Peripheral and central mechanisms of action of serotoninergic anorectic drugs

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Several pieces of evidence indicate that brain serotoninergic systems play an inhibitory role in feeding, being specifically involved in regulating satiety and food selection. The anorectic drug fenfluramine has been shown to exert its effects by activating serotoninergic mechanisms. Since fenfluramine influences both central and peripheral serotonin stores, it is difficult to establish the relative contributions of the central and peripheral serotoninergic mechanisms in the regulation of feeding behaviour. In the present paper evidence is presented that changes in feeding come about In the present paper evidence is presented that changes in feeding come about after interventions in either the brain or the periphery. This evidence includes the observation that serotonin itself given subcutaneously causes a dose-related anorexia in rats trained to eat four hours a day, an effect antagonized not only by metergoline but also by xilamidine, a serotonin antagonist that does not cross the blood-brain barrier. Since serotonin given systemically cannot reach the brain, its effect is ascribed to the activation of peripheral mechanisms. Furthermore, as is the case with fenfluramine, subcutaneous administration of serotonin is able to completely counteract the overeating induced by the glucoprivic agents insulin and 2-deoxy-D-glucose (2-DG). It is concluded that activation of peripheral serotoninergic mechanisms is sufficient not only to reduce eating in rats trained to eat four hours a day, but also to control the hyperphagias brought about by insulin or 2-DG.