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Pathophysiology of the Serotonin System in the Nervous System and Beyond

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 77649

Special Issue Editors

Prof. Dr. Philippe De Deurwaerdere

E-Mail Website
Guest Editor
Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5287), 33076 Bordeaux CEDEX, France
Interests: monoamines; neurochemistry; addiction; Parkinson's disease; schizophrenia; neuropharmacology; mood disorders
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Giuseppe Di Giovanni

E-Mail Website
Guest Editor
1. Department of Physiology & Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
2. Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK
Interests: serotonin; GABA; dopamine; epilepsy; addiction; mood disorders; electrophysiology; habenula; basal ganglia; serotonin2 receptors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Decades ago in the 1940s, Vittorio Erspamer found that an extract, which he named enteramine and prepared from enterochromaffin cells, made intestinal tissue contract. Ten years later, serotonin (5-hydroxytryptamine, 5-HT) was discovered in the mammalian central and peripheral nervous systems, and successively, its role as an essential neurotransmitter was revealed. Contextually, it was shown that enteramine was the same substance as serotonin. Strikingly, 5-HT is mostly found outside the nervous system, and virtually all 14 serotonin receptors are expressed outside as well as inside the brain. Indeed, serotonin is a neuromodulator present in most organs of numerous species, and plays a role in multiple biological functions. It is also involved in numerous diseases related to peripheral organ dysfunction (e.g., gastrointestinal disorders, cardiac arrhythmia, hypertension) and central nervous system dysfunction (e.g., obsessive-compulsive disorders, addiction, depression, anxiety, schizophrenia, neurodegenerative diseases). Serotonergic defects are often difficult to uncover in a given disease because they could originate from synthesis/catabolism dysfunction, alteration of the activity of serotonergic cells, changes in reuptake capabilities, and/or transmission. It is acknowledged that serotonin can exert its effects through a plethora of serotonin receptors, and that these receptors can be altered in most diseases. Additionally, an imbalance of serotonin transmission is associated with the dysfunction of other systems, including hormones, neurotrophins, inflammatory systems, and other neurotransmitter systems. The successful identification of the pathomechanisms associated with serotonin system dysfunctions at molecular/cellular levels is expected to enhance the existing serotonin-based medications for numerous diseases.

The purpose of this Special Issue is to collect original research articles and reviews that concern the pathophysiology of serotonergic systems in the nervous system and beyond. This Special Issue follows on from a past and very successful collection on “Serotonin in Health and Disease” (https://www.mdpi.com/journal/ijms/special_issues/Serotonin). Contributions from different fields of research at a molecular level are welcomed. Clinical research and survey studies are not suitable for this Special Issue of IJMS.

Prof. Dr. Philippe De Deurwaerdère
Prof. Dr. Giuseppe Di Giovanni
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pathophysiology
  • serotonin receptor
  • serotonin metabolism
  • pharmacology
  • molecular pathway
  • system interaction
  • “omics”
  • treatments
  • neurodegeneration

Published Papers (15 papers)

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Editorial

Jump to: Research, Review

4 pages, 220 KiB  
Editorial
Pathophysiology of the Serotonin System in the Nervous System and Beyond
by Philippe De Deurwaerdère and Giuseppe Di Giovanni
Int. J. Mol. Sci. 2022, 23(9), 4712; https://doi.org/10.3390/ijms23094712 - 25 Apr 2022
Viewed by 1854
Abstract
Serotonin (5-HT) is an attractive neurotransmitter system, in terms of physiology, physiopathology, and medicines [...] Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)

