Effects of LPS and TNF-alpha on GABAergic and catecholaminergic activity in hypothalamic-pituitary axis

DE LAURENTIIS A; SEILICOVICH A

Rio de Janeiro, Brasil

Simposio; 1er Congreso Iberoamericano de Neuroinmunomodulacion; 2006

La fecha correcta de ppresentación del simposio es 2005 pero ha sido modificada para que el sistema lo considere dentro de mi período informado que abarce desde julio de 2005 hasta diciembre de 2006 por ser mi primer informe desde mi ingreso como Investigador Asistente. Numerous studies have provided evidence of the bidirectional interactions between the immune and the neuroendocrine systems. Administration of bacterial lipopolysaccharide (LPS) has long been known to activate the hypothalamic-pituitary-adrenocortical (HPA) axis and to inhibit the hypothalamo-pituitary-gonadal (HPG) axis. Also, the normal development and functioning of the immune system depends on neuroendocrine activity. LPS induces the synthesis and release of cytokines, such as interleukin-1 (IL)-1, IL-6 and Tumor necrosis factor- alpha (TNF-alpha) that affects hypothalamic neurotransmitter release and pituitary hormone secretion, including prolactin. Prolactin plays a significant role in the regulation of the humoral and cellular immune responses in physiological as well as pathological states. Hyperprolactinemia has been observed in many cases of infectious or inflammatory diseases, however contradictory results exist. Since prolactin is a hormone that ensures the survivor of an organism through it fundamental role in the reproductive process and in the recovery of allostasis, we investigated the neuronal circuits that control the prolactin secretion in an acute model of infection of animals receiving LPS. We have shown that the ip administration of LPS in male rats decreases serum prolactin levels 1 or 3 hs after injection. The most important primary inhibitory neurotransmitter in the central nervous system is gamma aminobutyric acid (GABA). GABA acts at the anterior pituitary level as a prolactin-inhibiting hormone, although it has a stimulatory effect on prolactin secretion via the inhibition of the activity of tuberoinfundibular dopaminergic neurons. Since GABA plays an important role in the neuroendocrine regulation of anterior pituitary secretion, we hypothesized that the effects of cytokines on pituitary secretion could be related to the GABAergic activity in the hypothalamic-pituitary axis. Therefore, we investigated the in vitro effects of IL-6 and TNF-alpha on GABA release from mediobasal hypothalamus (MBH) and posterior pituitary (PP) of male rats. Our results demonstrate that IL-6 induces GABA release from MBH explants and PP in vitro. In contrast, TNF-alpha decreases GABA release from both tissues. These findings indicate that pro-inflammatory cytokines may differentially affect the hypothalamic-pituitary axis by acting on different groups of cells and/or through diverse mediators. They also suggest the possibility that GABAergic neurons could be involved in the neuroendocrine response to infection. Prolactin secretion is mainly under tonic inhibitory control of dopamine (DA). Therefore, it is possible that DA may be implicated in the infection-induced effects on prolactin secretion. Then we investigated the involvement of catecholaminergic neurons in the inhibition of prolactin secretion in our model of infection. We also studied the effect of central administration of TNF-alpha on serum prolactin levels and the dopaminergic activity in the hypothalamus and pituitary. We observed a lack of effect of LPS on plasma prolactin in the presence of sulpiride, a D2 dopaminergic receptor blocker, suggesting the involvement of dopaminergic activity in the decrease of serum prolactin induced by LPS. In fact, our results showed that LPS increased hypothalamic dopamine and DOPAC (DA metabolite) concentrations and the DOPAC/DA ratio, considered as a good index of dopaminergic-neuronal activity. Also, we observed an increase in DA and DOPAC concentrations in the anterior pituitary induced by LPS, indicating an enhanced supply of DA to the lactotroph. The intracerebroventricular injection of TNF-alpha also significantly lowered plasma prolactin levels, whereas it increased dopamine and DOPAC concentrations in the anterior pituitary suggesting that this cytokine may inhibit prolactin secretion by stimulating dopaminergic activity Our observations indicate that dopamine plays an important role in the inhibition of prolactin release during endotoxemia and suggest thatTNF-alpha synthesized in the brain could be involved in the stimulatory effect of LPS on dopaminergic activity in the hypothalamic-pituitary axis. In summary, the reduction in the secretion of prolactin, considered a proinflammatory factor could participate in the down-regulation of the immune response during the acute phase of endotoxemia.