Effects of manipulating catecholamines on the incidence of the preovulatory surge of luteinizing hormone and ovulation in the rat: Evidence for a necessary involvement of hypothalamic adrenaline in the normal or ‘midnight’ surge

Abstract

The preovulatory surge of luteinizing hormone reaches a maximum at 18.00 h on the day of pro-oestrus in female rats maintained with regular lighting from 06.00 to 20.00 h. This surge is initiated by a discharge of luteinizing hormone-releasing hormone into hypophysial portal blood. In this study, drugs which affect catecholamine-mediated neurotransmission were administered on the day of prooestrus and the effects on serum concentrations of luteinizing hormone and on subsequent ovulation were observed. α-Methyl- p-tyrosine, diethyldithiocarbamate and SKF 64139 inhibit catecholamine synthesis at the level of tyrosine hydroxylase, dopamine β-hydroxylase and phenylethanolamine N-methyltransferase, respectively. Although α-methyl- p-tyrosine suppressed ovulation, it had a negligible effect on the incidence of the preovulatory surge. In contrast, the various treatments with diethyldithiocarbamate and SKF 64139 resulted in a minimal occurence of the 18.00 h surge; at relatively low doses, however, these drugs frequently elicited a surge at 22.00 or 24.00 h which invariably resulted in ovulation. The failure of the surge after diethyldithiocarbamate or SKF 64139 was not associated with a loss of pituitary sensitivity to luteinizing hormone-releasing hormone. In terms of the hypothalamic concentration of dopamine, noradrenaline, adrenaline and 5-hydroxy-tryptamine at 18.00 h on pro-oestrus, the only common effect of diethyldithiocarbamate and SKF 64139, given in a dose which blocks the surge, was a severe depletion of adrenaline; α-methyl- p-tyrosine failed to produce this effect despite inducing a marked depression of dopamine and a moderate loss of noradrenaline. Neither the increase in hypothalamic dopamine after diethyldithiocarbamate, nor the α 2 receptor blocking properties of SKF 64139 appear to be relevant in this context since injections of l-dopa or piperoxane, an α 2 receptor antagonist, were without effect on the surge or ovulation. The failure of the surge after prazosin, an α 1 receptor antagonist, indicates that the function of adrenaline may be mediated postsynaptically by α 1 receptors. Clonidine, an α 2 receptor agonist which reduces the turnover rate of hypothalamic adrenaline, had effects on the surge and ovulation which were comparable to those of diethyldithiocarbamate and SKF 64139, the relatively low doses causing some of the surges to occur at 24.00 instead of 18.00h and higher doses suppressing the surge at both times and thus preventing ovulation. The hypotensive effects of clonidine are unlikely to be of significance in this respect since mecamylamine, a ganglionic blocking hypotensive agent, did not disturb the surge or ovulation. Piperoxane, an α 2 receptor antagonist which enhances the turnover rate of hypothalamic adrenaline, counteracted the effect of clonidine on the timing of the surge. The results of this study are consistent with a necessary role for adrenaline in the production of the spontaneous preovulatory luteinizing hormone surge. Evidence specifically implicating dopamine or noradrenaline in this process was not obtained. The results emphasize the importance of the sequential study of serum concentrations of luteinizing hormone and ovulation in individual animals and of recognizing the possibility of a delayed “midnight” surge. This study also indicates that tyrosine hydroxylase inhibition may fail to produce the functional deficits which follow the inhibition of enzymes involved in the subsequent biosynthetic pathway for adrenaline.