Formamidine pesticides and alpha 2-adrenoceptors: studies with amitraz and chlordimeform in rats and development of a radioreceptor binding assay.
The interaction of the formamidine pesticides chlordimeform (CDM) and amitraz (AMZ) with rat brain alpha2-adrenoceptors was investigated. Both compounds inhibited the binding of 3H-clonidine and 3H-yohimbine in vitro with IC50 values of 62-68 microM (CDM) and 95-110 nM (AMZ). In vivo administration of AMZ and CDM caused a dose-dependent inhibition of 3H-clonidine binding in rat forebrain. The inhibition was short-lasting (24 hr) following CDM administration, while after AMZ recovery of 3H-clonidine binding occurred only after 72 hr. Good correlations were found between inhibition of brain 3H-clonidine binding by the formamidines and "plasma equivalents" of these compounds and/or their biologically active metabolites, as measured by a new radioreceptor assay. These results suggest that 1) formamidines can interact in vivo with brain alpha 2-adrenoceptors when administered at doses previously shown to cause toxic effects on the central nervous system: and 2) this effect is reversible, both in vivo and in vitro, and appears to be linked to the presence of the formamidines and/or their active metabolites at the receptor sites.
Costa
L G
LG
Department of Environmental Health, University of Washington, Seattle 98195.
Wu
D S
DS
Olibet
G
G
Murphy
S D
SD
D000578:Amidines / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002742:Chlorphenamidine / Q000633:toxicity*; D003000:Clonidine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D010575:Pesticides / Q000633:toxicity*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D014052:Toluidines / Q000633:toxicity*; D015016:Yohimbine / Q000378:metabolism
D000578:Amidines; D007306:Insecticides; D010575:Pesticides; D011942:Receptors, Adrenergic, alpha; D014052:Toluidines; D015016:Yohimbine; C014983:amitraz; D002742:Chlorphenamidine; D003000:Clonidine