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.