Neural Control of Dieting Counting Species Names

SCIENTIFIC CORRESPONDENCE

supersensitivity, and also by acting, via its Neural control of dieting principal metabolite ( + )norfenfluramine, as an agonist at 5-HT2c receptors and SIR - Tecott et al. 1 have shown that trans 100 thereby directly inducing satiety. The genic mice lacking the receptor for 0 effects of dexfenf!uramine as an anorectic the 5-hydroxytryptamine neurotransmitter 75 agent in humans are abolished by the co subtype 5-HT2c become obese through administration of ritanserin 7• overeating, indicating a primary role for ~ These findings emphasize the role of this receptor in the satiety response; these dr 50 5-HT2c receptors in controlling food () animals do not respond to the 5-HT2c intake and satiety, and suggest that dex receptor agonist m-chlorophenylpiperazine 25 fenfluramine might reset the balance 2 (mCPP). Cowen et al. emphasized that between 5-HT release and 5-HT2c recep antagonists for this receptor, such as cloza tor stimulation. Further work is required 0 pine and mianserin, cause troublesome - 5 to define how control of this receptor weight-gain in people; clozapine abolishes system parallels other, recently described, the endocrine responses to mCPP in Cytosolic calcium levels in CHO cells trans• sytems such as glucagon-like peptide-1 fected with the human recombinant 5-HT2c 3 9 10 humans • These authors showed that diet receptor. The concentration-response cu rve (ref. 8) and leptin • , to modulate satiety ing may be difficult because of an imbal for (+)norfenfluramine for increase in intracel• and obesity. In this respect, both the ance of brain 5-HT release and 5-HT2 c lular calcium is expressed as a percentage of leptin receptor and 5-HT2c receptors are receptors: dieting lowers plasma trypto the final response to 5-HT (3 µM). highly expressed in the choroid plexus phan, the precursor for brain 5-HT, which and, to a lesser extent, the hypothalamus. lowers levels of this neurotransmitter in the (0.1- 10 µ,M) increases calcium levels in M. Spedding brain, but secondarily increases postsynap the transfected CHO cells (see figure); C. Ouvry tic 5-HT2c receptor sensitivity2. Cowen et this effect is blocked by the mixed M. Millan al. showed an increase in 5-HT2c receptor 5-HT2A/5-HT2c receptor antagonist J. Duhault sensitivity by administering mCPP to mesulergine (100 nM). The 5-HT2c C. Dacquet women undergoing a 1,000-kcal daily diet; agonist (-)2,5-dimethoxy-4-iodoamphet Institute de Recherche Servier, they observed a marked increase in the amine (3 µ,M) mimics the effects of 125 Chemin de Ronde, prolactin response among those who diet ( + )norfenfluramine by increasing intra Croissy sur Seine 78290, France ed, and suggested that lowered 5-HT levels cellular calcium in CHO cells transfected R. Wurtman cause receptor supersensitivity. with the 5-HT2c receptor. Thus, dexfen Department of Brain and Dexfenfluramine is a widely prescribed fluramine shows a unique pharmacologi Cognitive Sciences, dieting agent; it has been shown to be cal spectrum by releasing brain 5-HT, Massachusetts Institute of Technology, effective in causing weight loss4, although which will also prevent 5-HT2c receptor Cambridge, Massachusetts 02139, USA the mechanism has not been fully defined. Dexfenfluramine causes a marked release of 5-HT from neurons by inhibiting Counting species names uptake of this neurotransmitter and by direct release5• In this way, the drug will SIR - Many estimates of global biodiver were described using criteria that few, if counteract the effects of reduced trypto sity depend critically on the extent to any, contemporary biologists would agree phan levels. However, dexfenfluramine which species have been catalogued1- 3. upon. These names