RELATIONSHIP BETWEEN ABNORMAL CHOLESTEROL-SYNTHESIS AND RETARDED LEARNING IN RATS

We examined the relationship between brain sterol composition and asso ciative learning (classical conditioning of the eyeblink response) in newly weaned rats fed BM 15.766 (BM) for 4 months. This compound inhib its 7-dehydrocholesterol-Delta(7)-reductase, which catalyzes the conve rsion of 7-dehydrochoresterol to cholesterol, the last step in the syn thetic pathway. As countertreatment, half of the BM-treated rats were fed 2% cholesterol during the last 2 months. With BM, cholesterol conc entrations declined 91% in plasma, brat with cholesterol feeding, the levels increased 50% compared with baseline values. 7-Dehydrocholester ol, which was not detected at baseline, increased to 55% of plasma ste rols with BM but decreased to 5% of total plasma sterols when choleste rol was added. With BM, brain cholesterol levels decreased 60% and did nor increase after cholesterol was added. However, 7-dehydrocholester ol, which comprised 39% of brain sterols with BM, decreased to 31% (P < .05) when cholesterol was fed. Hydroxymethyl glutaryl coenzyme A (HM G-CoA) reductase activity in the liver increased 2.2-fold with BM and declined 95% after adding cholesterol, but did not change in the brain . BM treatment for 4 months prevented learning of the conditioned eyeb link response as compared with controls. In contrast, BM-treated rats supplemented with cholesterol acquired the conditioned eyeblink respon se. Chronic inhibition of 7-dehydrocholesterol-Delta(7)-reductase redu ced cholesterol and increased 7-dehydrocholesterol levels in plasma an d brain, and was associated with impaired learning, Cholesterol feedin g corrected plasma and hepatic sterol levels and reduced brain 7-dehyd rocholesterol concentrations to reestablish normal learning, Copyright (C) 1998 by W.B. Saunders Company.