Spatial memory impairment and central muscarinic receptor loss following prolonged treatment with organophosphates.
Memory impairment is one of the recurrent complaints of agricultural workers repeatedly exposed to organophosphorus insecticides. In an effort to establish an animal model for such behavioral effects, which would allow studying its underlying biochemical mechanism(s), in this study we evaluated spatial memory in animals following repeated organophosphate exposure. Male Long-Evans rats were given daily i.p. injections of either diisopropylfluorophosphate (DFP; 1 mg/kg/day) or disulfoton (O,O-diethyl S-[2-(ethylthio)ethyl] phosphorodithioate; 2 mg/kg/day) for 14 days. Acetylcholinesterase activity was inhibited 71-77% in the cortex, hippocampus, and striatum of rats treated with DFP, and 73-74% in those treated with disulfoton. Binding of [3H]quinuclidinyl benzilate ([3H]QNB) to cholinergic muscarinic receptors in the same brain areas was reduced 16-28% in organophosphate-treated rats. This decrease was due to a reduction in muscarinic receptor density (Bmax) with no changes in receptor affinity. At the end of the treatment rats were tested for spatial memory using the spontaneous alternation task in a T-maze. Rates of true spontaneous alternation were 64.4, 45.0, and 44.8% in animals which received corn oil, DFP, or disulfoton, respectively (P less than 0.05). These results indicate that prolonged inhibition of acetylcholinesterase caused by repeated organophosphate exposure alters spatial memory functions in rats, as well as causing a loss of muscarinic receptors. Considering the role of the cholinergic system in cognitive processes, these biochemical alterations could be related to the observed behavioral changes and may offer a potential explanation of the memory impairment reported by workers chronically exposed to organophosphates.
McDonald
B E
BE
Department of Environmental Health, University of Washington, Seattle 98195.
Costa
L G
LG
Murphy
S D
SD
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004222:Disulfoton / Q000633:toxicity; D006624:Hippocampus / Q000378:metabolism; D007531:Isoflurophate / Q000633:toxicity; D008297:Male; D008568:Memory / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects*
D009943:Organophosphorus Compounds; D011976:Receptors, Muscarinic; D007531:Isoflurophate; D004222:Disulfoton; D000110:Acetylcholinesterase