title: Mechanism for the acute effects of organophosphate pesticides on the adult 5-HT system.
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.
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Electronic address: s.j.judge@ncl.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Judge
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Claire Y
authors.initials: CY
authors.lastname: Savy
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dodds
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Larissa Kruger
authors.initials: LK
authors.lastname: Gomes
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Grace
authors.initials: G
authors.lastname: Laws
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Watson
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Blain
authors.affiliation: Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gartside
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000209:etiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004390:Chlorpyrifos / Q000009:adverse effects*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects*; D003863:Depression / Q000209:etiology; D003976:Diazinon / Q000009:adverse effects*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010575:Pesticides / Q000009:adverse effects*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D010575:Pesticides; D012701:Serotonin; D000110:Acetylcholinesterase; D004390:Chlorpyrifos; D003976:Diazinon
keywords: 5-HT; Anxiety; Depression; Organophosphate; Pesticide; Serotonin