Effect on striatal dopamine metabolism and differential motor behavioral tolerance following chronic cholinesterase inhibition with diisopropylfluorophosphate.

Rats were treated with diisopropylfluorophosphate (DFP), using 1 or 2 mg/kg acutely, or with 1 mg/kg daily for 4, 14 or 28 days. Their behaviors and striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels were studied. The behaviors: tremors, chewing-movements and hind-limb abduction induced by DFP increased in a steeply dose-dependent manner. Chronic treatment for up to 28 days produced biphasic patterns of change for all the behavioral parameters. Tremor occurred in a complex spectrum of slow to intense fast types. Except for chewing, tolerance developed for these parameters, but at different rates. After acute treatment striatal DA and DOPAC levels were altered and the DOPAC/DA ratios were consistently increased within about the first two hr, suggesting an increased turnover of DA. After chronic treatment for 4 and 14 but not 28 days, both DA and DOPAC levels were decreased without a change in their ratios. It is suggested that the changes in DA metabolism arose secondarily to an elevation of brain acetylcholine following cholinesterase inhibition. A prolonged change in the levels or turnover of DA could be responsible for increase of postsynaptic DA receptor density previously found by us [36], which might then partly mediate the behavioral tolerance to DFP.