Nitric oxide (NO) synthase (NOS), the enzyme that converts arginine into citrulline plus NO, the latter a highly active free radical, occurs in a large number of neurons in the brain, including certain neurons in the hypothalamus. Our previous experiments have shown that norepinephrine (NE)-induced prostaglandin E2(PGE2) release from medial basal hypothalamic explants (MBH) is mediated by NO. Because release of luteinizing hormone (LH)-releasing hormone (LHRH) is also driven by NE and PGE2, we hypothesized that NO controls pulsatile release of LHRH in vivo, which in turn induces pulsatile LH release. Indeed, in vivo and in vitro experiments using an inhibitor of NOS (NG-monomethyl-L-arginine; NMMA) demonstrated that pulsatile LH release is mediated by NO; LHRH release in vitro is also mediated by this free radical. Cytokines that are released from cells of the immune system during infection also inhibit LHRH release. We compared the action of one such cytokine, interleukin-1α(IL-1α), on LHRH release with that of substances which inhibit or induce NO release. Microinjection of IL-1α(0.06 pmol in 2μl) into the third cerebral ventricle (3V) of conscious, castrated male rats had an action similar to that of 3V microinjection of NMMA (1 mg in 5μl): it blocked pulsatile LH, but not follicle-stimulating hormone (FSH) release. The only difference between the responses to NMMA and IL-1αwas that the latency to onset was greater with IL-1α. When both NMMA and IL-1αwere microinjected together, there was an additive suppressive effect on LH release during the first hour after injection. As in the case of NMMA, there was no effect on pulsatile FSH release of IL-la injected alone or together with NMMA. The latter results suggest that hypothalamic control of FSH release is distinct from that of LH and does not involve NO. Previous in vitro experiments showed that IL-1αalso has an action identical to that of NMMA; inhibition of NE-induced PGE2and LHRH release from MBH explants. Therefore, IL-1αappears to act on its receptors on the NOergic neurons to prevent the release of NO, or on the LHRH terminals to inhibit the response to NO. To test the hypothesis that IL-1αdirectly inhibits the response of LHRH terminals to NO, we incubated MBH explants with sodium nitroprusside (NP; 500μM)twhich spontaneously releases NO. NP-induced LHRH release was inhibited by IL-1α(10 pM).We conclude that IL-1αdirectly suppresses the response of the LHRH terminals to NO.