The acute and chronic effects of the "serotonergic
anorectics"
quipazine and dl-
fenfluramine were examined in rats with substantial and specific depletions of brain
5-hydroxytryptamine (5-HT) induced by
5,7-dihydroxytryptamine (5,7-DHT). A "dessert" test which did not involve food deprivation was used to assess
anorexia. Markedly increased sensitivity to the L-5-HTP-induced behavioral syndrome in 5,7-DHT-lesioned rats indicated postsynaptic
5-HT receptor supersensitivity. We found low (2 mg/kg) and intermediate (5 mg/kg) doses of
fenfluramine, a putative presynaptic agent, were more effective in producing
anorexia in lesion rats versus controls. A higher dose of
fenfluramine (10 mg/kg) was less effective in lesion rats, suggesting that high dose and low dose
fenfluramine anorexia are mediated by different mechanisms. We found
quipazine, a putative
5-HT postsynaptic agonist, in a dose range of 2-10 mg/kg, to be no more effective in producing
anorexia in lesion rats compared to controls. The development of tolerance to both
fenfluramine and
quipazine anorexia was similar for lesion and control rats showing that an intact brain
5-HT system is not necessary for tolerance. Tolerance to the "behavioral syndrome" induced by high doses of these agents developed rapidly in controls but not at all in lesion rats. This suggests that the behavioral syndrome and
anorexia are independent effects of
fenfluramine and
quipazine. These results also challenge the popular notion that the primary
anorectic action of
fenfluramine is via brain
serotonin.