Background: The wide use of organophosphorus (OP) pesticides makes them an important public health concern. Persistent effects of exposure and the mechanism of neuronal degeneration are continuing issues in OP toxicology. To elucidate early steps in the mechanisms of OP toxicity, we studied alterations in global gene and protein expression in Caenorhabditis elegans exposed to OPs using microarrays and mass spectrometry. We tested two structurally distinct OPs (dichlorvos and fenamiphos) and employed a mechanistically different third neurotoxicant, mefloquine, as an outgroup for analysis. Treatment levels used concentrations of chemical sufficient to prevent the development of 10%, 50% or 90% of mid-vulval L4 larvae into early gravid adults (EGA) at 24 h after exposure in a defined, bacteria-free medium.

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Tacrine (THA) selectively modulates binding of M₁ ligands in an allosteric fashion causing positive cooperativity. The binding affinity of THA to M₁ and M₂ cholinoceptors is similar. It is therefore proposed that the allosteric selectivity of THA is a function of the binding site and not of THA itself. Its interaction of M₁ and M₂ cholinoceptors was examined in guinea pig brain homogenates using the selective M₁ and M₂ antagonists [³H]-pirenzepine ([³H]PZ) and [³H]AF-DX 384. The dissociation constants were 0.36 nmol/l for the M₁ receptor and 0.23 nmol/l for the M₂ receptor. We also compared the binding of THA and methoctramine (MTA) at M₂ receptors. Tacrine displayed similar binding affinity for both M₁ and M₂ receptor subtypes. MTA was 100 times more potent an inhibitor of [³H]AF-DX 384 binding at M₂ receptors than THA. In addition, THA was found to slow the dissociation of [³H]PZ from the M₁ receptor. In contrast, the dissociation of [³H]AF-DX 384 from M₂ receptor subtypes was unaffected. We conclude that THA acts as an agonist at M₁ cholinoceptors because it slowed the dissociation of [³H]PZ. At M₂ cholinoceptors its nature is that of an antagonist because it had no effect on [³H]AF-DX 384 dissociation.

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