Serotonin releasing agents: Neurochemical, therapeutic and adverse effects
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
References (125)
- et al.
Neurotransmitter transporters as molecular targets for addictive drugs
Drug Alcohol Depend
(1998) - et al.
TFMPP and RU24969 enhance serotonin release from rat hippocampus
Eur J Pharmacol
(1990) - et al.
Intravenous administration of the serotonin agonist m-chlorophenylpiperazine (mCPP) increases extracellular serotonin in the diencephalon of awake rats
Neuropharmacology
(1993) - et al.
1-(m-Chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain
Neuropsychopharmacology
(2001) - et al.
The substituted amphetamines 3,4-methylenedioxy-methamphetamine, methamphetamine, p-chloroamphetamine, and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine
Eur J Pharmacol
(1992) - et al.
Effects of chronic treatment with dexfenfluramine on serotonin in rat blood, brain, and lung tissue
Life Sci
(1994) - et al.
Cloning and expression of the mouse serotonin transporter
Brain Res Mol Brain Res
(1996) - et al.
Measurement of human brain dexfenfluramine concentration by 19F magnetic resonance spectroscopy
Brain Res
(1999) - et al.
Obesity drugs and the heart
Curr Probl Cardiol
(1999) - et al.
Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability
Trends Pharmacol Sci
(1997)
Effects of mCPP on the extracellular concentrations of serotonin and dopamine in rat brain
Neuropsychopharmacology
Blood pressure and plasma norepinephrine responses to dexfenfluramine in obese postmenopausal women
Am J Clin Nutr
Neurochemical mechanism of action of drugs which modify feeding via the serotoninergic system
Appetite
Differential effects of monoaminergic agonists on alcohol intake in rats fed a tryptophan-enhanced diet
Alcohol
Effects of phentermine and fenfluramine on alcohol consumption and alcohol withdrawal seizures in rats
Alcohol
Increased plasma serotonin in primary pulmonary hypertension
Am J Med
Combined serotonin and dopamine indirect agonists correct alcohol craving and alcohol-associated neurosis
J Subst Abuse Treat
d-, l- and dl-Fenfluramine cause long-lasting depletions of serotonin in rat brain
Brain Res
Ethanol consumption following acute fenfluramine, fluoxetine, and dietary tryptophan
Pharmacol Biochem Behav
BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension
Am J Hum Genet
Pulmonary hypertension, anorexigens, and 5-HT: pharmacological synergism in action?
Trends Pharmacol Sci
Allometric issues in drug development
J Pharm Sci
Serotonin-releasing effects of substituted piperazines in vitro
Biochem Pharmacol
Anorexigens and pulmonary hypertension in the United States: results from the Surveillance of North American Pulmonary Hypertension
Chest
Treatment of alcohol and cocaine addiction by the combination of pemoline and fenfluramine: a preliminary case series
J Subst Abuse Treat
Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin
Am J Cardiol
From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters
Biochim Biophys Acta
Appetite-suppressant drugs and the risk of primary pulmonary hypertension
N Engl J Med
Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study
Naunyn-Schmiedeberg's Arch Pharmacol
Neurotransmitter transporters: recent progress
Ann Rev Neurosci
Haemodynamic, metabolic, and endocrine effects of short-term dexfenfluramine treatment in young, obese women
Eur J Clin Pharmacol
Primary pulmonary hypertension. Report of the Commission of the German Society for research on blood circulation
Verh Dtsch Ges Kreislaufforsch
Cardiovascular safety of second-generation antihistamines
Am J Rhinol
Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan
Br J Clin Pharmacol
Combined phentermine/fenfluramine administration and central serotonin neurons
Synapse
Effects of d-fenfluramine and m-chlorophenylpiperazine on acute 5-HT release and long-term 5-HT depletion in rat brain
Soc Neurosci Abstr
The serotonin agonist m-chlorophenylpiperazine (mCPP) binds to serotonin transporter sites in human brain
NeuroReport
Functional consequences of central serotonin depletion produced by repeated fenfluramine administration in rats
J Neurosci
Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications
Synapse
Treatment of bulimia with fenfluramine and desipramine
J Clin Psychopharmacol
d-Fenfluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression
Obstet Gynecol
Dissociation of serotonergic regulation of anxiety and ethanol self-administration: a study with mCPP
Behav Pharmacol
Craving for cocaine in addicted users. Role of serotonergic mechanisms
Am J Addict
Effect of fenfluramine challenge on cocaine craving in addicted male users
Am J Addict
Pharmacokinetics of fenfluramine and norfenfluramine in volunteers given d- and dl-fenfluramine for 15 days
Eur J Clin Pharmacol
Factors that may affect the reduction of hunger and body weight following d-fenfluramine administration
Clin Neuropharmacol
Quantitation of dexfenfluramine/d-norfenfluramine concentration in primate brain using F-19 NMR-spectroscopy
Magn Reson Med
Valvular heart disease associated with fenfluramine–phentermine
N Engl J Med
Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine
Br J Pharmacol
Dexfenfluramine. An updated review of its therapeutic use in the management of obesity
Drugs
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