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BEHAVIORAL AND NEUROCHEMICAL CHANGES IN RATS DOSED REPEATEDLY WITH DIISOPROPYLFLUOROPHOSPHATE (DFP)
Citation:
Bushnell, P., S. Padilla, T. Ward, C. Pope, AND V. Olszyk. BEHAVIORAL AND NEUROCHEMICAL CHANGES IN RATS DOSED REPEATEDLY WITH DIISOPROPYLFLUOROPHOSPHATE (DFP). U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-91/089 (NTIS PB91200238), 1991.
Description:
Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. o characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (delayed matching-to-position), reference memory (visual discrimination) and motor function (choice response latencies and inter-response times [IRTs] during delay). aily s.c. post-testing injections of 0.2 mg/kg diisopropylfluorophosphate (DFP) caused no visible cholinergic signs, did not affect body weight or reference memory, but progressively impaired working memory and motor function. hese effects recovered in 7 of 8 treated rats after termination of DFP treatment. esumption of daily DFP at 0.1 injections of 0.2 mg/kg/day DFP, rats were subsensitive to the hypothermia induced by acute oxotremorine (0.2 mg/kg i.p.), as expected after OP-induced downregulation of muscarinic ACh receptors. vidence for supersensitivity to scopolamine (0.03 and 0.056 mg.kg, i.p.) in DFP-treated rats was mixed, with additive effects predominating on measures of both cognitive and motor function. fter 18 days of 0.1 mg.kg DFP, AChE was inhibited 50-75% and muscarinic ACh receptor density was reduced 15-20% in hippocampus and frontal cortex. rogressive declines in AChE activity in hippocampus and frontal cortex across 15 daily doses with DFP at 0.1 and 0.2 mg/kg were observed in other rats; QNB binding was significantly reduced in hippocampus after 15 doses at both levels of DFP. hese results indicated that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the motoric and mnemonic demands of a working memory task. he nature of this impairment suggests further that it results from compensatory changes in the CNS, e.g., muscarinic receptor downregulation, considered to produce "tolerance" to OPs in exposed animals.