Accumulation of hypothalamic endorphins after repeated injections of anorectics which release serotonin

Two anorectic drugs which stimulate serotonin neuronal activity by releasing serotonin from nerve terminals, d-fenfluramine and CM 57 277 (4-amino-[6-chloro-2-pyridyl]-1-piperidine HCl), were studied in rats. Both drugs, when given for 5 days at doses of 15 mg of d-fenfluramine per kg/day and 20 mg of CM 57 277 per kg/day, decreased body weight gain and increased content of Met5-enkephalin and beta-endorphin in hypothalamus, but not in frontal cortex or pituitary. The increase in the hypothalamic content of the two opioid peptides elicited by d-fenfluramine was reversed by metergoline and p-chlorophenylalanine, suggesting that it is mediated by serotonin. The content of two other hypothalamic neuropeptides, cholecystokinin and substance P, were not affected by d-fenfluramine. Although Met5-enkephalin content in striatum was increased transiently by d-fenfluramine, this was not a serotonin-mediated effect because it was not abolished by metergoline. The decrease in body weight gain was prevented by metergoline, but not by i.p. injection of p-chlorophenylalanine. The effect of p-chlorophenylalanine on intestine may contribute to its failure in reversing the anorectic effect of d-fenfluramine. Naltrexone, an antagonist of opiate receptor, decreased body weight gain but exerted no effect on hypothalamic Met5-enkephalin or beta-endorphin content. Taking into consideration that the increase in Met5-enkephalin and beta-endorphin may have resulted from accumulation due to decreased utilization, the anorectic effects of serotonin releasing drugs may be mediated by a reduction in the functional role of hypothalamic opioid peptides.