Research

Jump to: Editorial, Review

21 pages, 5999 KiB  
Article
The Development of Hindlimb Postural Asymmetry Induced by Focal Traumatic Brain Injury Is Not Related to Serotonin 2A/C Receptor Expression in the Spinal Cord
by Marlene Storm Andersen, Dilârâ Bedriye Güler, Jonas Larsen, Karen Kalhøj Rich, Åsa Fex Svenningsen and Mengliang Zhang
Int. J. Mol. Sci. 2022, 23(10), 5358; https://doi.org/10.3390/ijms23105358 - 11 May 2022
Viewed by 1868
Abstract
Brain injury and stroke are leading causes of adult disability. Motor deficits are common problems, and their underlying pathological mechanisms remain poorly understood. The serotoninergic system is implicated in both functional recovery from and the occurrence of spasticity after injuries to the central [...] Read more.
Brain injury and stroke are leading causes of adult disability. Motor deficits are common problems, and their underlying pathological mechanisms remain poorly understood. The serotoninergic system is implicated in both functional recovery from and the occurrence of spasticity after injuries to the central nervous system. This study, which was conducted on rats, investigated the development of limb postural changes and their relationship to the expression of serotonin (5-HT) 2A and 2C receptors in the spinal cord in the 4 weeks after focal traumatic brain injury (TBI) to the right hindlimb sensorimotor cortex. The limb motor deficits were assessed by measuring gait pattern changes during walking and hindlimb postural asymmetry at different time intervals (3–28 days) after surgery. The expressions of the 5-HT2A and 2C receptors in the lumbar spinal cord were investigated using immunohistochemistry. The results showed that all the rats with TBI, independently of the duration of the interval, displayed postural asymmetry with flexion on the contralateral (left) side (>2 mm), while the sham-operated rats showed no apparent postural asymmetry. The TBI rats also had longer stride lengths during walking in both their hindlimbs and their forelimbs compared with the sham rats. For both the TBI and the sham rats, the hind-paw placement angles were larger on the contralateral side in some of the groups. Compared to the sham-operated rats, the 5-HT2A and 2C receptor expression did not significantly change on either side of the lumbar spinal cords of the TBI rats in any of the groups. These results suggest that focal TBI can induce motor deficits lasting a relatively long time, and that these deficits are not related to the expression of the 5-HT2A and 2C receptors in the spinal cord. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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14 pages, 1477 KiB  
Article
Regulation of Serotonin 1A Receptor SUMOylation by SENP2 and PIASxα
by Sugandha Gupta, Mengya Wang, Yoshiaki Azuma and Nancy A. Muma
Int. J. Mol. Sci. 2021, 22(24), 13176; https://doi.org/10.3390/ijms222413176 - 07 Dec 2021
Cited by 5 | Viewed by 2396
Abstract
Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs [...] Read more.
Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs are SUMOylated by SUMO1 in the rat brain. Agonist stimulation increased SUMOylation and was further enhanced when combined with 17β-estradiol-3-benzoate (EB), which are treatments that cause the transient and prolonged desensitization of 5-HT1AR signaling, respectively. In the current study, we identified the protein inhibitor of activated STAT (PIAS)xα as the enzyme that facilitates SUMOylation, and SENP2 as the protein that catalyzes the deSUMOylation of 5-HT1ARs. We demonstrated that PIASxα significantly increased in the membrane fraction of rats co-treated with EB and an agonist, compared to either the EB-treated or vehicle-treated groups. The acute treatment with an agonist alone shifted the location of SENP2 from the membrane to the cytoplasmic fraction, but it has little effect on PIASxα. Hence, two separate mechanisms regulate SUMOylation and the activity of 5-HT1ARs by an agonist and EB. The effects of EB on 5-HT1AR SUMOylation and signaling may be related to the higher incidence of mood disorders in women during times with large fluctuations in estrogens. Targeting the SUMOylation of 5-HT1ARs could have important clinical relevance for the therapy for several neuropsychiatric disorders in which 5-HT1ARs are implicated. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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Graphical abstract

