SCIENTIFIC CORRESPONDENCE Neural control of dieting

SIRTecott el al.' have shown that (ransgenic mice lacking the receptor for the 5-hydroxytryptamine neurotransmittcr subtype 5-HTx become obese through overeating, indicating a primary rolc for this receptor in the satiety response; these animals do not respond to the 5-HTx. receptor agonist m-chlorophenylpiperazine (mCPP). Cowen et al.2 emphasized that antagonists for this receptor, such as cIozapine and mianserin, cause troublesome weight-gain in people; cIozapine abolishes the endocrine responses to mCPP in humans>. These authors showed that dieting may be difficultbecauseof an imbalance of brain 5-HT release and 5-HT2C receptors: dieting lowers plasma tryptophan, the precursor for brain 5-HT,which lowers levels of this neurotransmitter in the brain, but secondarily increases postsynaptic 5-HT2C receptor sensitivitY. Cowen et al. showed an increase in 5-Hf2C receptor sensitivity by administering mCPP to womenundergoinga 1,OOO-kcal daily diet; they observed a marked increase in the prolactin response among those who dieted, and suggested that lowered 5-HT levels cause receptor supersensitivity. Dexfenfluramine is a widely prescribed dieting agent; it has been shown to be effective in causing weight loss4, although the mechanism has not been fully defined. Dexfenfluramine causes a marked release of 5-Hf from neurons by inhibiting uptake of this neurotransmitt~r and by direct releases. In this way, the drug will counteract the effects of reduced tryptophan levels. However, dexfenfluramine has negligible affinity for 5-Hf receptors. The principal metabolite of dexfenfluramine, (+ )norfenfluramine, is a potent ligand in displacing r>H]-mesulergine binding to human recombinant 5-HT2C receptors transfected into cultured CHO cells,with a Kj of 1.6 :!:0.3 fJ.M(nHilh 0.8 :!:0.1; dexfenfluramine Kj, 16.4:!: 3.3 fJ.M; I1Hilh 1.0:!:0.2), confirmingpreviousbinding experiments in neuronal tissue". Brain levels of (+ )norfenfluramine. in rats given dexfenfIuramine at an appropriate anorectic dose (1.3 mg per kg intraperitoneally) are of the order of 3.6 nmol per g (ref. 6), several times the threshold for receptor occupation. We also show that ( + )norfenfluramine is an agonist at 5HT:c receptors, as (+ )norfenfIuramine