Dichlorvos-induced central apnea: effects of selective brainstem exposure in the rat

The area of the brain responsible for organophosphate (OP)-induced central apnea is unknown. Automatic breathing is governed by circuits in the medulla and pons. Respiratory-related neurons in the brainstem are concentrated in a few areas, including ventral regions of the medulla, which contains a number of sites critical for respiratory rhythmogenesis, including the pre-Bötzinger complex (preBötC). The preBötC contains cholinergic receptors, making it a candidate site of action for the apnea-inducing effect of OP. We analyzed respiratory output during a series of experiments using both intact and reduced Wistar rat preparations exposed to dichlorvos (2,2-dichlorovinyl dimethyl phosphate). Exposure of the brainstem using a working heart-brainstem preparation resulted in a central apnea similar to that seen in intact animal models. In contrast, microdialysis of locally toxic doses of dichlorvos to the ventral region of the medulla resulted in delayed and mild respiratory depression in most animals and apnea in only 29% of the animals. We conclude that exposure of the entire brainstem to OP is sufficient to induce central apnea. Our microdialysis experiments suggest that the neural substrate for OP-induced central apnea involves a specific brainstem site other than the ventral region of the medulla, or apnea might result from a distributed effect involving cholinergic toxicities of multiple brainstem sites.