SELECTIVE SEROTONIN REUPTAKE INHIBITORS DISSOCIATE FENFLURAMINES ANORECTIC AND NEUROTOXIC EFFECTS - IMPORTANCE OF DOSE, SPECIES AND DRUG

Fenfluramine, a clinically prescribed appetite suppressant, has been f ound to damage brain serotonin (5-HT) neurons in every animal species tested to date. Recent findings indicate that fluoxetine, a selective 5-HT reuptake inhibitor (SSRI), can prevent fenfluramine-induced 5-HT neurotoxicity without blocking fenfluramine-induced appetite suppressi on. The purpose of our studies was several-fold: 1) To determine wheth er the ability for fluoxetine to dissociate fenfluramine-induced anore xia and neurotoxicity is dose-related; 2) to ascertain whether other S SRIs also prevent fenfluramine-induced neurotoxicity without altering its anorectic effect; 3) to determine whether similar fluoxetine/fenfl uramine interactions are seen in another animal species (i.e., mice) a nd 4) to determine whether decreases in food intake seen after the flu oxetine/fenfluramine combination can be attributed to nonspecific beha vioral suppression. Results from our studies indicate that fluoxetine' s effects are, indeed, dose-related, because higher doses of fluoxetin e are required to protect against the 5-HT neurotoxic effects of highe r doses of fenfluramine. Further, our results indicate that fluoxetine 's effects generalize to all other SSRIs tested (citalopram, paroxetin e and sertraline), as well as to other species (mice). Finally, our re sults demonstrate that anorexia in animals receiving the fenfluramine/ fluoxetine combination is not secondary to nonspecific behavioral supp ression, because water intake is increased although food intake is dec reased in the same animals. Together, these data suggest that the anor ectic and 5-HT neurotoxic effects of fenfluramine may involve differen t mechanisms, and that by combining fenfluramine with SSRIs, it may be possible to exploit fenfluramine's clinically useful properties (e.g. , anorexia) without risking brain 5-HT neural injury.