International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Serotonin in Health and Disease

by Philippe De Deurwaerdère and Giuseppe Di Giovanni

Int. J. Mol. Sci. 2020, 21(10), 3500; https://doi.org/10.3390/ijms21103500 - 15 May 2020

Cited by 59 | Viewed by 6862

Abstract

The International Journal of Molecular Sciences Special Issue “Serotonin in health and diseases” covers several aspects of the multiple and still mysterious functions of serotonin (5-hydroxytryptamine; 5-HT). 5-HT is neurotransmitter acting in the central nervous system (CNS), blood factor, and neurohormone controlling the [...] Read more.

The International Journal of Molecular Sciences Special Issue “Serotonin in health and diseases” covers several aspects of the multiple and still mysterious functions of serotonin (5-hydroxytryptamine; 5-HT). 5-HT is neurotransmitter acting in the central nervous system (CNS), blood factor, and neurohormone controlling the function of several peripheral organs. Beyond its widespread implication in physiology, the 5-HT system is involved in numerous diseases of the CNS (e.g., depression, anxiety, schizophrenia, obsessive-compulsive disorders, addiction, Parkinson’s disease) and peripheral organs (e.g., gastrointestinal disorders, cardiac arrhythmia, hypertension). The Special Issue includes 14 articles dealing with molecular and cellular effects of 5-HT in periphery and CNS, from functional aspects in lower animals to clinical practices. Beyond physiology, the Special Issue also covers the influence of 5-HT and its receptors in the mechanism of action of psychoactive molecules including antipsychotics, antidepressants, and drug of abuse. The recent progress made on the function and dysfunction of the 5-HT system will certainly increase the understanding of the widespread role of 5-HT ultimately leading to better apprehend its targeting in human diseases. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

Research

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15 pages, 876 KiB

Open AccessArticle

HTR1A, HTR1B, HTR2A, HTR2C and HTR6 Gene Polymorphisms and Extrapyramidal Side Effects in Haloperidol-Treated Patients with Schizophrenia

by Mirko Grubor, Maja Zivkovic, Marina Sagud, Matea Nikolac Perkovic, Alma Mihaljevic-Peles, Nela Pivac, Dorotea Muck-Seler and Dubravka Svob Strac

Int. J. Mol. Sci. 2020, 21(7), 2345; https://doi.org/10.3390/ijms21072345 - 28 Mar 2020

Cited by 15 | Viewed by 5727

Abstract

Schizophrenia is a serious, chronic psychiatric disorder requiring lifelong treatment. Extrapyramidal side effects (EPS) are common adverse reactions to antipsychotic medications. In addition to the dopaminergic system, serotonergic mechanisms, including serotonin (5-HT) receptors, might be involved in EPS development. This study aimed to [...] Read more.

Schizophrenia is a serious, chronic psychiatric disorder requiring lifelong treatment. Extrapyramidal side effects (EPS) are common adverse reactions to antipsychotic medications. In addition to the dopaminergic system, serotonergic mechanisms, including serotonin (5-HT) receptors, might be involved in EPS development. This study aimed to examine molecular associations of HTR1A, HTR1B, HTR2A, HTR2C and HTR6 gene polymorphisms with acute EPS in 229 male schizophrenia patients, following two weeks of haloperidol monotherapy. The Simpson–Angus Rating Scale for Extrapyramidal Side Effects (SAS), Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS) were used to evaluate EPS severity. Genotyping was performed using real-time PCR, following extraction of blood DNA. Significant acute EPS appeared in 48.03% of schizophrenia patients. For the rs13212041 HTR1B gene polymorphism, affecting microRNA regulation of HTR1B gene expression, a higher frequency of TT carriers was found among haloperidol-treated patients with akathisia when compared to the group without akathisia symptoms. In comparison to C-allele carriers, patients carrying the TT genotype had higher akathisia severity, as determined by the SAS, BARS and ESRS scales. These molecular findings suggest potential involvement of 5-HT_1B receptors in akathisia development following haloperidol treatment, as well as possible epigenetic mechanisms of serotonergic modulation associated with antipsychotic-induced EPS. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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17 pages, 3396 KiB

