Effect of Acute and Chronic Cholinesterase Inhibition with Diisopropylfluorophosphate on Muscarinic, Dopamine, and GABA Receptors of the Rat Striatum

Abstract

The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.

Motor functions but not learning and memory are impaired upon repeated exposure to sub-lethal doses of methyl parathion

“…We reported that the changes in dopaminergic system arose secondarily to an elevation of brain acetylcholine following cholinesterase inhibition [17,18]. Chronic administration of DFP reduced the number of muscarinic sites, but increased dopamine and GABA receptor densities [17]. Further, a decrease in dopamine level at striatum was detected after both acute and chronic exposure to DFP [18].…”

“…Earlier studies in this lab already addressed the involvement of other neurotransmitter systems, dopaminergic and GABAergic system) in OP antiAChE-induced neurotoxicity. We reported that the changes in dopaminergic system arose secondarily to an elevation of brain acetylcholine following cholinesterase inhibition [17,18]. Chronic administration of DFP reduced the number of muscarinic sites, but increased dopamine and GABA receptor densities [17].…”

Four-Week-Long Tabun Low-Level Exposure in Rats

“…Although at least part of the explanation for the occurrence of tolerance to tabun in rats should be found in its metabolism (31), there is no doubt that the other part should rest on the grounds of desensitisation and down-regulation cholinergic and probably some other brain receptors (32).…”

Effects of Acute and Subchronic Exposures to Dimethoate on Rat Cerebral Cortex GABAergic System

“…[15][16][17][18][19] On long-term exposure, some organophosphorus compounds, such as diisopropylfluorophosphate caused significant changes of GABA A receptor following 14 days of treatment. 20) The foregoing evidences indicate that the effects produced by organophosphates include a variety of behavioral and neurological manifestations, all of which can not be attributed to cholinergic hyperactivity solely. Other systems may, in addition or independently, be involved in OPs intoxicatin.…”

“…Other systems may, in addition or independently, be involved in OPs intoxicatin. 20,21) Since the alterations of GABAergic system on OPs pesticides intoxication process remains obscured, more remedial approaches are needed to understand the GABAergic mechanisms involved in OPs intoxication. The present paper investigates the alterations of GABAergic system in rat cortex consequent to acute and subchronic dimethoate administration to explore the role of the IAA system in OPs poisoning.…”