TUMOR-NECROSIS-FACTOR-ALPHA MEDIATES ENDOTOXIN-INDUCED SUPPRESSION OFGONADOTROPIN-RELEASING-HORMONE PULSE-GENERATOR ACTIVITY IN THE RAT

Bacterial endotoxin lipopolysaccharide (LPS) is known to suppress gona dotropin secretion and this effect is assumed to be mediated by cytoki nes. In the present study, we examined whether LPS affected hypothalam ic electrical activity associated with LH pulses, and whether tumor ne crosis factor-alpha (TNF-alpha), a major cytokine induced by LPS, was involved in this process. Ovariectomized rats were fitted with chronic ally implanted electrode arrays in the mediobasal hypothalamus, and mu ltiunit activity (MUA) was recorded under conscious, unrestrained cond itions. Blood samples were withdrawn every 6 min through an indwelling atrial catheter for determining serum LH concentrations. Intravenous (iv) injection of LPS (1 mu g) suppressed characteristic increases (vo lleys) in MUA associated with LH pulses throughout the experimental pe riod up to 5 h. This suppressive effect of LPS on MUA volleys was sign ificantly attenuated by simultaneous intracerebroventricular (icv) inj ection of the antibody (50 ng) to TNF-alpha through an indwelling cann ula in the lateral ventricle. These changes in MUA were faithfully ref lected in the LH secretory pattern. further, either iv (0.4-2 mu g) or icv (20-250 ng) injection of TNF-alpha suppressed the frequency of MU A volleys and associated LH pulses in a dose-dependent manner. These r esults suggest that LPS leads to the suppression of gonadotropin-relea sing hormone pulse generator activity through a mechanism involving TN F-alpha.