Open AccessArticle

The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion

by Yuma Nagai, Kaito Takayama, Naoya Nishitani, Chihiro Andoh, Masashi Koda, Hisashi Shirakawa, Takayuki Nakagawa, Kazuki Nagayasu, Akihiro Yamanaka and Shuji Kaneko

Int. J. Mol. Sci. 2020, 21(6), 2160; https://doi.org/10.3390/ijms21062160 - 21 Mar 2020

Cited by 38 | Viewed by 7871

Abstract

Background: Reward processing is fundamental for animals to survive and reproduce. Many studies have shown the importance of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in this process, but the strongly correlative link between the activity of DRN 5-HT neurons and rewarding/aversive potency [...] Read more.

Background: Reward processing is fundamental for animals to survive and reproduce. Many studies have shown the importance of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in this process, but the strongly correlative link between the activity of DRN 5-HT neurons and rewarding/aversive potency is under debate. Our primary objective was to reveal this link using two different strategies to transduce DRN 5-HT neurons. Methods: For transduction of 5-HT neurons in wildtype mice, adeno-associated virus (AAV) bearing the mouse tryptophan hydroxylase 2 (TPH2) gene promoter was used. For transduction in Tph2-tTA transgenic mice, AAVs bearing the tTA-dependent TetO enhancer were used. To manipulate the activity of 5-HT neurons, optogenetic actuators (CheRiff, eArchT) were expressed by AAVs. For measurement of rewarding/aversive potency, we performed a nose-poke self-stimulation test and conditioned place preference (CPP) test. Results: We found that stimulation of DRN 5-HT neurons and their projections to the ventral tegmental area (VTA) increased the number of nose-pokes in self-stimulation test and CPP scores in both targeting methods. Concomitantly, CPP scores were decreased by inhibition of DRN 5-HT neurons and their projections to VTA. Conclusion: Our findings indicate that the activity of DRN 5-HT neurons projecting to the VTA is a key modulator of balance between reward and aversion. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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18 pages, 1241 KiB

Open AccessArticle

Effects of Thryptophan Hydroxylase Blockade by P-Chlorophenylalanine on Contextual Memory Reconsolidation after Training of Different Intensity

by Irina B. Deryabina, Viatcheslav V. Andrianov, Lyudmila N. Muranova, Tatiana K. Bogodvid and Khalil L. Gainutdinov

Int. J. Mol. Sci. 2020, 21(6), 2087; https://doi.org/10.3390/ijms21062087 - 18 Mar 2020

Cited by 14 | Viewed by 3775

Abstract

The processes of memory formation and its storage are extremely dynamic. Therefore, the determination of the nature and temporal evolution of the changes that underlie the molecular mechanisms of retrieval and cause reconsolidation of memory is the key to understanding memory formation. Retrieval [...] Read more.

The processes of memory formation and its storage are extremely dynamic. Therefore, the determination of the nature and temporal evolution of the changes that underlie the molecular mechanisms of retrieval and cause reconsolidation of memory is the key to understanding memory formation. Retrieval induces the plasticity, which may result in reconsolidation of the original memory and needs critical molecular events to stabilize the memory or its extinction. 4-Chloro-DL-phenylalanine (P-chlorophenylalanine-PCPA) depresses the most limiting enzyme of serotonin synthesis the tryptophan hydroxylase. It is known that PCPA reduces the serotonin content in the brain up to 10 times in rats (see Methods). We hypothesized that the PCPA could behave the similar way in snails and could reduce the content of serotonin in snails. Therefore, we investigated the effect of PCPA injection on contextual memory reconsolidation using a protein synthesis blocker in snails after training according to two protocols of different intensities. The results obtained in training according to the first protocol using five electrical stimuli per day for 5 days showed that reminding the training environment against the background of injection of PCPA led to a significant decrease in contextual memory. At the same time, the results obtained in training according to the second protocol using three electrical stimuli per day for 5 days showed that reminding the training environment against the injection of PCPA did not result in a significant change in contextual memory. The obtain results allowed us to conclude that the mechanisms of processes developed during the reconsolidation of contextual memory after a reminding depend both on the intensity of learning and on the state of the serotonergic system. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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18 pages, 5578 KiB

Open AccessArticle

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

by Cristiano Bombardi, Francis Delicata, Claudio Tagliavia, Massimo Pierucci, Gabriele Deidda, Maurizio Casarrubea, Philippe De Deurwaerdère and Giuseppe Di Giovanni

Int. J. Mol. Sci. 2020, 21(5), 1873; https://doi.org/10.3390/ijms21051873 - 9 Mar 2020

Cited by 15 | Viewed by 5619

Abstract

Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is [...] Read more.

Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is particularly interesting are the 5-HT_2A receptors (5-HT_2ARs) and the lateral habenula (LHb), a central area in nicotine addiction that we showed to be under a strong 5-HT_2AR-modulation. Single-cell extracellular recording of LHb neurons was used to study the 5-HT_2AR function by intravenously administrating the potent agonist TCB-2. Acute nicotine (2 mg/kg, intraperitoneal, i.p.) and chronic nicotine (6 mg/kg/day for 14 days) differently affected both the 5-HT_2AR-immuno reactive (IR) neuron number and the 5-HT_2AR immunostaining area in the different brain areas studied. After acute nicotine, TCB-2 cumulative doses (5–640 µg/kg, intravenous, i.v.) bidirectionally affected the activity of 74% of LHb recorded neurons. After chronic nicotine treatment, TCB-2 was only capable of decreasing the LHb firing rate. The expression of 5-HT_2AR under acute and chronic nicotine exposure was studied in the LHb and in other brain areas involved in nicotine effects in rats by using immunohistochemistry. These data reveal that acute and chronic nicotine differentially affect the 5-HT_2AR function in different brain areas and this might be relevant in nicotine addiction and its treatment. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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12 pages, 1918 KiB

Open AccessArticle

Implication of 5-HT in the Dysregulation of Chloride Homeostasis in Prenatal Spinal Motoneurons from the G93A Mouse Model of Amyotrophic Lateral Sclerosis

by Elodie Martin, William Cazenave, Anne-Emilie Allain, Daniel Cattaert and Pascal Branchereau

Int. J. Mol. Sci. 2020, 21(3), 1107; https://doi.org/10.3390/ijms21031107 - 7 Feb 2020

Cited by 17 | Viewed by 3353

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. The early presymptomatic onset of abnormal processes is indicative of cumulative defects that ultimately lead to a late manifestation of clinical symptoms. It remains of [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. The early presymptomatic onset of abnormal processes is indicative of cumulative defects that ultimately lead to a late manifestation of clinical symptoms. It remains of paramount importance to identify the primary defects that underlie this condition and to determine how these deficits lead to a cycle of deterioration. We recently demonstrated that prenatal E17.5 lumbar spinal motoneurons (MNs) from SOD1^G93A mice exhibit a KCC2-related alteration in chloride homeostasis, i.e., the E_GABAAR is more depolarized than in WT littermates. Here, using immunohistochemistry, we found that the SOD1^G93A lumbar spinal cord is less enriched with 5-HT descending fibres than the WT lumbar spinal cord. High-performance liquid chromatography confirmed the lower level of the monoamine 5-HT in the SOD1^G93A spinal cord compared to the WT spinal cord. Using ex vivo perforated patch-clamp recordings of lumbar MNs coupled with pharmacology, we demonstrated that 5-HT strongly hyperpolarizes the E_GABAAR by interacting with KCC2. Therefore, the deregulation of the interplay between 5-HT and KCC2 may explain the alteration in chloride homeostasis detected in prenatal SOD1^G93A MNs. In conclusion, 5-HT and KCC2 are two likely key factors in the presymptomatic phase of ALS, particular in familial ALS involving the SOD1^G93A mutation. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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7 pages, 717 KiB

Open AccessCommunication

Bisphenol A (BPA)-Induced Changes in the Number of Serotonin-Positive Cells in the Mucosal Layer of Porcine Small Intestine—the Preliminary Studies

by Slawomir Gonkowski

Int. J. Mol. Sci. 2020, 21(3), 1079; https://doi.org/10.3390/ijms21031079 - 6 Feb 2020

Cited by 17 | Viewed by 2326

Abstract

Bisphenol A (BPA) is a substance used in the production of plastics which has a negative impact on many internal organs. Because BPA is normally toxic for the gastrointestinal (GI) tract, the intestine is especially vulnerable to the adverse effects of this substance. [...] Read more.

Bisphenol A (BPA) is a substance used in the production of plastics which has a negative impact on many internal organs. Because BPA is normally toxic for the gastrointestinal (GI) tract, the intestine is especially vulnerable to the adverse effects of this substance. The aim of this investigation was to study the influence of two doses of BPA (0.05 mg and 0.5 mg/kg body weight/day) on the number of mucosal cells in the porcine small intestine and containing serotonin (5-hydroxytryptamine, 5-HT). During the experiment, it was demonstrated that both applied BPA doses caused an increase in the number of 5-HT-positive cells located in the mucosal layer of the duodenum, jejunum, and ileum. These changes may be connected with the direct impact of BPA on the intestinal mucosa, the pro-inflammatory and immunomodulatory properties of this substance, and/or the influence of BPA on the neurochemical characterization of nervous structures supplying the intestine. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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20 pages, 4561 KiB

Open AccessArticle

Transcriptome Modifications in the Porcine Intramuscular Adipocytes during Differentiation and Exogenous Stimulation with TNF-α and Serotonin

by Asuka Tada, Md Aminul Islam, AKM Humayun Kober, Kohtaro Fukuyama, Michihiro Takagi, Manami Igata, Leonardo Albarracin, Wakako Ikeda-Ohtsubo, Kenji Miyazawa, Kazutoyo Yoda, Fang He, Hideki Takahashi, Julio Villena, Hisashi Aso and Haruki Kitazawa

Int. J. Mol. Sci. 2020, 21(2), 638; https://doi.org/10.3390/ijms21020638 - 18 Jan 2020

Cited by 17 | Viewed by 5724

Abstract

Adipocytes are dynamic cells that have critical functions to maintain body energy homeostasis. Adipocyte physiology is affected by the adipogenic differentiation, cell program, as well as by the exogenous stimulation of biochemical factors, such as serotonin and TNF-α. In this work, we investigated [...] Read more.

Adipocytes are dynamic cells that have critical functions to maintain body energy homeostasis. Adipocyte physiology is affected by the adipogenic differentiation, cell program, as well as by the exogenous stimulation of biochemical factors, such as serotonin and TNF-α. In this work, we investigated the global transcriptome modifications when porcine intramuscular preadipocyte (PIP) was differentiated into porcine mature adipocyte (pMA). Moreover, we studied transcriptome changes in pMA after stimulation with serotonin or TNF-α by using a microarray approach. Transcriptome analysis revealed that the expression of 270, 261, and 249 genes were modified after differentiation, or after serotonin and TNF-α stimulation, respectively. Expression changes in APP, HNF4A, ESR1, EGR1, SRC, HNF1A, FN1, ALB, STAT3, CBL, CEBPB, AR, FOS, CFTR, PAN2, PTPN6, VDR, PPARG, STAT5A and NCOA3 genes which are enriched in the ‘PPAR signaling’ and ‘insulin resistance’ pathways were found in adipocytes during the differentiation process. Dose-dependent serotonin stimulation resulted in a decreased fat accumulation in pMAs. Serotonin-induced differentially expressed genes in pMAs were found to be involved in the significant enrichment of ′GPCR ligand-binding′, ‘cell chemotaxis’, ‘blood coagulation and complement’, ‘metabolism of lipid and lipoproteins’, ‘regulation of lipid metabolism by PPARA’, and ‘lipid digestion, mobilization and transport’ pathways. TNF-α stimulation also resulted in transcriptome modifications linked with proinflammatory responses in the pMA of intramuscular origin. Our results provide a landscape of transcriptome modifications and their linked-biological pathways in response to adipogenesis, and exogenous stimulation of serotonin- and TNF-α to the pMA of intramuscular origin. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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18 pages, 2903 KiB

Open AccessArticle

Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT_1A Receptor with 5-HT₃ Receptor Inhibition in Rats

by Motohiro Okada, Ruri Okubo and Kouji Fukuyama

Int. J. Mol. Sci. 2019, 20(24), 6235; https://doi.org/10.3390/ijms20246235 - 10 Dec 2019

Cited by 29 | Viewed by 5462

Abstract

Vortioxetine is a novel, multimodal antidepressant with unique targets, including the inhibition of the serotonin transporter (SET), of serotonin 5-HT₃ (5-HT3R), and of 5-HT₇ (5-HT7R) receptors and partial agonism to serotonin 5-HT_1A (5-HT1AR) receptors in humans. Vortioxetine has a lower [...] Read more.