were progressively has negligible affinity for 5-HT receptors. Estimating the number of recorded lumped into only seven quite variable The principal metabolite of dexfenflu species is not straightforward, because an 'species' (excluding those living in the ramine, ( + )norfenfluramine, is a potent unknown fraction of published descr\~ Nile), resulting in huge lists of synonyms. ligand in displacing [3H]-mesulergine tions refers to previously named species ·4. However, there is now strong and growing binding to human recombinant 5-HT2c It has recently been proposed that the evidence that this group has undergone a receptors transfected into cultured CHO overall fraction of synonyms can be esti remarkable diversification in the area7; cells, with a Ki of 1.6 ± 0.3 µ,M (nHi 11, 0.8 mated from extrapolations of revisions of even so, this upwards revision has only a ± 0.1; dexfenfluramine K;, 16.4 ± 3.3 µ,M; particular groups . However, the statistics slight impact on the synonymy rate, which nHilh 1.0 ± 0.2), confirming previous bind involved are tricky, and it is unclear drops from 99 to 93%. ing experiments in neuronal tissue5 • Brain whether the groups used to estimate 'syn A very different situation occurs in levels of ( + )norfenfluramine in rats onymy rates' are representative1• hydrobiids, minute snails often living in given dexfenfluramine at an appropriate The point can be illustrated with three springs and subterranean waters. Their anorectic dose (1.3 mg per kg intraperi groups of molluscs from the Mediter small size and the general absence of con toneally) are of the order of 3.6 nmol per ranean region. Melanopsids are relatively spicuous characters on their shells have g (ref. 6), several times the threshold for large, conspicuous freshwater snails. In kept them away from taxonomists. But receptor occupation. We also show that this century, the number of species most of the 50 species described in Iberias ( + )norfenfluramine is an agonist at 5- accepted by different workers has pro represent valid species, and indeed there HT2 c receptors, as ( + )norfenfluramine gressively diminished from more than 100 to only one, extremely variable, exceed ingly ancient 'species'5• Thus, the estimat 1. May, R, M. & Nee, S. Nature 378, 447-448 (1995). 1. Tecott, L. H. et al. Nature 374, 542- 546 (1995). 2. May, R, M. Phil. Trans. R. Soc. Land. B330, 293-304 2. Cowen, P. J., Clifford, E. M. , Williams, C., Walsh, A. E. S. ed synonymy rate in this group ranges (1990). & Fairburn. C. G. Nature 376, 557 (1995). from O to more than 99%. Comparative 3. Savage, J. BioScience 45, 673-679 (1995). 3. Kahn, R. S. Biol. Psychiat. 35, 903- 908 (1994). anatomy and molecular genetics unequiv 4. Solow, A. R., Mound, L.A. & Gaston, K. J. Syst. Biol. 44, 4 . Guy-Grand, B. et al. Lancet II, 1142- 1145 (1989). 93- 96 (1995). 5. Caccia, S. et al. Naunyn-Schmiedebergs Archs Pham1ak. ocally show that the number of species is 5. Brown, D. S. Freshwater Snails of Africa and Their 347, 306- 312 (1993). indeed fairly large6• A taxonomic revision Medical Importance 2nd edn (Taylor & Francis, London, 6. Garattini, S. Int. J. Obs. 16, S41- S48 (1992). 1994). 7. Goodall, E. M. Psychophannacology112, 461-466 in progress indicates that the amount of 6. Altaba, C, R. thesis, Univ. Pennsylvania (1991). (1994). synonyms is probably near 40%. 7. Altaba, C. R. But/I. Inst. Cat. Hist. Nat. 60, 23-44 8 . Turton, M. D. et al. Nature 379, 69- 72 (1996). (1993). 9 . Zhang, Y. et al. Nature 372, 425-432 (1994). Freshwater mussels (unionoids) have a 8. Boeters, H. D. Arch. Moll. 118, 181- 261 (1988). 10. Tartaglia, L. A. et al. Cell 83, 1263- 1271 (1995). similar taxonomic history. Many species 9. May, R. Nature 347, 129-130 (1990). 488 NATURE · VOL 380 · 11 APRIL 1996