Conceptually, this proposal concerns the control of episodic luteinizing hormone (LH) secretion in males. Previous studies have focused on the stimulation of intermittent LH secretory episodes by luteinizing hormone releasing hormone (LHRH) and have assumed that the LH pulse generator is positively regulated. In male mice, for example, abrupt elevations of plasma LH occur approximately once every 3.5 hours. Castration increases the rate of pulsatile LH release to 30 minute intervals, although intermittent periods of secretory quiescence are observed. Following hypothalamic deafferentation in mice, I recently observed LH secretory episodes at 40 minute intervals in intact males and the absence of periodic gaps in episodic LH release after castration. These results suggest that deafferentation of the medial basal hypothalamus (MBH) releases episodic LH secretion from inhibition, which usually acts either directly on the pituitary or indirectly on LHRH neurons in the MBH. I therefore propose to examine the hypothesis that the LH pulse generator has inhibitory as well as stimulatory components. First, I will confirm my initial results with regionally restricted deafferentations of the MBH, and then I will test two alternative interpretations. Potential impairment of androgen feedback will be evaluated by measuring the accumulation of 3H-steroids in the MBH after deafferentation. The ability of the pituitary to respond to high frequency pulses of exogenous LHRH after electrolytic lesions of the median eminence will be assessed. Next I will attempt to identify the inhibitory substance using a pharmacological approach, because the actions of the biogenic amines on LH release have been emphasized in the literature. Intracerebroventricular (ICV) injections of noradrenergic agonists will be given to mice after deafferentation in an effort to restore their normal pulsatile LH release. Similarly, an attempt will be made to create the episodic pattern typical of deafferented males in normal mice using ICV injections of noradrenergic antagonists. One final experiment will explore the role of the tentatively identified inhibitory substance in modulating the reflexive release of LH in males observed during sexual encounters. Thus, within the framework of a novel experimental hypothesis, the proposed studies offer new insights into the neural control of males' gonadotropin secretion; consequently, fertility regulation.
