Marks M J, Artman L D, Collins A C
Pharmacol Biochem Behav. 1983 Jul;19(1):103-13. doi: 10.1016/0091-3057(83)90318-0.
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.
开发了一种新程序，用于定量小鼠在长期输注毒蕈碱激动剂氧化震颤素时产生的耐受性。通过对个体动物进行连续注射，构建了氧化震颤素对体温和转棒性能影响的累积剂量-反应曲线。这些剂量-反应曲线与通过向个体动物注射几种剂量之一构建的曲线相比具有优势。采用连续注射技术评估对氧化震颤素耐受性发展的程度。观察到氧化震颤素输注速率（剂量）与转棒性能受损的ED50值变化幅度之间存在线性关系，接受1.0mg/kg/hr输注速率的动物的ED50增加了24倍。耐受动物的剂量-反应曲线与未接触过药物的动物构建的曲线平行。在以1.0mg/kg/hr处理的组中，将体温降至35℃所需的氧化震颤素剂量（ED35℃）比对照组大80倍。耐受动物的剂量-反应曲线与未接触过药物的动物的曲线不平行。从氧化震颤素激发剂量恢复的时间进程表明，在慢性输注期间代谢变化不大。慢性输注氧化震颤素导致QNB结合位点总数减少。高亲和力和低亲和力位点的数量均减少。由于未观察到毒蕈碱激动剂氨甲酰胆碱的K1发生变化，因此毒蕈碱受体对激动剂的亲和力似乎不太可能发生变化。仅在接受较高剂量氧化震颤素的动物中检测到受体数量有显著变化。慢性氧化震颤素处理对从五个脑区中的任何一个制备的突触体摄取胆碱没有影响。
