Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response.
Smith-Lemli-Opitz (SLO) syndrome is a congenital disorder characterized by severe mental retardation. Patients with SLO lack 7-dehydrocholesterol (7 dH) reductase, which catalyzes the last step of cholesterol synthesis. Administration of an agent that blocks 7 dH cholesterol reductase, BM 15.766 (BM), leads to a biochemical profile which resembles that of SLO patients, i.e., lower plasma, liver, and brain cholesterol levels accompanied by the appearance of the precursors 7 dH and 8 dH cholesterol. In this article we address the functional consequences of chronic BM treatment on new motor learning by assessing acquisition of the classically conditioned eyeblink response. Just-weaned rats were fed BM by gavage for four months, with half of these rats given exogenous cholesterol during the last two months of BM treatment. Acquisition of the eyeblink response was impaired in BM-treated rats. Impaired acquisition of the eyeblink response was not accompanied by alterations in responsiveness to either the conditioned or unconditioned stimulus. Exogenous cholesterol, a clinically relevant countertreatment, failed to correct for the learning impairment produced by BM treatment. Chronic treatment with a cholesterol synthesis-blocking agent impaired associative learning in just-weaned rats.
O'Brien
W T
WT
Department of Neurosciences, New Jersey Medical School, Newark, USA.
Xu
G
G
Tint
G S
GS
Salen
G
G
Servatius
R J
RJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001767:Blinking / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012815:Signal Processing, Computer-Assisted; D013261:Sterols / Q000097:blood / Q000737:chemistry / Q000378:metabolism
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D013261:Sterols; C047457:BM 15766; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase