Serotonin: A never-ending story

doi:10.1016/j.ejphar.2014.10.031

European Journal of Pharmacology

Volume 753, 15 April 2015, Pages 2-18

https://doi.org/10.1016/j.ejphar.2014.10.031 Get rights and content

Abstract

The neurotransmitter serotonin is an evolutionary ancient molecule that has remarkable modulatory effects in almost all central nervous system integrative functions, such as mood, anxiety, stress, aggression, feeding, cognition and sexual behavior. After giving a short outline of the serotonergic system (anatomy, receptors, transporter) the author׳s contributions over the last 40 years in the role of serotonin in depression, aggression, anxiety, stress and sexual behavior is outlined. Each area delineates the work performed on animal model development, drug discovery and development. Most of the research work described has started from an industrial perspective, aimed at developing animals models for psychiatric diseases and leading to putative new innovative psychotropic drugs, like in the cases of the SSRI fluvoxamine, the serenic eltoprazine and the anxiolytic flesinoxan. Later this research work mainly focused on developing translational animal models for psychiatric diseases and implicating them in the search for mechanisms involved in normal and diseased brains and finding new concepts for appropriate drugs.

Section snippets

Serotonin, history, drugs

My career in serotonin research started in Groningen at the Biological Psychiatry laboratory of Professor Herman van Praag in 1973 where I contributed to the PhD research of Netty Bouhuys (Bouhuys, 1976). At that time the involvement of serotonin (5-hydroxytryptamine; 5-HT) in mental functions was only emerging after the first suggestions in the 1950s (Gaddum, 1954, Brodie et al., 1955). Initially much research was performed into the synthesis and degradation of this neurotransmitter. In the

Serotonin and depression

A neuronal reuptake mechanism for terminating action of neurotransmitters released from nerve terminals was first found for noradrenaline (Hertting and Axelrod, 1961), followed for other neurotransmitters, including serotonin (Blackburn et al., 1967, Ross and Renyi, 1967). Soon it was realized that this mechanism had an important regulatory function in the activity of serotonergic neurons. Moreover, due to the then existing theories about the relationship between (low) activity of

Serotonin and aggression

My story on aggression started at Groningen University, where I did an undergraduate study in neurobiology on the role of the ventromedial hypothalamus in social behavior in male mice. Electrolytic lesions of the median hypothalamus led to complex behavioral changes in feeding, aggression and sexual behavior (Olivier and Wiepkema, 1974). Subsequently I continued my graduate studies on the role of the hypothalamus in social and aggressive behavior in the rat receiving my PhD in 1977 (Olivier,

Serotonin and anxiety/stress

In the serenics program performed in the 1970s and early 1980s, a number of compounds synthesized exerted blood pressure lowering effects (Bevan et al., 1986; Wouters et al., 1988). The serenic line appeared devoid of this activity, but directed synthesis of compounds to optimize the blood pressure lowering effects led to the discovery and development of flesinoxan (DU29373). Upon testing in humans the drug was completely devoid of anti-hypertensive activity and consequently this line of

Serotonin and sexual behavior

During my PhD studies I examined the behavioral role of the medial hypothalamus in social, including sexual behavior in the rat (Olivier, 1977a, Olivier, 1977b). Before and after specific hypothalamic lesions (anterior or posterior lesions in the medial aspects of the hypothalamus) among other behaviors the sexual behavior of male rats was studied. If bilateral lesions were positioned in the preoptic area/anterior hypothalamus sexual behavior was severely disrupted whereas posterior

Future

It has become evident over the last decades that the serotonergic system in the CNS is extremely important in practically all areas where subtle modulation is needed in processes involved in regulation of amongst others, mood, anxiety, appetite regulation, aggression, sexual behavior and cognition. It is astonishing that one neurotransmitter is able to play such a role. The distribution of the serotonergic innervation in the CNS, the 14 different receptors, the localizations and the intrinsic

References (258)

