Abstract
In order further to understand factors affecting cholesterol metabolism in adult animals, we have studied the effect of a central nervous system stimulant, methylphenidate (Ritalin), on brain cholesterol metabolism. Structurally, this compound is related to compounds having a hypocholesterolemic effect (1,2,3), and also acts as a central nervous system stimulant(4). A preliminary report of these experiments has been published (5). The present paper is a more complete study of the effect of this drug on acetate incorporation into brain cholesterol.
Experimental. Radioactive precursors. Acetate-2-3H (10 mC/m-mole); acetate-l-14C (2.8 mC/m-mole); acetate-2-14C (1.5 mC/m-mole) were used simultaneously in these studies. Radioactive nutrients were dissolved in physiological saline, with benzyl alcohol (0.9%) added as a preservative. The resultant solutions were injected intraperitoneally.
The drug (methylphenidate) Ritalin, donated by Ciba Pharmaceutical Co. (H. Sheppard), was prepared as a 1% solution in saline. The stock solution was diluted shortly before injection.
Methylphenidate was studied at 2 dose levels, 4 mg/kg and 20 mg/kg, representing respectively 1/35 and 1/7 of the usual LD50. At these drug levels, no loss of appetite for food in solid or liquid form was observed nor was loss of weight noted. During the experimental period, weight gained by animals on the drug regime was comparable to that of the control group.
Dose level and schedule of treatment, before isotope injections, were established partially from experiments previously reported (4). These prior studies showed that maximum drug action appeared after one hour and lasted for several hours. The drug was excreted rapidly; over 80% was found in the urine in approximately 8 hours. By giving the mice subcutaneous doses of 2 mg/kg or oral doses of 15 mg/kg, spontaneous movement was increased by a factor of 4 or more.
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