Oestrogen can act on the brain to exert negative and positive feedback effects on the secretion of gonadotrophin releasing hormone (GnRH), but this cannot be effected through the GnRH cells themselves because they have no oestrogen receptors. We have used intraventricular injection of agonists and antagonists of various transmitters to determine which systems are involved in the control of GnRH by steroid hormones. We have also developed a model for the injection of drugs directly into the medial pre-optic area of the sheep brain to study the action on the GnRH cell bodies. Opioid systems seem to be involved in the mediation of the feedback effects of progesterone, but not oestrogen. Noradrenalin appears to be involved in the negative feedback regulation of GnRH secretion during the anoestrous period. Thus, under the strong negative influence of oestrogen at this time GnRH/luteinizing hormone (LH) secretion is reduced but can be restored by the preoptic micro-injection of noradrenaline. Gamma-amino-butyric acid (GABA) agonists and antagonists inhibit LH secretion when injected into the medial pre-optic region of the hypothalamus of ovariectomized ewes with or without oestrogen treatment. We have no evidence that GABA is involved in the negative feedback regulation of GnRH, since neither agonists nor antagonists will reverse the effects of steroid feedback. There appears to be a shift in the GABA receptor subtype function with season; in the breeding season only GABAA ligands are effective, whereas during the non-breeding season both GABAA and GABAB type ligands will affect LH secretion. This suggests that the seasonal shift in responsiveness to the negative feedback effects of oestrogen involves a shift in the function of GABA receptor subtypes.