A. Adell et al.
Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei
Brain Res. Rev.
(2002)
E. Akimova et al.
The serotonin-1A receptor in anxiety disorders
Biol. Psychiatry
(2009)
V. Arango et al.
Genetics of the serotonergic system in suicidal behavior. J
Psychiatry Res.
(2003)
F. Artigas
Serotonin receptors involved in antidepressant effects
Pharmacol. Ther.
(2013)
N.M. Barnes et al.
A review of central 5-HT receptors and their function
Neuropharmacology
(1999)
N. Bel et al.
Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study
Eur. J. Pharmacol.
(1992)
H.H. Berendsen et al.
Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure
Eur. J. Pharmacol.
(1994)
E.Y. Bijlsma et al.
Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?
Pharmacol. Biochem. Behav.
(2014)
K.J. Blackburn et al.
5-Hydroxytryptamine uptake by rat brain in vitro
Life Sci.
(1967)
Y. Borre et al.
Minocycline restores spatial but not fear memory in olfactory bulbectomized rats
Eur. J. Pharmacol.
(2012)

Y. Borre et al.

Celecoxib delays cognitive decline in an animal model of neurodegeneration

Behav. Brain Res.

(2012)

F. Borsini

Role of the serotonergic system in the forced swimming test

Neurosci. Biobehav. Rev.

(1995)

J.A. Bouwknecht et al.

Absence of 5-HT_1B receptors is associated with impaired impulse control in male 5-HT_1B knockout mice

Biol. Psychiatry

(2001)

M.E. Breuer et al.

Long-term behavioral changes after cessation of chronic antidepressant treatment in olfactory bulbectomized rats

Biol. Psychiatry

(2007)

M.E. Breuer et al.

The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects

Eur. Neuropsychopharmacol.

(2008)

M.E. Breuer et al.

Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats

Eur. J. Pharmacol.

(2009)

G.K.L. Brown et al.

Aggression in humans correlates with cerebrospinal fluid amine metabolites

Psychiatry Res.

(1979)

L.H. Calizo et al.

Raphe serotonin neurons are not homogenous: electrophysiological, morphological and neurochemical evidence

Neuropharmacology

(2011)

J.S.W. Chan et al.

Translational research into sexual disorders: pharmacology and genomics

Eur. J. Pharmacol.

(2008)

J.S. Chan et al.

The serotonin transporter plays an important role in male sexual behaviour: a study in serotonin transporter knockout rats

J. Sex. Med.

(2011)

P. Clément et al.

Effect of dapoxetine on ejaculatory performance and related brain neuronal activity in rapid ejaculator rats

J. Sex. Med.

(2012)

P.J. Cowen

Psychopharmacology of 5-HT(1A) receptors

Nucl. Med. Biol.

(2000)

T.I. Cremers et al.

Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram

Eur. J. Pharmacol.

(2000)

J.F. Cryan et al.

Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test

Neurosci. Biobehav. Rev.

(2005)

J.F. Cryan et al.

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice

Neurosci. Biobehav. Rev.

(2005)

S.F. de Boer et al.

5-HT_1A and 5-HT_1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis

Eur. J. Pharmacol.

(2005)

E. Giacalone et al.

Brain serotonin metabolism in isolated aggressive mice

Biochem. Pharmacol.

(1968)

J. Gommans et al.

Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-100635

Eur. J. Pharmacol.

(1995)

N.A. Gray et al.

Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder

Biol. Psychiatry

(2013)

L. Groenink et al.

The 5-HT_1A receptor is not involved in emotional stress-induced rises in stress hormones

Pharmacol. Biochem. Behav.

(1996)

S.M. Haensel et al.

Sex behavior of male and female Wistar rats affected by the serotonin agonist 8-OH-DPAT

Pharmacol. Biochem. Behav.

(1991)

J. Haller et al.

Classical and novel approaches to the preclinical testing of anxiolytics: a critical evaluation

Neurosci. Biobehav. Rev.

