title: Comparative study on short- and long-term behavioral consequences of organophosphate exposure: relationship to AChE mRNA expression.
abstract: Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme.
authors.affiliation: Departamento de Psicología, Universidad de Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, La Cañada, 04120 Almería, Spain; Department of Molecular Pharmacology, Albert Einstein College of Medicine of Yeshiva University, Bronx, 10461 NY, USA.
authors.forename: Caridad
authors.initials: C
authors.lastname: López-Granero
authors.affiliation: Departamento de Enfermería, Fisioterapia y Medicina, Universidad de Almería, La Cañada, 04120 Almería, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Cardona
authors.affiliation: Departamento de Biología Vegetal y Ecología, E. Politécnica Superior, Universidad de Almería, La Cañada, 04120 Almería, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Giménez
authors.affiliation: Departamento de Biología Aplicada, Centro de Investigación en Biotecnología Agroalimentaria, Universidad de Almería, La Cañada, 04120 Almería, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lozano
authors.affiliation: Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Barril
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine of Yeshiva University, Bronx, 10461 NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Departamento de Psicología, Universidad de Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, La Cañada, 04120 Almería, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Sánchez-Santed
authors.affiliation: Departamento de Psicología, Universidad de Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, La Cañada, 04120 Almería, Spain. Electronic address: jcanadas@ual.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cañadas
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D062025:Organophosphate Poisoning / Q000378:metabolism* / Q000523:psychology*; D010755:Organophosphates / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010755:Organophosphates; D012333:RNA, Messenger; D000110:Acetylcholinesterase
keywords: Acylpeptide hydrolase; Impulsive choice; Organophosphates; Read-through AChE, Synaptic AChE; Spatial learning