Interactions of formamidines with the platelet serotonin uptake system
An important aspect of boxicology is the determination of the actions of pesticidal compounds. In addition to providing information on the mechanisms of toxicity such studies also provide knowledge of the physiology and biochemistry of affected target and non-target species, and can lead to the future development of effective and selective pesticides. Some types of pesticides, such as organophosphate insecticides, have a well-defined mode of action. However, information about the actions of members of other classes of compounds remains obscure. The forrnamidines are one such group. The forerunner of the formarnidines is chlordimeforrn or N'-(4-chloro-o-tolyl)-N, N-dimethylforrnamidine. Chlordimeforrn, which is sold under the brands Galecror® and Fundal®, is active against insects and acarines and is especially toxic to those that are resistant to organophosphates. Chlordimeforrn and other forrnamidines are known to interact with physiologic processes involving biogenic amines in both arthropods and mammals. Since biogenic amines include important neurotransmitters and neurohorrnones, interference with their formation, degradation, or function could have serious physiological consequences. For example, an essential regulatory function at aminergic synapses and receptor sites is the uptake of neuroactive biogenic amines. Interference with amine uptake at these sites could result in abnormal physiological and behavioral actions. Rat blood platelets provide an easily accessible model for the study of amine uptake mechanisms. Thus, it was used to investigate the influence of chlordimeform and other formamidines on the uptake of serotonin or 5-hydroxytryptamine (5-HT). The specific objectives of this investigation were: 1. To determine whether chlordimeform inhibited the uptake of 5-HT by rat blood platelets, 2. To determine the relationship between formamidine structure and 5-HT uptake inhibitory potency, 3. To study the mechanism by which formamidines inhibit 5-HT uptake using chlordimeform as a model compound, and 4. To determine the effect of formamidines on the release of 5-HT from platelets.