Vortioxetine is a novel, multimodal antidepressant with unique targets, including the inhibition of the serotonin transporter (SET), of serotonin 5-HT₃ (5-HT3R), and of 5-HT₇ (5-HT7R) receptors and partial agonism to serotonin 5-HT_1A (5-HT1AR) receptors in humans. Vortioxetine has a lower affinity to 5-HT1AR and 5-HT7R in rats compared with humans, but several behavior studies have demonstrated its powerful antidepressant-like actions. In spite of these efforts, detailed effects of the subchronic administration of vortioxetine on serotonergic transmission remain to be clarified. This study examined the mechanisms underlying the clinical effects of vortioxetine by measuring the releases of 5-HT and GABA in the medial prefrontal cortex (mPFC) of freely moving rats compared with the selective SET inhibitor, escitalopram. Inhibition of 5-HT3R in the mPFC enhanced regional 5-HT release via GABAergic disinhibition. Activation of somatodendritic 5-HT1AR in the dorsal raphe nucleus (DRN) and presynaptic 5-HT1AR in the mPFC inhibited 5-HT release in the mPFC. Escitalopram subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN and of 5-HT3R in the mPFC; however, vortioxetine also subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN but not of 5-HT3R in the mPFC. These demonstrations, the desensitization of 5-HT1AR with the inhibition of 5-HT3R (without 5-HT3R desensitization), at least partially, contribute to the multimodal antidepressant action of vortioxetine in rats. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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21 pages, 3783 KiB

Open AccessArticle

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT₆ Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

by Gniewomir Latacz, Annamaria Lubelska, Magdalena Jastrzębska-Więsek, Anna Partyka, Małgorzata Anna Marć, Grzegorz Satała, Daria Wilczyńska, Magdalena Kotańska, Małgorzata Więcek, Katarzyna Kamińska, Anna Wesołowska, Katarzyna Kieć-Kononowicz and Jadwiga Handzlik

Int. J. Mol. Sci. 2019, 20(14), 3420; https://doi.org/10.3390/ijms20143420 - 12 Jul 2019

Cited by 48 | Viewed by 4152

Abstract

Among serotonin receptors, the 5-HT₆ subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT₆R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due [...] Read more.

Among serotonin receptors, the 5-HT₆ subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT₆R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT₆R ligands. For the most active triazine 5-HT₆R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT₆R binding properties. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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16 pages, 3210 KiB

Open AccessArticle

Analysis of Expression and Functional Activity of Aromatic L-Amino Acid Decarboxylase (DDC) and Serotonin Transporter (SERT) as Potential Sources of Serotonin in Mouse Ovary

by Denis A. Nikishin, Nina M. Alyoshina, Maria L. Semenova and Yuri B. Shmukler

Int. J. Mol. Sci. 2019, 20(12), 3070; https://doi.org/10.3390/ijms20123070 - 23 Jun 2019

Cited by 13 | Viewed by 4568

Abstract

The origin of serotonin in the ovary is the key question for understanding mechanisms of serotonergic regulation of reproductive function. We performed a study of the expression and functional activity of the serotonin transporter (SERT) and the enzyme for the synthesis of serotonin, [...] Read more.

