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Pung T, Klein B, Blodgett D, Jortner B, Ehrich M: Examination of concurrent exposure to repeated stress and chlorpyrifos on cholinergic, glutamatergic, and monoamine neurotransmitter systems in rat forebrain regions. Int J Toxicol. 2006 Jan-Feb;25(1):65-80.
Repeated stress has been reported to cause reversible impairment in the central nervous system (CNS). It was proposed that alterations in glutamatergic, cholinergic, and monoamine neurotransmitter systems after exposure to stress are initial CNS events contributing to this impairment and that exacerbation could occur with concurrent exposure to cholinesterase inhibitors. Effects of concurrent exposure to repeated stress and chlorpyrifos on activities of acetylcholinesterase (AChE), carboxylesterase, and choline acetyltransferase (ChAT); concentrations of excitatory amino acids, monoamines, and their metabolites; and maximum binding densities (B (max)) and equilibrium dissociation rate constants (K (d)) of glutamatergic N-methyl-d-aspartate (NMDA) and total muscarinic cholinergic receptors were studied in the blood, hippocampus, cerebral cortex, or hypothalamus of adult Long-Evans rats. Stress treatments extended over 28 days included (1) control rats handled 5 days/week; (2) rats restrained 1 h/day for 5 days/week; (3) rats swum 30 min for 1 day/week; or (4) rats restrained 4 days/week and swum for 1 day/week. On day 24, each stress treatment group was randomly divided and injected either with corn oil or chlorpyrifos, 160 mg/kg subcutaneously (sc) (60% of the maximum tolerated dose), 4 h after restraint. Blood and brain tisssues were collected on day 28. Rats restrained and swum had a statistical trend toward increasing concentrations of glutamate in the hippocampus when compared to rats only swum (p = .064). Chlorpyrifos administration decreased restraint-induced elevated aspartate in the hippocampus, and decreased B (max) of total muscarinic receptors in the cerebral cortex. In addition, chlorpyrifos decreased B (max) and K (d) of total muscarinic receptors in the cerebral cortex of swum rats. Results demonstrated that chlorpyrifos inhibited AChE activity in blood, cerebral cortex, and hippocampus, but stress did not affect AChE activity. Carboxylesterase activity was inhibited by chlorpyrifos and by repeated restraint with swim. Swim stress decreased concentrations of norepinephrine in the hippocampus and hypothalamus, and increased concentrations of dopamine and its metabolite, DOPAC, in the hypothalamus. Both stress and chlorpyrifos altered serotonin concentrations, and the interactions of repeated stress and chlorpyrifos on serotonin approached significance in the hippocampus (p = .06) and hypothalamus (p = .08). Therefore, stress models were demonstrated to alter glutamatergic and monoamine responses, whereas chlorpyrifos alone had effects on cholinergic and monoamine systems in the rat CNS. However, the interactions between stress and chlorpyrifos significant at p < 0.05 were restricted to attenuation of elevated aspartate in the hippocampus of restrained with swim rats and decreased K (d) of acetylcholine receptors in the cerebral cortex of swum rats and restrained rats. |
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