Janis Carlton

Inhibition of gastric emptying by peripheral and central fenfluramine in rats: correlation with anorexia

Rats treated acutely with i.p. fenfluramine showed a profound inhibition of emptying of a chow meal from the stomach. This inhibition was attenuated by previous chronic treatment with fenfluramine. Tolerance to the gastric slowing occurred with as few as 2-4 prior injections, a time course which closely matches tolerance to the anorectic effects of the drug. Cerebroventricular injections of fenfluramine and norfenfluramine in anorectic doses also inhibited gastric emptying.

Metabolic and neurochemical correlates of glucoprivic feeding

Various hypotheses are reviewed concerning the mechanisms of feeding induced by insulin or 2DG. New data are presented to show that elevated plasma ketone levels are not sufficient to suppress 2DG feeding, suggesting that nourishment of the brain either does not occur or is not sufficient to stop 2DG feeding. We find that both acetoacetate and hydroxybutyrate suppress spontaneous feeding. Another series of studies investigated the effects of 2DG and insulin on catecholamine turnover in several brain regions of animals that do (rat, mouse) or do not (hamster) eat in response to these stimuli. The effects of glucoprivic stimuli on NE turnover were minimal; however, 2DG did appear to inhibit DA turnover, especially in nucleus accumbens. Thus, brain NE does not seem specifically involved in glucoprivic feeding, data which are supported by a lack of additivity of feeding induced by 2DG and by clonidine. Finally, to resolve some of the disparate data concerning the effects of glucose infusion on insulin-induced feeding, we examined the time course for effects on feeding and for glucose tolerance. It appears that glucose strongly inhibits feeding only when it is utilized.

Different behavioral mechanisms underlie tolerance to the anorectic effects of fenfluramine and quipazine

Chronic administration of fenfluramine or quipazine before scheduled faily feeding sessions led to rapid and complete tolerance to the initial anorexia. Rats that received daily injections of fenfluramine after the daily meal also developed full tolerance. In contrast, quipazine administration after meals led to the development of little tolerance, indicating that quipazine tolerance appears to be learned or contingent. The implications of these data for neurochemical mechanisms of satiety are discussed.

Tolerance to fenfluramine anorexia: fact or fiction?

Recent findings in this laboratory with regard to tolerance to fenfluramine anorexia are reviewed with respect to generality of the behavioural phenomenon. A systematic relationship between initial body weight and fenfluramine-induced weight change in rats is described. The possible roles of peripheral factors in fenfluramine anorexia and tolerances, including gastric emptying and peripheral serotonin, are discussed. The role of central factors is also considered. It appears that fenfluramine, and possibly other anorectic agents have multiple sites of action and affect multiple behaviours. Some clinical implications are noted.

Failure of 2-deoxy-D-glucose to stimulate feeding in deermice

Deermice (Peromyscus maniculatus) did not increase their food intake above baseline following treatment with 2-deoxy-D-glucose (2DG, 500 or 1000 mg/kg). They did eat more following food deprivation or treatment with insulin at a high dose (100 U/kg). House mice (Mus musculus) showed hyperphagia to 2DG, low dose of insulin (5 U/kg) and deprivation.

Effects of fenfluramine on food intake, body weight, gastric emptying and brain monoamines in syrian hamsters

In the first experiment, dose-inhibition and -time functions are documented for the anorectic effects of d,l-fenfluramine in Syrian hamsters (Mesocricetus auratus). A dose of 20 mg/kg (IP) inhibited feeding for at least 2-4 hr. In the second experiment, chronic treatment of hamsters housed either in running wheels (exercise) or standard (sedentary) conditions with d,l-fenfluramine (20 mg/kg) produced an attenuation of weight gain relative to vehicle-treated controls. However, there was no differential weight loss in the exercising drug-treated group. This result was also obtained using 10 mg/kg d-fenfluramine. In the third experiment, d,l-fenfluramine greatly inhibited gastric emptying of a test meal in hamsters. In the fourth experiment, hamsters were found to sustain only small and transient decreases in brain 5HT and 5HIAA levels after acute or chronic treatment with d,l-fenfluramine. These findings are compared and contrasted with the known effects of fenfluramine in rats. It is concluded that there may be species differences in the impact of fenfluramine on brain function, and that this may not be in any simple way related to the anorexigenic action of this drug.

Effect of chronic administration of fenfluramine and quipazine on body weight gain after ovariectomy and on brain serotonin receptor binding.

Chronic fenfluramine administration prevented excess weight gain following ovariectomy in rats but did not alter weight gain in sham-operated controls. Chronic quipazine treatment had no long-term effect on body weight. In one experiment, fenfluramine treatment for 28 days produced a 13% decrease in [3H]-serotonin binding to hypothalamic membranes and no change in [3H]-spiroperidol binding to striatum. In a second experiment, however, chronic fenfluramine had no effect on [3H]-serotonin binding to diencephalon. These results are discussed in terms of central and peripheral mechanisms of action and tolerance to fenfluramine.

Effect of dexfenfluramine on taste preferences and aversions in rats

Administration of D-fenfluramine immediately following ingestion of a distinctively flavored solid or liquid diet led to subsequent rejection of that flavor when offered in a two-flavor choice test. This effect occurred with both solid and liquid diets.