Wehner J M, Upchurch M
Institute for Behavioral Genetics, University of Colorado, Boulder 80309.
Pharmacol Biochem Behav. 1989 Feb;32(2):543-51. doi: 10.1016/0091-3057(89)90194-9.
C57BL mice were treated with 0.5 mg/kg/hr oxotremorine through an implanted subcutaneous cannula for 6 days. Tolerance to oxotremorine was evaluated after treatment by constructing cumulative dose-response curves and measuring body temperature and rotarod performance. At 2 hr after removal, mice exhibited a 15-fold tolerance as measured by body temperature and a 4-fold tolerance as measured by rotarod performance. This tolerance as measured by body temperature was lost by two days after removal from treatment. Immediately after treatment, 3H-QNB binding was reduced in cortex, hippocampus, midbrain, hindbrain, and hypothalamus. Receptors returned to normal within 4 to 8 days after cessation of treatment depending on the brain region. Spatial learning was examined using the Morris water task. Mice that began their training in this task 1 day after they were removed from oxotremorine treatment were impaired in their spatial ability as evidenced by a lack of preference for the trained site during a probe trial. Mice that began their training 2 days after cessation of oxotremorine treatment showed no evidence of impairment in spatial learning. These results suggest that a loss of muscarinic receptors after oxotremorine treatment can be dissociated from tolerance loss and spatial learning deficits.
通过植入的皮下套管以0.5毫克/千克/小时的剂量给C57BL小鼠注射氧化震颤素，持续6天。治疗后，通过构建累积剂量反应曲线以及测量体温和转棒性能来评估对氧化震颤素的耐受性。在撤药2小时后，通过体温测量，小鼠表现出15倍的耐受性，通过转棒性能测量则表现出4倍的耐受性。从治疗中撤药两天后，通过体温测量的这种耐受性消失。治疗后立即观察到，在皮质、海马体、中脑、后脑和下丘脑，3H-QNB结合减少。根据脑区不同，治疗停止后4至8天内，受体恢复正常。使用莫里斯水迷宫任务检测空间学习能力。从氧化震颤素治疗中撤药1天后开始在此任务中训练的小鼠，在探测试验期间对训练位点缺乏偏好，这表明其空间能力受损。在氧化震颤素治疗停止2天后开始训练的小鼠，没有表现出空间学习受损的迹象。这些结果表明，氧化震颤素治疗后毒蕈碱受体的丧失与耐受性丧失和空间学习缺陷无关。
