Papel da exposição neonatal a bromocriptina (agonista dopaminérgico tipo 2) sobre o perfil hormonal e metabólico de ratos

Abstract

The maternal prolactin inhibition at the end of lactation, using bromocriptine (BRO), increases the leptin transfer through the milk and causes hyperleptinemia and malnutrition in the pups at weaning (PN21), while at adulthood (PN180) leads to higher visceral fat, dyslipidemia, leptina and insulin resistance, hypothyroidism, hypoprolactinemia, hypercorticosteronemia and increase of catecholamine adrenal content, hypothalamic NPY and anxiety. Since it is known that some of these changes are found in the model of neonatal hyperleptinemia, it is possible that these changes are associated with the higher leptin transfer via milk. Also, we cannot discard the fact that BRO is transferred through the milk. Thus, our first aim (Experiment 1) was to evaluate in the maternal hypoprolactin model, the presence of a second peak of leptin at PN30, as already showed in the model of neonatal hyperleptinemia. The second aim of our research (Experiment 2) was to evaluate the long-term effects of the BRO, directly injected in the pups. Experiment 1: lactating rats were treated with bromocriptine (BRO), 0.5mg twice a day or methanol-saline (CON) during the last 3 days of lactation. The animals was killed on PN22 and PN30. Experiment 2: male rats received BRO, 0.1g once daily, (BRO) or methanol-saline (CON), from postnatal day 1 to 10 or from postnatal day 11 to 20, the animals was killed on PN180. The animals of experiment 1 showed at PN22 lower body mass, food intake, glycemia and leptin mRNA expression, and higher hypothalamic leptin sensitivity. At PN30 the animals showed lower body lenght and mesenteric fat, but with more leptin mRNA expression in this tissue, hyperleptinemia, hyperglycemia, higher plasma and hepatic cholesterol, and lower HDL-c. The animals of experiment 2 that received BRO at PN1-10, showed at PN180 lower food intake, hypoprolactinemia, higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) content in the VTA, higher Dopa Decarboxylase (DDc), D2R and u-Opioid receptor in the NAc, besides more anxiety. Lower leptin action, lower TRH, TSH, T3, Dio1, mGPD and UCP-1 were also detected. The animals the received BRO at PN11-20, showed at adulthood, higher food intake and hyperprolactinemia, higher blood pressure, hypercorticosteronemia, lower POMC in the ARC, lower TH in the VTA and lower dopamine transporter (DAT) in the NAc, besides less anxiety, higher OBR-b, TRH, T3, higher Dio2, mGPD and UCP1. In conclusion, similar to the hyperleptinemia model, the secondary peak of leptin at PN30 suggests a crucial role of leptin as an imprinting factor in the model of maternal hypoprolactinaemia. The direct BRO exposure during neonatal life is deleterious, inducing metabolic and hormone disorders as well as dopaminergic and behavior dysfunction, which are dependent on the period of development in which the insult is caused.