The origin of serotonin in the ovary is the key question for understanding mechanisms of serotonergic regulation of reproductive function. We performed a study of the expression and functional activity of the serotonin transporter (SERT) and the enzyme for the synthesis of serotonin, aromatic l-amino acid decarboxylase (DDC) in mouse ovary. A pronounced peak of SERT mRNA expression occurs at the age of 14 days, but serotonin synthesis enzymes are expressed at the maximum level in the ovaries of newborn mice. SERT is detected immunohistochemically in all cellular compartments of the ovary with a maximum level of immunostaining in the oocytes of growing ovarian follicles. DDC immunolocalization, in contrast, is detected to a greater extent in primordial follicle oocytes, and decreases at the later stages of folliculogenesis. Serotonin synthesis in all cellular compartments occurs at very low levels, whereas specific serotonin uptake is clearly present, leading to a significant increase in serotonin content in the oocytes of growing primary and secondary follicles. These data indicate that the main mechanism of serotonin accumulation in mouse ovary is its uptake by the specific SERT membrane transporter, which is active in the oocytes of the growing ovarian follicles. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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16 pages, 1560 KiB

Open AccessArticle

Effect of the 5-HT_2C Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study

by Sara Whitestone, Philippe De Deurwaerdère, Lynn Baassiri, Julien Manem, Youssef Anouar, Giuseppe Di Giovanni, Rahul Bharatiya and Abdeslam Chagraoui

Int. J. Mol. Sci. 2019, 20(12), 2925; https://doi.org/10.3390/ijms20122925 - 14 Jun 2019

Cited by 14 | Viewed by 4850

Abstract

The effects triggered by serotonin2C (5-hydroxytryptamin_2C, 5-HT_2C) receptor agonists in the brain are often subtle, and methodologies highlighting their widespread actions to account for their multiple modulatory influences on behaviors are still lacking. We report an extended analysis of [...] Read more.

The effects triggered by serotonin2C (5-hydroxytryptamin_2C, 5-HT_2C) receptor agonists in the brain are often subtle, and methodologies highlighting their widespread actions to account for their multiple modulatory influences on behaviors are still lacking. We report an extended analysis of a neurochemical database on monoamines obtained after the intraperitoneal administration of the preferential 5-HT_2C receptor agonist WAY-163909 (0.3 and 3 mg/kg) in 29 distinct rat brain regions. We focused on the metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), the metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the index of the turnovers 5-HIAA/5-HT and DOPAC/DA. WAY-163909 increased and decreased 5-HIAA tissue levels in the amygdala and dorsolateral orbitofrontal cortex, respectively, and decreased the 5-HT turnover in the infralimbic cortex. It enhanced HVA levels in the medial orbitofrontal cortex and DOPAC levels in the amygdala. WAY-163909 increased and decreased DA turnover in the medial orbitofrontal cortex and the anterior insular cortex, respectively. The correlative analysis of the turnovers between pairs of brain regions revealed low levels of correlations across the brain but presented a distinct pattern of correlations after WAY-163909 was compared to saline-treated rats. WAY-163909, notably at 0.3 mg/kg, favored cortico-cortical and cortico-subcortical correlations of both turnovers separately, and frontal DOPAC/DA ratio with cortical and subcortical 5-HIAA/5-HT ratios at 3 mg/kg. In conclusion, the qualitative, but not the quantitative analysis shows that WAY-163909 alters the pattern of correlations across the brain, which could account for its multiple behavioral influences. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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Review

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23 pages, 1804 KiB

Open AccessReview

Serotonin in Animal Cognition and Behavior

by Julien Bacqué-Cazenave, Rahul Bharatiya, Grégory Barrière, Jean-Paul Delbecque, Nouhaila Bouguiyoud, Giuseppe Di Giovanni, Daniel Cattaert and Philippe De Deurwaerdère

Int. J. Mol. Sci. 2020, 21(5), 1649; https://doi.org/10.3390/ijms21051649 - 28 Feb 2020

Cited by 210 | Viewed by 16458

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator of nervous systems in both invertebrates and vertebrates. It has been proposed for several decades that it impacts animal cognition and behavior. In spite of a completely distinct organization of the 5-HT systems across [...] Read more.

Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator of nervous systems in both invertebrates and vertebrates. It has been proposed for several decades that it impacts animal cognition and behavior. In spite of a completely distinct organization of the 5-HT systems across the animal kingdom, several lines of evidence suggest that the influences of 5-HT on behavior and cognition are evolutionary conserved. In this review, we have selected some behaviors classically evoked when addressing the roles of 5-HT on nervous system functions. In particular, we focus on the motor activity, arousal, sleep and circadian rhythm, feeding, social interactions and aggressiveness, anxiety, mood, learning and memory, or impulsive/compulsive dimension and behavioral flexibility. The roles of 5-HT, illustrated in both invertebrates and vertebrates, show that it is more able to potentiate or mitigate the neuronal responses necessary for the fine-tuning of most behaviors, rather than to trigger or halt a specific behavior. 5-HT is, therefore, the prototypical neuromodulator fundamentally involved in the adaptation of all organisms across the animal kingdom. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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19 pages, 286 KiB

Open AccessReview

SSRIs and SNRIs (SRI) in Pregnancy: Effects on the Course of Pregnancy and the Offspring: How Far Are We from Having All the Answers?

by Asher Ornoy and Gideon Koren

Int. J. Mol. Sci. 2019, 20(10), 2370; https://doi.org/10.3390/ijms20102370 - 14 May 2019

Cited by 41 | Viewed by 9274

Abstract

Serotonin has important roles in the development of the brain and other organs. Manipulations of synaptic serotonin by drugs such as serotonin reuptake inhibitors (SRI) or serotonin norepinephrine reuptake inhibitors (SNRI) might alter their development and function. Of interest, most studies on the [...] Read more.

Serotonin has important roles in the development of the brain and other organs. Manipulations of synaptic serotonin by drugs such as serotonin reuptake inhibitors (SRI) or serotonin norepinephrine reuptake inhibitors (SNRI) might alter their development and function. Of interest, most studies on the outcome of prenatal exposure to SRI in human have not found significant embryonic or fetal damage, except for a possible, slight increase in cardiac malformations. In up to a third of newborns exposed to SRI, exposure may induce transient neonatal behavioral changes (poor neonatal adaptation) and increased rate of persistent pulmonary hypertension. Prenatal SRI may also cause slight motor delay and language impairment but these are transient. The data on the possible association of prenatal SRIs with autism spectrum disorder (ASD) are inconsistent, and seem to be related to pre-pregnancy treatment or to maternal depression. Prenatal SRIs also appear to affect the hypothalamic hypophyseal adrenal (HPA) axis inducing epigenetic changes, but the long-term consequences of these effects on humans are as yet unknown. SRIs are metabolized in the liver by several cytochrome P450 (CYP) enzymes. Faster metabolism of most SRIs in late pregnancy leads to lower maternal concentrations, and thus potentially to decreased efficacy which is more prominent in women that are rapid metabolizers. Studies suggest that the serotonin transporter SLC6A4 promoter is associated with adverse neonatal outcomes after SRI exposure. Since maternal depression may adversely affect the child’s development, one has to consider the risk of SRI discontinuation on the fetus and the child. As with any drug treatment in pregnancy, the benefits to the mother should be considered versus the possible hazards to the developing embryo/fetus. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

17 pages, 975 KiB

Open AccessReview

The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice

by James Francescangeli, Kunal Karamchandani, Meghan Powell and Anthony Bonavia

Int. J. Mol. Sci. 2019, 20(9), 2288; https://doi.org/10.3390/ijms20092288 - 9 May 2019

Cited by 99 | Viewed by 62134

Abstract

The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. As the number of patients experiencing medically-treated major depressive disorder increases, so does the population at risk for experiencing serotonin syndrome. Excessive synaptic stimulation of 5-HT_2A receptors [...] Read more.

The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. As the number of patients experiencing medically-treated major depressive disorder increases, so does the population at risk for experiencing serotonin syndrome. Excessive synaptic stimulation of 5-HT_2A receptors results in autonomic and neuromuscular aberrations with potentially life-threatening consequences. In this review, we will outline the molecular basis of the disease and describe how pharmacologic agents that are in common clinical use can interfere with normal serotonergic pathways to result in a potentially fatal outcome. Given that serotonin syndrome can imitate other clinical conditions, an understanding of the molecular context of this condition is essential for its detection and in order to prevent rapid clinical deterioration. Full article

(This article belongs to the Special Issue Serotonin in Health and Disease)

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