Abstract
The neurotransmitter serotonin (5-HT) is involved in mood disorder aetiology and it has been reported that (organophosphate) OP exposure affects 5-HT turnover. The aim of this study was to elucidate the mechanism underlying OP effects on the adult 5-HT system. First, acute in vivo administration of the OP diazinon (0, 1.3, 13 or 39 mg/kg i.p.) to male Hooded Lister rats inhibited the activity of the cholinergic enzyme acetylcholinesterase in blood and in the hippocampus, dorsal raphe nucleus (DRN), striatum and prefrontal cortex. Diazinon-induced cholinesterase inhibition was greatest in the DRN, the brain's major source of 5-HT neurones. Second, acute in vivo diazinon exposure (0 or 39 mg/kg i.p.) increased the basal firing rate of DRN neurones measured ex vivo in brain slices. The excitatory responses of DRN neurones to α1-adrenoceptor or AMPA/kainate receptor activation were not affected by in vivo diazinon exposure but the inhibitory response to 5-HT was attenuated, indicating 5-HT1A autoreceptor down-regulation. Finally, direct application of the diazinon metabolite diazinon oxon to naive rat brain slices increased the firing rate of DRN 5-HT neurones, as did chlorpyrifos-oxon, indicating the effect was not unique to diazinon. The oxon-induced augmentation of firing was blocked by the nicotinic acetylcholine receptor antagonist mecamylamine and the AMPA/kainate glutamate receptor antagonist DNQX. Together these data indicate that 1) acute OP exposure inhibits DRN cholinesterase, leading to acetylcholine accumulation, 2) the acetylcholine activates nicotinic receptors on 5-HT neurones and also on glutamatergic neurones, thus releasing glutamate and activating 5-HT neuronal AMPA/kainate receptors 3) the increase in 5-HT neuronal activity, and resulting 5-HT release, may lead to 5-HT1A autoreceptor down-regulation. This mechanism may be involved in the reported increase in risk of developing anxiety and depression following occupational OP exposure.
Highlights
Organophosphate (OP) chemicals are commonly used as domestic and agricultural pesticides
Despite clinical evidence to suggest that the 5-HT system may be affected by OP exposure, this is the first study to demonstrate the functional effects of OP pesticide exposure on the dorsal raphe nucleus (DRN), the major source of forebrain 5-HT in the brain and demonstrate a Mecamylamine + chlorpyrifos oxon (CPFO)
Changes in anxiety and mood are associated with alterations in the 5-HT system
Summary
Organophosphate (OP) chemicals are commonly used as domestic and agricultural pesticides. Diazinon (Dimpylate) is used in sheep dip and in dog and cat flea collars, and chlorpyrifos is a very commonly used insecticide for crops. OPs are Abbreviations: AChE, acetylcholinesterase; AMPA, a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid; DMSO, dimethyl sulfoxide; DNQX, 6,7dinitroquinoxaline-2,3-dione; DRN, dorsal raphe nucleus; 5-HT, 5hydroxytryptamine; OP, organophosphate. S.J. Judge et al / Chemico-Biological Interactions 245 (2016) 82e89 between occupational OP exposure and neuropsychology [9,30,34]. Judge et al / Chemico-Biological Interactions 245 (2016) 82e89 between occupational OP exposure and neuropsychology [9,30,34] These inconsistencies may be due in part to the limitations of retrospective human exposure studies, in particular the lack of comprehensive exposure data and adequate control subjects [29]. The potential association between OPs and psychiatric symptoms remains a contentious issue and, without a plausible mechanism of action, it is unlikely to be resolved
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