Interaction of formamidine pesticides with the presynaptic alpha(2)-adrenoceptor regulating [H-3]noradrenaline release from rat hypothalamic synaptosomes

The effects of the formamidine pesticides amitraz and chlordimeform on the alpha (2)-adrenergic receptor subtype that mediates the release of [H-3]nor adrenaline by synaptosomes from rat hypothalami were studied. We initially characterized the presynaptic autoreceptor on noradrenergic nerve endings u sing selective antagonists. Yohimbine (a nonselective alpha (2) antagonist) and BRL 44408 (selective for subtypes alpha (2A)/alpha (2D)) diminished th e inhibitory effect of xylazine on K+-evoked release of [H-3]noradrenaline; the K-B values were 481 and 154 nM, respectively. In contrast, prazosin (a selective alpha (2B)/alpha (2C) antagonist) did not modify the inhibitory effect of xylazine, These results indicate that the release of noradrenalin e by noradrenergic nerve endings in the rat hypothalamus is regulated by al pha (2D)-adrenoceptors, a species variation of the human alpha (2A) subtype , We then assessed the effects of the two pesticides on the K+-evoked relea se of [H-3]noradrenaline. Amitraz reduced release in a dose-dependent manne r; the effect observed at the maximal concentration tested (10 muM) was 13. 0 +/- 2.0% and it was reversed by yohimbine, Amitraz also diminished the in hibitory effects of the alpha (2)-adrenergic agonists clonidine and xylazin e, Chlordimeform displayed no effects, possibly because the true active com pound of this insecticide is its demethylated metabolite. Based on these fi ndings we conclude that the formamidine pesticides act as partial agonists of presynaptic alpha (2D)-adrenergic receptors in the rat hypothalamus, Thi s interaction may be responsible for the in vivo alterations in catecholami nergic regulation of cyclic variations in gonadotropin-releasing hormone (G nRH) secretion, which can have grave functional repercussions on the reprod uctive system of mammals exposed to these xenobiotics. (C) 2001 Academic Pr ess.