title: Repeated exposures to diisopropylfluorophosphate result in impairments of sustained attention and persistent alterations of inhibitory response control in rats.
abstract: Organophosphate (OP)-based chemicals are used worldwide for many purposes and they have likely saved millions of people from starvation and disease. However, due to their toxicity they can also pose a significant environmental risk. While considerable research has focused on the acute symptoms and long-term consequences of overtly toxic exposures to OPs, less attention has been given to the subject of repeated exposures to levels that are not associated with acute symptoms (subthreshold exposures). There is clinical evidence indicating that this type of OP exposure can lead to prolonged deficits in cognition; however only a few studies have addressed this issue prospectively in animal models. In this study, repeated subthreshold exposures to the OP nerve agent diisopropylfluorophosphate (DFP) were evaluated in a 5-Choice Serial Reaction Time Task (5C-SRTT), an animal model of sustained attention. Adult rats were trained to stably perform the 5C-SRTT and then injected subcutaneously with vehicle or DFP of 0.5mg/kg every other day for 30days. Behavioral testing occurred daily during the DFP-exposure period and throughout a 45day (OP-free) washout period. Compared to vehicle-treated controls, DFP-treated rats exhibited deficits in accuracy, increases in omissions and timeout responses during the OP exposure period, while no significant effects on premature responses, perseverative responses, or response latencies were noted. While the increase in timeout responses remained detectible during washout, all other DFP-related alterations in 5C-SRTT performance abated. When the demands of the task were increased by the presentation of variable intertrial intervals, premature responses were also elevated in DFP-treated rats during the washout period. These results indicate that repeated exposures to subthreshold doses of DFP lead to reversible impairments in sustained attention as well as persistent impairments of inhibitory response control in rats.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States; Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, United States. Electronic address: aterry@gru.edu.
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States; Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Callahan
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Beck
authors.affiliation: Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Leah
authors.initials: L
authors.lastname: Vandenhuerk
authors.affiliation: Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Samantha
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Kristy
authors.initials: K
authors.lastname: Bouchard
authors.affiliation: Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Rose
authors.initials: R
authors.lastname: Schade
authors.affiliation: Department of Biostatistics, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Waller
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood; D007266:Inhibition, Psychological; D007531:Isoflurophate / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D002802:Cholinesterases
keywords: Cholinesterase inhibitor; Cognition; Memory; Nerve agent; Organophosphate; Pesticide