title: Impaired glutamatergic and GABAergic transmission by amitraz in primary hippocampal cells.
abstract: Amitraz is a formamidine pesticide that has been reported to be a neurotoxic compound that induces convulsions among other effects. Excitatory and inhibitory neurotransmission is mediated mainly by glutamate and GABA, respectively, so their alteration could be responsible for induction of seizures. In this regard, amitraz α2 adrenergic agonist action, which has been suggested as likely responsible for this effect, could alter these neurotransmitter systems and lead to seizure induction. Moreover, other amitraz mechanisms such as histamine H1 receptor inhibition could be involved. To confirm if amitraz disrupts glutamatergic/GABAergic transmission by these mechanisms, we evaluated, in primary hippocampal neurons, the effect of amitraz (0.01 μM to 100 μM) with or without the α2 adrenergic antagonist idazoxan (1 μM) and/or the H1 receptor agonist n-methylhistaprodifen (30 μM) co-treatment on 4-aminobutyrate aminotransferase, glutamate decarboxylase 65 (GAD 65), succinate-semialdehyde dehydrogenase and glutaminase gene expression and on glutamate and GABA levels after 24h treatment. We observed that amitraz disrupts glutaminase and GAD 65 gene expression, altering glutamatergic and GABAergic transmission. These effects were mediated partially by H1 and α2 receptors suggesting that other mechanisms could be involved. These data could help explain the mechanism by which amitraz induces seizures and provide a therapeutic strategy to protect against this effect in case of poisoning.
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain. Electronic address: jdelpino@pdi.ucm.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Del Pino
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Frejo
authors.affiliation: Department of Toxicology and Legal Medicine, Medicine School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María José Anadon
authors.initials: MJ
authors.lastname: Baselga
authors.affiliation: Department of Toxicology and Legal Medicine, Medicine School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Moyano
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Díaz
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics; D005971:Glutamates / Q000032:analysis*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects*; D010574:Pesticide Synergists / Q000633:toxicity*; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*; D014052:Toluidines / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000032:analysis*
chemical_list: D005971:Glutamates; D010574:Pesticide Synergists; D014052:Toluidines; C014983:amitraz; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: Amitraz; GABA; GAD 65; Glutamate; Glutaminase; Primary hippocampal cells