Russell R W, Booth R A, Jenden D J, Chang A S, Rice K M, Roch M, Lauretz S D
Department of Pharmacology, UCLA School of Medicine 90024.
Pharmacol Biochem Behav. 1992 Feb;41(2):433-44. doi: 10.1016/0091-3057(92)90123-w.
In previous reports, we described the experimental development of a hypocholinergic state in rats following the total replacement of dietary choline by an artificial isostere, N-aminodeanol (NADe). NADe shares most of the physicochemical and biochemical characteristics of choline (Ch) but is utilized less efficiently in pathways leading to the formation of both acetylcholine and phospholipids. This experimental model mimics many of the features of human degenrative dementias. We now discuss the behavioral and physiological effects of restoring a normal diet after the hypocholinergic state has become well established. The procedure by which that state was induced has been described in detail in earlier publications. After replacing Ch in the diets of weanling rats for 270 days, NADe replaced 70-85% of the phospholipid-bound Ch in plasma, brain, and peripheral tissue. When dietary NADe was removed and Ch was restored in the diet, NADe disappeared and plasma and erythrocyte (RBC) choline levels returned to normal within 30-60 days. Quinuclidinyl benzilate (QNB) binding showed that muscarinic receptors continued to be depressed in animals remaining on the NADe diet, but returned to control levels in the reversal group. There were no differences in cholinesterase activity among the three treatments. Choline acetyltransferase activity returned to control levels, while continuing to be lower in the NADe animals. Liver lipids were elevated in the latter and not significantly different in the control and reversal groups. Among physiological functions, body weight increased more rapidly in the reversal group than in animals continuing on the NADe diet. Brain weights of the reversal animals were significantly greater than those of animals not reversed, but less than controls. Core body temperatures did not differ from controls at any time during the reversal period. Behaviorally, nociceptive thresholds indicative of sensory-reflexive and sensory-perceptual responses remained significantly below normal, that is, a hyperalgesic state. Reversal animals also remained hyperactive and displayed memory significantly poorer than those on the normal diet, that is, no improvement over animals continuing on NADe. In general, the results suggest that behavioral losses induced by NADe reflect persisting changes in the CNS, despite essentially complete recovery of biochemical parameters. The changes may be morphological or be associated with adaptive changes in other neurochemical events in the CNS.
在之前的报告中，我们描述了用人工等排体N -氨基乙醇（NADe）完全替代膳食胆碱后大鼠体内低胆碱能状态的实验进展。NADe具有胆碱（Ch）的大部分物理化学和生化特性，但在导致乙酰胆碱和磷脂形成的途径中利用效率较低。这个实验模型模拟了人类退行性痴呆的许多特征。我们现在讨论在低胆碱能状态充分确立后恢复正常饮食的行为和生理影响。诱导该状态的过程已在早期出版物中详细描述。在将断奶大鼠饮食中的Ch替换270天后，NADe替代了血浆、脑和外周组织中70 - 85%与磷脂结合的Ch。当去除饮食中的NADe并恢复Ch时，NADe消失，血浆和红细胞（RBC）胆碱水平在30 - 60天内恢复正常。苯甲托品（QNB）结合显示，继续食用NADe饮食的动物中，毒蕈碱受体持续受到抑制，但在反转组中恢复到对照水平。三种处理之间胆碱酯酶活性没有差异。胆碱乙酰转移酶活性恢复到对照水平，而在NADe动物中仍继续低于对照水平。后者的肝脏脂质升高，而对照和反转组没有显著差异。在生理功能方面，反转组动物的体重增加比继续食用NADe饮食的动物更快。反转动物的脑重量显著大于未反转的动物，但小于对照组。在反转期间的任何时候，核心体温与对照组没有差异。在行为方面，表明感觉反射和感觉知觉反应的伤害性阈值仍显著低于正常水平，即处于痛觉过敏状态。反转动物也仍然多动，并且显示出的记忆力明显比正常饮食的动物差，也就是说，与继续食用NADe的动物相比没有改善。总体而言，结果表明，尽管生化参数基本完全恢复，但NADe诱导的行为损失反映了中枢神经系统的持续变化。这些变化可能是形态学上的，或者与中枢神经系统中其他神经化学事件的适应性变化有关。