(2013)

J.R. Homberg et al.

Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system

Neuroscience

(2007)

B.L. Jacobs et al.

Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats

Brain Res.

(1974)

S. Jancsar et al.

Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat

Prog. Neuropsychopharmacol. Biol. Psychiatry

(1984)

P.K.C. Janssen et al.

Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation

J. Sex. Med.

(2009)

P.K.C. Janssen et al.

The 5-HT_1A receptor gene C(1019)G polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

Pharmacol. Biochem. Behav.

(2014)

P.R. Albert et al.

Modifying 5-HT_1A receptor gene expression as a new target for antidepressant therapy

Front. Neurosci.

(2010)

S.C. Altieri et al.

Rethinking 5-HT_1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior

ACS Chem. Neurosci.

(2013)

K.E. Andersson et al.

Pharmacokinetic and pharmacodynamic features of dapoxetine, a novel drug for ‘on-demand’ treatment of premature ejaculation

BJU Int.

(2006)

F. Artigas et al.

Pindolol augmentation of antidepressant response

Curr. Drug Targets

(2006)

F. Artigas

Future direction for serotonin and antidepressants

ACS Chem. Neurosci.

(2013)

M.B. Assié et al.

F15599, a highly selective post-synaptic 5-HT_1A receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity

Int. J. Neuropsychopharmacol.

(2010)

E. Audero et al.

Suppression of serotonin neuron firing increases aggression in mice

J. Neurosci.

(2013)

J.E. Barrett et al.

Anticonflict effects of the 5-HT_1A compound flesinoxan

J. Psychopharmacol.

(1989)

S.G. Beck et al.

Median and dorsal raphe neurons are not electrophysiologically identical

J. Neurophysiol.

(2004)

A. Benko et al.

Significant association between the C(-1019)G functional polymorphism of the HTR1A gene and impulsivity

Am. J. Med. Genet. B

(2010)

P. Bevan et al.

Investigation on the effects of DU29373 on the cardiovascular system of the cat

Br. J. Pharmacol.

(1986)

D.K. Biezonski et al.

The nature of 3,4-methylenedoxymethamphetamine (MDMA)-induced serotonergic dysfunction: evidence for and against the neurodegeneration hypothesis

Curr. Neuropharmacol.

(2011)

P. Blier et al.

Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression

J. Clin. Psychopharmacol.

(1987)

Cited by (191)

