Dissociation of the antiaggression and serotonin-depleting effects of fenfluramine

Fenfluramine or non-fenfluramine produced a marked and persistent depletion of whole-brain serotonin and antagonized potently the apomorphine-induced aggression response in Long Evans male rats. Chronic treatment with fenfluramine or norfenfluramine resulted in the development of complete tolerance to the antiaggression action of fenfluramine whereas tolerance to the serotonin-depleting action was not observed. Pretreatment with chlorimipramine antagonized both the anti-aggression and the serotonin-depleting activity of fenfluramine yet the antiaggression activity of haloperidol was unaffected. Neither p-chlorophenylalanine nor the combination of α-methyl-p-tyrosine and reserpine affected the antiaggression activity of fenfluramine. It is concluded that the serotonin-depleting and antiaggression effects are dependent upon the ability of fenfluramine to gain access into the serotonergic neuron and that whereas serotonin release can account for the antiaggression action, release does not seem to explain adequately the depleting action of fenfluramine.