DIFFERENTIAL REGULATION OF MUSCARINIC RECEPTOR SUBTYPES IN RAT-BRAIN REGIONS BY REPEATED INJECTIONS OF PARATHION

Repeated injections with increasing moderate doses of parathion into a dult male rats for 21 days resulted in 84-90% inhibition of acetylchol inesterase in the brain without overt signs of toxicity. Muscarinic ac etylcholine receptor (mAChR) affinities for ligands were unaffected, b ut there was significant down-regulation of the m4 receptor subtype ge ne product, ml mRNA and m3 mRNA in the frontal cortex as well as the m 4 subtype and m4 mRNA in the striatum. However, in the hippocampus, th ere were no significant reductions in either the m1 receptor subtype n or its mRNA. The data suggest that the receptor subtype down-regulatio ns in the cortex and striatum are due to reductions in mRNA expression . Since the degrees of inhibition of acetylcholinesterase were similar in the 3 brain regions, it is suggested that the in situ concentratio ns of paraoxon were also similar. Accordingly, the absence of downregu lation of the ml receptor in the hippocampus is not due to a lower con centration of paraoxon than in the cortex or striatum. It is possible that injections of higher parathion doses would produce down-regulatio n of mAChRs in the hippocampus, and that the hippocampus may have diff erences in the feed-back mechanisms for receptor regulation from those in the frontal cortex and the striatum.