Genetic influences on cholinergic drug response.

Three mouse strains were tested for oxotremorine effects on open-field activity and body temperature. Open-field activity was depressed less severely in C3H mice than in C57BL, which were less affected than DBA. While no differences in the hypothermic effects of oxotremorine were observed 15 min after injection, the time courses of the drug effect on body temperature indicated that C3H were less affected than C57BL or DBA. No differences in the activities of acetylcholinesterase of choline acetyltransferase were found among the three strains in cortex, cerebellum, hindbrain (pons-medulla), or total midbrain. While no differences in muscarinic receptor levels were found in the four large brain areas, finer dissection of the midbrain revealed small differences in total receptor number in striatum, hippocampus, and remaining midbrain areas. C3H mice exhibited greater QNB binding than C57BL and DBA mice in striatum; DBA mice exhibited greater QNB binding in hippocampus than C57BL (C3H mice were not different from either strain); and C57BL had less QNB binding than the other two strains in midbrain. All of these differences were small (20% or less). No differences in KD were observed. The inhibition of receptor binding by either oxotremorine or nicotine was the same in all strains, but the IC50 for oxotremorine varied from region to region. While behavioral differences in the effects of oxotremorine are clear, there is no obvious biochemical explanation for these differences.