance. These changes are physiologically appropriate, providing increased energy reserves to help meet the high metabolic demands of fetal development and lactation. We have demonstrated that intracerebroventricular (i.c.v.) leptin is unable to suppress food intake in pregnant rats, as it does in non-pregnant animals (4). In addition, we have shown a specific suppression of leptin-induced phosphorylation of STAT3 (pSTAT3) in specific regions of the hypothalamus during pregnancy (5). To investigate the mechanism underlying this pregnancy-induced leptin resistance, we have investigated effects of hormone treatments on hypothalamic responses to leptin in a pseudopregnant rat model. Pseudopregnant rats were hyperphagic but did not become leptin resistant, even when given progesterone implants to extend pseudopregnancy beyond the time that resistance develops during pregnancy. Chronic i.c.v. infusion of ovine prolactin to mimic patterns of placental lactogen secretion characteristic of pregnancy, however, completly blocked the ability of leptin to suppress food intake. These data suggest that placental lactogen secretion may mediate the hormone-induced loss of response to leptin. Thus, prolactin appears to be implicated in two of the major neuroendocrine adaptations in the maternal brain, consistent with the hypothesis that prolactin acts as an important afferent signal of the pregnant state, mediating a range of adaptive responses in the maternal brain. Acknowledgements: This research was supported by the Royal Society of New Zealand Marsden FundReference 1 : Grattan D.R. Behavioural significance of prolactin signalling in the central nervous system during pregnancy and lactation. Reproduction 123, 497-506 (2002)Reference 2 : Kokay I.C. and Grattan D.R. Expression of mRNA for prolactin receptor (long form) in dopamine and pro-opiomelanocortin neurons in the arcuate nucleus of non-pregnant and lactating rats Journal of Neuroendocrinology 17, 827-835 (2005)Reference 3 : Anderson GM, Beijer P, Bang AS, Fenwick MA, Bunn SJ, Grattan DR. Suppression of Prolactin-induced STAT5b Signaling and Induction of SOCS mRNA in the Hypothalamic Arcuate Nucleus of the Rat During Late Pregnancy and Lactation. Endocrinology 147, 4996-5005, (2006)Reference 4 : Ladyman S.R. and Grattan D.R. Region specific reduction in leptin-induced phosphorylation of STAT3 in the rat hypothalamus is associated with leptin resistance during pregnancy. Endocrinology 145, 3704-3711 (2004)Reference 5 : Ladyman S.R. and Grattan D.R. Suppression of leptin receptor mRNA and leptin responsiveness in the ventromedial nucleus of the hypothalamus during pregnancy in the rat. Endocrinology 146, 3868-3874 (2005)