An analysis on the accumulation of serotonin indicates the positively correlation between MdT5H5 and serotonin content in apple fruits
2024, Scientia Horticulturae
Serotonin (5-hydroxytryptamine, 5-HT), a tryptophan derivative, is an important functional component in fruits. Although 5-HT was found in most fruits, the accumulation characteristics of its biosynthesis in apple fruits remain unclear. Here, we conducted a large-scale survey of 148 apple fruits in 5-HT content, and investigated the biosynthesis differences of 5-HT. Our results displayed a broad skewed normal distribution of 5-HT in apple fruits. 5-HT accumulated in all tissues of apple plants, with the highest content in the seeds and the higher content in the pulp than that of the peel. A significant increase of 5-HT at ripening stage was observed in the fruits with high 5-HT content, however, the 5-HT content did not change significantly during fruit development in the fruits with low 5-HT content. The bagging reduced the 5-HT biosynthesis compared to the fruits exposed to light conditions. In addition, the expression level of MdT5H5 was positively correlated with the 5-HT content, suggesting that MdT5H5 may play a key regulatory role in the 5-HT biosynthesis in apple fruits.
Neonatal treatment with para-chlorophenylalanine (pCPA) induces adolescent hyperactivity associated with changes in the paraventricular nucleus Crh and Trh expressions
2024, Behavioural Brain Research
Disruption of the brain serotoninergic (5-HT) system during development induces long-lasting changes in molecular profile, cytoarchitecture, and function of neurons, impacting behavioral regulation throughout life. In male and female rats, we investigate the effect of neonatal tryptophan hydroxylase (TPH) inhibition by using para-chlorophenylalanine (pCPA) on the expression of 5-HTergic system components and neuropeptides related to adolescent social play behavior regulation. We observed sex-dependent 5-HT levels decrease after pCPA-treatment in the dorsal raphe nucleus (DRN) at 17 and 35 days. Neonatal pCPA-treatment increased playing, social and locomotory behaviors assessed in adolescent rats of both sexes. The pCPA-treated rats demonstrated decreased Crh (17 days) and increased Trh (35 days) expression in the hypothalamic paraventricular nucleus (PVN). There was sex dimorphism in Htr2c (17 days) and VGF (35 days) in the prefrontal cortex, with the females expressing higher levels of it than males. Our results indicate that neonatal pCPA-treatment results in a long-lasting and sex-dependent DRN 5-HT synthesis changes, decreased Crh, and increased Trh expression in the PVN, resulting in a hyperactivity-like phenotype during adolescence. The present work demonstrates that the impairment of TPH function leads to neurobehavioral disorders related to hyperactivity and impulsivity, such as attention deficit hyperactivity disorder (ADHD).
Maternal exposure to bisphenol S reduces anxiety and impairs collective antipredator behavior of male zebrafish (Danio rerio) offspring through dysregulation of their serotonergic system
2024, Aquatic Toxicology
Bisphenol S (BPS) is a common endocrine-disrupting chemical globally used in several consumer and industrial products. Although previous studies suggested that BPS induces multiple effects in exposed organisms, very little is known about its intergenerational effect on offspring behavior and/or the potential underlying mechanisms. To this end, adult female zebrafish Danio rerio were exposed to BPS (0, 10, 30 µg/L) and 1 µg/L of 17-β-estradiol (E2) as a positive control for 60 days. Afterwards, female fish were bred with untreated males, and their offspring were raised to 6 months old in control water. Maternal exposure to BPS decreased male offspring anxiety and antipredator behaviors while boldness remained unaffected. Specifically, maternal exposure to 10 and 30 µg/L BPS and 1 µg/L E2 were found to impact male offspring anxiety levels as they decreased the total time that individuals spent in the dark zone in the light/dark box test and increased the total track length in the center of the open field test. In addition, maternal exposure to all concentrations of BPS and E2 disrupted antipredator responses of male offspring by decreasing shoal cohesion in the presence of chemical alarm cues derived from conspecifics, which communicated high risk. To elucidate the possible molecular mechanism underlying these neuro-behavioral effects of BPS, we assessed the serotonergic system via changes in mRNA expression of serotonin receptors, including the 5-HT_1A, 5-HT_1B, and 5-HT_1D subtypes, the serotonin transporter and monoamine oxidase (MAO). The impaired anxiety and antipredator responses were associated with reduced levels of 5-HT_1A subtype and MAO mRNA expression within the brain of adult male offspring. Collectively, the results of this study demonstrate that maternal exposure to environmental concentrations of BPS can interfere with the serotonergic signaling pathway in the developing brain, subsequently leading to the onset of a suite of behavioral deficits in adult offspring.
Biomarkers of fatigue in oncology: A systematic review
2024, Critical Reviews in Oncology/Hematology
Cancer-related fatigue (CRF) is a distressing side effect of cancer and treatment, affecting both patients during active treatment and survivors, negatively impacting quality of life. While its exact cause remains uncertain, various mechanisms such as immune dysfunction, HPA-axis dysfunction, and treatment toxicity are proposed. Inflammatory biomarkers of CRF have been explored in previous research, but non-inflammatory markers have not been comprehensively studied. This systematic review analysed 33 studies to identify non-inflammatory peripheral blood biomarkers associated with CRF. Promising markers included Hb, blood coagulation factors, BDNF, tryptophan, GAA, mtDNA, platinum, CA125, and cystatin-C. Inconsistent findings were observed for other markers like VEGF, leptin, and stress hormones. Most studies focused on adults. Research in pediatrics is limited. This review showed partial evidence for the inflammaging hypothesis (neurotoxicity due to neuro-inflammation) laying at the basis of CRF. Further research, especially in pediatrics, is needed to confirm this hypothesis and guide future biomarker studies.
Benzeneseleninic Acids (BSA) and Photocatalysis: An Alternative Duo for the Synthesis of 3-Selanylindoles
2023, Asian Journal of Organic Chemistry
A novel eco‐friendly methodology for the synthesis of 3‐selanylindoles has been established, circumventing the requirement for transition metal catalysis, strong oxidants and elevated reaction temperatures. In the present protocol a photocatalytic strategy was elegantly developed for the use of benzeneseleninic acid (BSA) derivatives as a selenium‐source reagent, reacting with indole derivatives, to access 3‐selanylindoles in moderate to good yields. A total of fourteen derivatives were selectively prepared, which among three are unprecedented. In addition to the synthetic advantages, this study gives significant insights into the use of BSA derivatives as reagent to construct Se(II)‐decorated products.
Pharmacotherapy and cognitive bias modification for the treatment of anxiety disorders
2024, Expert Review of Neurotherapeutics

