Quantitation of tolerance development after chronic oxotremorine treatment

A new procedure was developed to quantitate the tolerance which develops as mice are chronically infused with the muscarinic agonist, oxotremorine. Cumulative dose-response curves were constructed for the effects of oxotremorine on body temperature and rotarod performance by administering sequential injections to individual animals. These dose-response curves compare favorably to those constructed by injecting individual animals with one of several doses. The sequential injection technique was used to assess the magnitude of tolerance development to oxotremorine. A linear relationship between oxotremorine infusion rate (dose) and magnitude of change of the ED50 value for impairment of rotarod performance was observed, with animals receiving an infusion rate of 1.0 mg/kg/hr showing a 24-fold increase in ED50. Dose-response curves for tolerant animals were parallel to those constructed for naive animals. The oxotremorine dose required to decrease body temperature to 35 degrees C (ED35 degrees) was 80-fold greater than control in the group treated with 1.0 mg/kg/hr. The dose-response curves for tolerant animals were not parallel to those seen in naive animals. Time courses of recovery from a challenge dose of oxotremorine suggest little change in metabolism occurred during chronic infusion. Chronic oxotremorine infusion resulted in a decrease in the total number of QNB binding sites. Both high- and low-affinity sites were reduced in number. Since no change in K1 for the muscarinic agonist, carbamylcholine, was observed, it seems unlikely that a change occurs in the affinity of the muscarinic receptor for agonists. Significant change in receptor number was detected only in animals that received higher doses of oxotremorine. Chronic oxotremorine treatment had no effect on choline uptake by synaptosomes prepared from any of five brain regions.