Incomplete reversibility of an experimentally induced hypocholinergic state: biochemical and physiological, but not...

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.