title: Therapeutic and adverse actions of serotonin transporter substrates.
abstract: A variety of drugs release serotonin (5-HT, 5-hydroxytryptamine) from neurons by acting as substrates for 5-HT transporter (SERT) proteins. This review summarizes the neurochemical, therapeutic, and adverse actions of substrate-type 5-HT-releasing agents. The appetite suppressant (+/-)-fenfluramine is composed of (+) and (-) isomers, which are N-de-ethylated in the liver to yield the metabolites (+)- and (-)-norfenfluramine. Fenfluramines and norfenfluramines are potent 5-HT releasers. (+/-)-3,4-Methylenedioxymethamphetamine ((+/-)-MDMA, "ecstasy") and m-chlorophenylpiperazine (mCPP) are substrate-type 5-HT releasers. Fenfluramines, (+/-)-MDMA, and mCPP release neuronal 5-HT by a common non-exocytotic diffusion-exchange mechanism involving SERTs. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of valvular heart disease, whereas the latter activity is implicated in the anorexic effect of systemic fenfluramine. Appetite suppressants that increase the risk for developing primary pulmonary hypertension (PPH) are all SERT substrates, but these drugs vary considerably in their propensity to increase this risk. For example, fenfluramine and aminorex are clearly linked to the occurrence of PPH, whereas other anorectics are not. Similarly, some SERT substrates deplete brain tissue 5-HT in animals (e.g., fenfluramine), while others do not (e.g., mCPP). In addition to the established indication of obesity, 5-HT releasers may help treat psychiatric disorders, such as drug and alcohol dependence, depression, and premenstrual syndrome. Viewed collectively, we believe new medications can be developed that selectively release 5-HT without increasing the risk for adverse effects of valvular heart disease, PPH, and neurotoxicity. Such agents may be useful for treating a variety of psychiatric disorders.
authors.affiliation: Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, P. O. Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. rothman@intra.nida.nih.gov
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D006349:Heart Valve Diseases / Q000139:chemically induced; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced; D011985:Receptors, Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000009:adverse effects* / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D001067:Appetite Depressants; D011985:Receptors, Serotonin; D018490:Serotonin Agents