Interaction of Formamidine Pesticides with the Presynaptic α2-Adrenoceptor Regulating [3H]Noradrenaline Release from Rat Hypothalamic Synaptosomes

Abstract

The effects of the formamidine pesticides amitraz and chlordimeform on the α2-adrenergic receptor subtype that mediates the release of [3H]noradrenaline by synaptosomes from rat hypothalami were studied. We initially characterized the presynaptic autoreceptor on noradrenergic nerve endings using selective antagonists. Yohimbine (a nonselective α2 antagonist) and BRL 44408 (selective for subtypes α2A/α2D) diminished the inhibitory effect of xylazine on K+-evoked release of [3H]noradrenaline; the KB values were 481 and 154 nM, respectively. In contrast, prazosin (a selective α2B/α2C antagonist) did not modify the inhibitory effect of xylazine. These results indicate that the release of noradrenaline by noradrenergic nerve endings in the rat hypothalamus is regulated by α2D-adrenoceptors, a species variation of the human α2A subtype. We then assessed the effects of the two pesticides on the K+-evoked release of [3H]noradrenaline. Amitraz reduced release in a dose-dependent manner; the effect observed at the maximal concentration tested (10 μM) was 13.0 ± 2.0% and it was reversed by yohimbine. Amitraz also diminished the inhibitory effects of the α2-adrenergic agonists clonidine and xylazine. Chlordimeform displayed no effects, possibly because the true active compound of this insecticide is its demethylated metabolite. Based on these findings we conclude that the formamidine pesticides act as partial agonists of presynaptic α2D-adrenergic receptors in the rat hypothalamus. This interaction may be responsible for the in vivo alterations in catecholaminergic regulation of cyclic variations in gonadotropin-releasing hormone (GnRH) secretion, which can have grave functional repercussions on the reproductive system of mammals exposed to these xenobiotics.