Pharmacology Bh~chemistry& Behavior, Vol. 14, pp. 661-667, 1981.Printed in the U.S.A. Tolerance to Anorectic Drugs: Pharmacological or Artifactual DAVID A. LEVITSKY, BARBARA J. STRUPP AND JANET LUPOLI Division of Nutritional Sciences and Department of Psychology 114 Savage Hall, Cornell University, Ithaca, NY 14853 Received 23 July 1980 LEVITSKY, D. A., B. J. STRUPP AND J. LUPOLI. Tolerance to anorectic drugs: Pharmacoh~gical or art(factual. PHARMAC. BIOCHEM. BEHAV. 14(5) 661-667, 1981.--The results of three studies are presented which demonstrate that the anorexia produced by amphetamine and fenfluramine is secondary to a direct weight suppressing effect of these drugs. Furthermore, these data strongly suggest that the decreasing weight loss and the return to normal appetite that occurs with repeated drug usage is not due to pharmacological tolerance, but rather reflects a successful physiological and behavioral adjustment to a lowered level of body weight. Anorectic drugs Tolerance Body weight regulation Food intake Appetite AMPHETAMINE has long been used in the treatment of obesity, due to its effectiveness in suppressing appetite [11,20]. However, there are several properties of this drug that make its use in therapy less than ideal. One of the major deleterious properties is the development of tolerance. Tolerance, as classically defined, is the decrease in the ef- fectiveness of a drug with repeated administration [12]. Tolerance to the anorectic effects of amphetamines has been repeatedly observed in both animals [18] and humans [1]. What is unusual about the tolerance to amphetamines is that it seems to be limited to the anorexia, since other behavioral effects of the drug such as increased motor activity and stereotypy [ 18] do not show tolerance with repeated adminis- trations. The traditional explanation of drug tolerance is based on a decrease in the sensitivity of drug receptors (pharmaco- dynamic tolerance) or an increase in the effectiveness of the drug degrading systems (drug disposition tolerance). However, an alternative explanation of the tolerance to anorectic drugs is also possible. One consequence of an ad- ministration of an anorectic drug is a loss in body weight. It is possible that the effectiveness of the anorectic drug is directly related to level of body weight. Thus, what appears as the development of tolerance with repeated administra- tion of the drug may, in fact, be the result of the accompany- ing decline in body weight. The studies reported below ex- plore this latter explanation of the development of tolerance to two commonly used anorectic drugs, amphetamine and fenfluramine. EXPERIMENT 1: EFFECT OF PRIOR WEIGHT LOSS ON AMPHETAMINE-INDUCED ANOREXIA If the weight loss hypothesis of tolerance is correct, then the anorectic effectiveness of amphetamine should be greatly diminished by reducing body weight prior to drug adminis- tration. METHOD Thirty-nine albino female rats were divided into four groups matched on the basis of body weight and daily food intake. Both the control group (C) (n=9) and the weight re- duced (RC) nondrugged group (n=10) received l cc of tap water daily, administered through stomach gavage, from day 1 to day 60 of the experiment. Two groups, the drugged (D) (n= 10) and weight reduced drugged (RD) (n= 10) group, re- ceived 1 cc of water via stomach gavage from day l until day 6, then were given 30 mg/kg of d-amphetamine sulfate from day 7 until day 60. The dosage was calculated according to body weight on day 1 and was held constant throughout the experiment. The weight reduced groups were deprived of food during the first 6 days of the experiment; thereafter they received free access to ground Agway rat chow in their home cages. Food intake was calculated daily for each animal to the nearest tenth gram, and was equal to the difference be- tween the starting weight of the food cup plus chow and the ending weight, minus the spillage. All animals were housed singly, had continual access to water, and were maintained on a 12-hour light-dark cycle. Room temperature was held constant at 25°C. RESULTS AND DISCUSSION The results of these manipulations on food intake and body weight can be seen in Fig. 1. The conventionally drug treated animals which received the drug at their normal body weight showed the typical tolerance pattern. When drug treatment began there was a statistically significant suppres- sion in daily food intake of D group compared to RD group ~Support for these studies was provided by a grant from the National Science Foundation, and New York State Hatch funds. Copyright ~ 1981 ANKHO International Inc.--0091-3057/81/050661-07501.20/0