View all citing articles on Scopus

View full text

ReviewSerotonin: A never-ending story

Abstract

Section snippets

Serotonin, history, drugs

Serotonin and depression

Serotonin and aggression

Serotonin and anxiety/stress

Serotonin and sexual behavior

Future

Brain Res. Rev.

Biol. Psychiatry

Psychiatry Res.

Pharmacol. Ther.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Life Sci.

Eur. J. Pharmacol.

Behav. Brain Res.

Neurosci. Biobehav. Rev.

Biol. Psychiatry

Biol. Psychiatry

Eur. Neuropsychopharmacol.

Eur. J. Pharmacol.

Psychiatry Res.

Neuropharmacology

Eur. J. Pharmacol.

J. Sex. Med.

J. Sex. Med.

Nucl. Med. Biol.

Eur. J. Pharmacol.

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Biol. Psychiatry

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neurosci. Biobehav. Rev.

Neuroscience

Brain Res.

Prog. Neuropsychopharmacol. Biol. Psychiatry

J. Sex. Med.

Pharmacol. Biochem. Behav.

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Front. Neurosci.

Rethinking 5-HT1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior

ACS Chem. Neurosci.

Pharmacokinetic and pharmacodynamic features of dapoxetine, a novel drug for ‘on-demand’ treatment of premature ejaculation

BJU Int.

Pindolol augmentation of antidepressant response

Curr. Drug Targets

Future direction for serotonin and antidepressants

ACS Chem. Neurosci.

F15599, a highly selective post-synaptic 5-HT1A receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity

Int. J. Neuropsychopharmacol.

Suppression of serotonin neuron firing increases aggression in mice

J. Neurosci.

Anticonflict effects of the 5-HT1A compound flesinoxan

J. Psychopharmacol.

Median and dorsal raphe neurons are not electrophysiologically identical

J. Neurophysiol.

Significant association between the C(-1019)G functional polymorphism of the HTR1A gene and impulsivity

Am. J. Med. Genet. B

Investigation on the effects of DU29373 on the cardiovascular system of the cat

Br. J. Pharmacol.

The nature of 3,4-methylenedoxymethamphetamine (MDMA)-induced serotonergic dysfunction: evidence for and against the neurodegeneration hypothesis

Curr. Neuropharmacol.

Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression

J. Clin. Psychopharmacol.

Review
Serotonin: A never-ending story

Modifying 5-HT_1A receptor gene expression as a new target for antidepressant therapy

Rethinking 5-HT_1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior

F15599, a highly selective post-synaptic 5-HT_1A receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity

Anticonflict effects of the 5-HT_1A compound flesinoxan