title: Behavioral comparison of the oximes TMB-4, 2-PAM, and HI-6 in rats using operant conditioning.
abstract: It has recently been shown that oximes can amplify the ability of cholinesterases to scavenge organophosphorus (OP) agents. Since both OP agents and oximes can disrupt performance, behavioral evaluation of bioscavenger therapies using oximes can be hindered. Therefore, we investigated the ability of three oximes, administered alone, to disrupt performance. The effects of trimedoxime bromide (TMB-4) (3.16-56.2 mg/kg), pralidoxime chloride (2-PAM) (10.0-237.1 mg/kg), and, 1-([[4-amincarbonyl)pyridino]-methoxy]-methyl)-2, 4-bis[(hydroxyimino)methyl] pyridinium dichloride monohydrate (HI-6) (10.0-237.1 mg/kg) were evaluated in rats using a variable-interval 56 (VI 56) s schedule of food reinforcement. Under control conditions, the VI 56 s schedule produced a constant rate of responding (i.e., lever-pressing). All three oximes produced dose-dependent decreases in responding, and the largest doses of TMB-4 and 2-PAM produced complete or nearly complete suppression of responding in all rats. Only the largest dose of HI-6 suppressed responding. Analysis of the dose-effect functions demonstrated that TMB-4 was substantially more potent than 2-PAM, which was slightly more potent than HI-6, for producing response suppression. These results establish doses of each oxime that will not contribute to disruption of responding, and thus, facilitate future evaluation of bioscavenger therapies against OP toxicity.
authors.affiliation: Division of Neurosciences, Walter Reed Army Institute of Research, Washington, D.C. 20307, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Genovese
authors.forename: B P
authors.initials: BP
authors.lastname: Doctor
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010091:Oximes; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D014289:Trimedoxime / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D014289:Trimedoxime; C022870:asoxime chloride; C028797:pralidoxime