OBJECTIVETo study the tolerance of rats induced by 28 day pretreatment with low dosage of dimthoate and the toxic effects challenged by higher dosage of dimethoate, and to investigate the change of M receptor and the mechanism of tolerance formation.

METHODSSD rats were given 25 mg/kg dimethoate daily(sc) while control group was given saline daily instead for 28 days. The activity of whole blood acetylcholinesterase (AChE) was examined. On the 29th day three groups of administrated rats were challenged by saline solution, 50 mg/kg and 100 mg/kg dimethoate, respectively. The density and mRNA level of brain M(1), M(2) receptor were determined. Lymphocytes of peripheral blood were isolated, and basal, inducible M(3) gene expression were measured by RT-PCR.

RESULTSDuring pretreatment, blood AChE activity decreased continually, it reached the lowest on the 13th day. And it decreased more after exposed to higher dosage of dimethoate. Brain AChE activity in the pretreated groups was lower than that in control group and decreased with the increase in challenging dosage. The density of M(1) receptor in negative control, pretreated, and 50, 100 mg/kg challenging groups were 979.15, 856.54, 539.46, 539.14 fmol/mg pro respectively. The change in relative levels of mRNA of M(1) receptor (2.59, 2.47, 2.20, 1.81) were consistent with the density of receptor but the level declined continually as the challenging dosage increased. The density of M(2) receptor were 507.38, 611.11, 548.42, 337.47 fmol/mg pro respectively, which were not obviously affected by pretreatment but decreased as the challenging dosage increased. The change in levels of M(2) receptor mRNA was not obvious. The basal gene expression of M(3) receptor mRNA was not different among all experimental groups while the inducible gene expression decreased with the increase in challenging dosage.

CONCLUSIONLow level dosage of dimethoate could induce animals to tolerate dimethoate toxicity. Reduction of M(1) receptor density which may be induced by the decrease in its gene expression may be the mechanism of tolerance. The change of M(3) receptor mRNA inducible expression in lymphocyte accorded with M(1) receptor mRNA expression in the brain.