Interaction of formamidine pesticides with the presynaptic alpha(2)-adrenoceptor regulating [H-3]noradrenaline release from rat hypothalamic synaptosomes
D. Altobelli et al., Interaction of formamidine pesticides with the presynaptic alpha(2)-adrenoceptor regulating [H-3]noradrenaline release from rat hypothalamic synaptosomes, TOX APPL PH, 172(3), 2001, pp. 179-185
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.