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Sub-acute exposure to anti-cholinesterase organophosphorous compounds induces, in humans, cognitive and emotional deficits which include depression, anxiety, emotional lability, and schizophrenic-like symptoms. Neuroleptic drugs used to treat similar clinical conditions bind to serotonergic (S2) and dopaminergic (D2) receptors, suggesting that these sites are involved in the psychiatric consequences of organophosphate exposure. Rats were given saline or soman (50 micrograms/kg, SC) on a sub-acute regimen (three times weekly for four weeks) and killed 1 hr, 1 day or 3 days after the final injection. Response of regional neuroleptic receptors to soman intoxication was assessed using 3H-spiperone as ligand. Initial high affinity binding experiments using mianserine, haloperidol, or both to identify specific cortical binding revealed that mianserine displaceable binding sites showed the greatest down-regulation in response to soman. Subsequent kinetic analyses of mianserine displaceable 3H-spiperone binding indicated a dramatic decrease in the number of hippocampal binding sites and a decrease in the affinity of cortical binding sites. These S2 sites, considered to be involved with neural excitation, have the ability to self-regulate and appear to be involved in the expression of soman neurotoxicity.

Synaptosomes were incubated at various time intervals following injection of 120 micrograms/kg SC of soman or sarin or with various concentrations (10(-8) to 10(-2) M) of soman or sarin in vitro. Total cholinesterase (ChE) activities in each brain region were also measured. Following soman injection, sodium-dependent, high affinity choline uptake (SDHACU) was decreased from 1 to 4 hr in the cortex and from 1 to 2 hr in the hippocampus, but increased from 2 to 24 hr in the striatum. Similarly, following sarin injection SDHACU was decreased at 0.5 hr in the cortex and from 1 to 4 hr in the hippocampus, but increased at 1 hr in the striatum. Injection of soman severely inhibited (83-99%) total ChE activity in the cortex, hippocampus and striatum from 1 to 24 hr. In contrast, sarin did not severely inhibit ChE activity in these regions and maximal inhibition (40-60%) did not occur until 24 hr after injection. With both compounds, by 168 hr ChE activity in all regions had partially recovered. Incubation of synaptosomes with soman or sarin in vitro at concentrations below 10(-4) M did not affect SDHACU in any of the brain regions. These data demonstrated that acute soman and sarin injection produced similar effects upon SDHACU in different brain regions, although the time-course of these effects was different for the two compounds. These effects were probably neither due to a direct action of these compounds on the uptake process nor dependent on ChE inhibition.