Serotonin releasing agents: Neurochemical, therapeutic and adverse effects

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Abstract

This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents. The 5-HT releaser (±)-fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (−)-fenfluramine, which are N-de-ethylated to yield the metabolites, (+)-norfenfluramine and (−)-norfenfluramine. Fenfluramines and norfenfluramines are 5-HT transporter substrates and potent 5-HT releasers. Other 5-HT releasing agents include m-chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant drug trazodone. Findings from in vitro and in vivo studies support the hypothesis that fenfluramines and mCPP release neuronal 5-HT via a non-exocytotic carrier-mediated exchange mechanism involving 5-HT transporters. (+)-Norfenfluramine is a potent 5-HT2B and 5-HT2C receptor agonist. The former activity may increase the risk of developing valvular heart disease (VHD), whereas the latter activity is implicated in the anorectic effect of systemic fenfluramine. Anorectic agents that increase the risk of developing primary pulmonary hypertension (PPH) share the common property of being 5-HT transporter substrates. However, these drugs vary considerably in their propensity to increase the risk of PPH. In this regard, neither trazodone nor mCPP is associated with PPH. Similarly, although some 5-HT substrates can deplete brain 5-HT (fenfluramine), others do not (mCPP). In addition to the established indication of obesity, 5-HT releasers may be helpful in treating psychiatric problems such as drug and alcohol dependence, depression and premenstrual syndrome. Viewed collectively, it seems possible to develop new medications that selectively release 5-HT without the adverse effects of PPH, VHD or neurotoxicity. Such agents may have utility in treating a variety of psychiatric disorders.

Introduction

Monoamine neurons in the brain possess membrane-bound proteins that function to transport neurotransmitter molecules from the extracellular space back into the cytoplasm (Amara and Kuhar, 1993). It is now well established that distinct transporter proteins are expressed on NE neurons (i.e., NE transporters, NET), DA neurons (i.e., DA transporters, DAT) and 5-HT neurons (i.e., 5-HT transporters, SERT). These proteins are members of a superfamily of sodium/chloride-dependent transporters that share genetic, structural and functional homologies (Uhl and Johnson, 1994). Under normal circumstances, the transporter-mediated uptake of monoamine transmitters is the principal mechanism for inactivation of monoaminergic transmission in the brain. Moreover, monoamine transporters are targets for a variety of therapeutic and abused drugs (Amara and Sonders, 1998).

Drugs that interact with transporters can be divided into two basic classes: reuptake inhibitors and substrate-type releasers. Reuptake inhibitors bind to transporter proteins, but are not transported. These drugs elevate extracellular concentrations of transmitter by blocking transporter-mediated uptake of transmitters from the synapse. Substrate-type releasers also bind to transporter proteins, but these drug molecules are subsequently transported into the cytoplasm of nerve terminals. Releasers elevate extracellular transmitter concentrations by a two-pronged mechanism: (1) they increase cytoplasmic levels of transmitter by disrupting storage of transmitters in vesicles and (2) they promote non-exocytotic release of transmitters by a process of carrier-mediated exchange (Rudnick and Clark, 1993). Because substrate-type releasing agents must be transported into the nerve terminal to promote neurotransmitter release, reuptake inhibitors can block the effects of releasers.

Reuptake inhibitors and substrate-type releasers both elevate extracellular concentrations of transmitter via transporter-dependent processes, but there are important differences in their precise mode of action. In particular, the ability of reuptake inhibitors to elevate extracellular neurotransmitter requires that nerve terminals release neurotransmitters via exocytosis. This, in turn, requires electrical depolarization and extracellular calcium. Thus, the ability of reuptake inhibitors to increase extracellular neurotransmitter levels is said to be impulse- and calcium-dependent. Releasing agents, on the other hand, increase synaptic levels of neurotransmitter by a process that is independent of ongoing neuronal firing. Since the action of reuptake inhibitors requires ongoing neuronal firing, autoreceptor-mediated negative feedback mechanisms serve to dampen the ability of 5-HT reuptake inhibitors to elevate synaptic transmitter. Such negative feedback effects exist for 5-HT Adell and Artigas, 1991, Rutter et al., 1995, Smith and Lakoski, 1997, DA (Hinerth et al., 2000) and NE (Mateo et al., 1998) neuron systems, and these effects do not alter the actions of releasers. Because of negative feedback inhibition, reuptake inhibitors tend to produce small increases in extracellular neurotransmitter whereas releasers tend to produce more robust increases. The in vivo microdialysis data in Fig. 1 illustrate the modest and sustained elevation of extracellular 5-HT evoked by the 5-HT reuptake inhibitor fluoxetine compared to the much larger and transient effect of the 5-HT releaser, (+)-fenfluramine Berger et al., 1992, Crespi et al., 1997.

A number of 5-HT selective reuptake inhibitors (SSRIs), such as fluoxetine, sertraline and citalopram, are widely prescribed medications used in the treatment of psychiatric disorders including depression, panic disorder and obsessive–compulsive disorder (for reviews, see Gorman and Kent, 1999, Zohar and Westenberg, 2000). By contrast, there are far fewer 5-HT releasing agents. Because of the withdrawal of the 5-HT releasers, fenfluramine and dexfenfluramine, from the market in September 1997 (Connolly and McGoon, 1999), there are currently no clinically available 5-HT releasing agents. A main goal of this paper is to summarize the potential therapeutic uses and reported adverse effects of 5-HT releasing agents. Furthermore, we hope this review will stimulate continued interest in the development of novel and selective 5-HT releasers that can be used as effective medications.

Section snippets

Neurochemical mechanisms of 5-HT releasing agents

(±)-Fenfluramine (Pondimin) and its more potent stereoisomer, (+)-fenfluramine (dexfenfluramine, Redux), are substituted amphetamine derivatives. These drugs were used for the treatment of obesity until they were withdrawn from the market in September 1997, due to reports of cardiac valvulopathy (Connolly and McGoon, 1999). (±)-Fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (−)-fenfluramine, which are N-de-ethylated in the liver to form the metabolites, (+)-norfenfluramine

Therapeutic applications of 5-HT releasers

As noted above, (±)-fenfluramine and (+)-fenfluramine are the only 5-HT releasers ever approved for use in humans, and mCPP has been used clinically as an investigational drug. In fact, all three drugs are “promiscuous” ligands. While these drugs potently release 5-HT, their activation of 5-HT2B and 5-HT2C receptors undoubtedly contributes to their in vivo pharmacological effects. Our inferences concerning potential therapeutic uses of 5-HT releasing agents necessarily derive from studies of

Adverse effects of 5-HT releasing agents

Both (±)-fenfluramine and (+)-fenfluramine produce mild and reversible side effects in some patients Weintraub and Bray, 1989, Weintraub et al., 1984, Hanotin et al., 1998. Of greater concern to the risk-benefit ratio of these medications is the increased risk of developing serious side effects such as primary pulmonary hypertension (PPH), valvular heart disease (VHD) and perhaps neurotoxicity. In fact, as noted above, a marked increase in the incidence of VHD in patients treated with

Summary

The pharmacology of 5-HT releasing agents is relatively unexplored. This situation is likely due to the limited number of drugs that selectively release 5-HT relative to DA and NE. Additionally, all of the available 5-HT releasers possess significant 5-HT receptor affinities. When administered systemically, (±)-fenfluramine generates a total of four active drugs; these drugs not only release endogenous 5-HT but also activate multiple 5-HT receptors including 5-HT2B and 5-HT2C subtypes. Only two

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