14 pages, 1436 KiB  
Article
Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1
by Emilie Doucet, Katarzyna Grychowska, Pawel Zajdel, Joël Bockaert, Philippe Marin and Carine Bécamel
Int. J. Mol. Sci. 2021, 22(18), 10178; https://doi.org/10.3390/ijms221810178 - 21 Sep 2021
Cited by 6 | Viewed by 2511
Abstract
Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range [...] Read more.
Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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8 pages, 17127 KiB  
Article
Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures
by Péter Sere, Nikolett Zsigri, Timea Raffai, Szabina Furdan, Fanni Győri, Vincenzo Crunelli and Magor L. Lőrincz
Int. J. Mol. Sci. 2021, 22(17), 9466; https://doi.org/10.3390/ijms22179466 - 31 Aug 2021
Cited by 5 | Viewed by 2447
Abstract
(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have [...] Read more.
(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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20 pages, 3291 KiB  
Article
BDNF Overexpression in the Ventral Hippocampus Promotes Antidepressant- and Anxiolytic-Like Activity in Serotonin Transporter Knockout Rats
by Danielle M. Diniz, Francesca Calabrese, Paola Brivio, Marco A. Riva, Joanes Grandjean and Judith R. Homberg
Int. J. Mol. Sci. 2021, 22(9), 5040; https://doi.org/10.3390/ijms22095040 - 10 May 2021
Cited by 10 | Viewed by 2574
Abstract
BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). [...] Read more.
BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT−/−) is one of the animal models used to investigate the underlying molecular mechanisms of depression in humans. They present decreased BDNF levels, and anxiety- and depression-like behavior. To investigate whether upregulating BDNF would ameliorate the phenotype of SERT−/− rats, we overexpressed BDNF locally into the ventral hippocampus and submitted the animals to behavioral testing. The results showed that BDNF overexpression in the vHIP of SERT−/− rats promoted higher sucrose preference and sucrose intake; on the first day of the sucrose consumption test it decreased immobility time in the forced swim test and increased the time spent in the center of a novel environment. Furthermore, BDNF overexpression altered social behavior in SERT−/− rats, which presented increased passive contact with test partner and decreased solitary behavior. Finally, it promoted decrease in plasma corticosterone levels 60 min after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT−/− rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential target to new therapeutic approaches to improve depressive symptoms. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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17 pages, 4919 KiB  
Article
Lateral Habenula 5-HT2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures
by Cristiano Bombardi, Francis Delicata, Claudio Tagliavia, Annamaria Grandis, Massimo Pierucci, Antonella Marino Gammazza, Maurizio Casarrubea, Philippe De Deurwaerdère and Giuseppe Di Giovanni
Int. J. Mol. Sci. 2021, 22(9), 4775; https://doi.org/10.3390/ijms22094775 - 30 Apr 2021
Cited by 5 | Viewed by 2528
Abstract
Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial [...] Read more.
Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT2CR agonist Ro 60-0175 (5–640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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14 pages, 34414 KiB  
Article
A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain
by Nakul Ravi Raval, Annette Johansen, Lene Lundgaard Donovan, Nídia Fernandez Ros, Brice Ozenne, Hanne Demant Hansen and Gitte Moos Knudsen
Int. J. Mol. Sci. 2021, 22(2), 835; https://doi.org/10.3390/ijms22020835 - 15 Jan 2021
Cited by 86 | Viewed by 24925
Abstract
A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. [...] Read more.
A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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22 pages, 2346 KiB  
Article
A Subset of Purposeless Oral Movements Triggered by Dopaminergic Agonists Is Modulated by 5-HT2C Receptors in Rats: Implication of the Subthalamic Nucleus
by Mélanie Lagière, Marion Bosc, Sara Whitestone, Abdelhamid Benazzouz, Abdeslam Chagraoui, Mark J. Millan and Philippe De Deurwaerdère
Int. J. Mol. Sci. 2020, 21(22), 8509; https://doi.org/10.3390/ijms21228509 - 12 Nov 2020
Cited by 5 | Viewed by 2099
Abstract
Dopaminergic medication for Parkinson’s disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT2C) receptor agonists. However, the neural substrates underlying these [...] Read more.
Dopaminergic medication for Parkinson’s disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT2C) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03–0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2–0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the “hyperdirect” (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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26 pages, 3806 KiB  
Article
Chronic Administration of Fipronil Heterogeneously Alters the Neurochemistry of Monoaminergic Systems in the Rat Brain
by Rahul Bharatiya, Abdeslam Chagraoui, Salomé De Deurwaerdere, Antonio Argiolas, Maria Rosaria Melis, Fabrizio Sanna and Philippe De Deurwaerdere
Int. J. Mol. Sci. 2020, 21(16), 5711; https://doi.org/10.3390/ijms21165711 - 09 Aug 2020
Cited by 12 | Viewed by 4244
Abstract
Fipronil (FPN), a widely used pesticide for agricultural and non-agricultural pest control, is possibly neurotoxic for mammals. Brain monoaminergic systems, involved in virtually all brain functions, have been shown to be sensitive to numerous pesticides. Here, we addressed the hypothesis that chronic exposure [...] Read more.
Fipronil (FPN), a widely used pesticide for agricultural and non-agricultural pest control, is possibly neurotoxic for mammals. Brain monoaminergic systems, involved in virtually all brain functions, have been shown to be sensitive to numerous pesticides. Here, we addressed the hypothesis that chronic exposure to FPN could modify brain monoamine neurochemistry. FPN (10 mg/kg) was chronically administered for 21 days through oral gavage in rats. Thereafter, the tissue concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); and noradrenaline (NA) were measured in 30 distinct brain regions. FPN significantly decreased DA and its metabolite levels in most striatal territories, including the nucleus accumbens and the substantia nigra (SN). FPN also diminished 5-HT levels in some striatal regions and the SN. The indirect index of the turnovers, DOPAC/DA and 5-HIAA/5-HT ratios, was increased in numerous brain regions. FPN reduced the NA content only in the nucleus accumbens core. Using the Bravais–Pearson test to study the neurochemical organization of monoamines through multiple correlative analyses across the brain, we found fewer correlations for NA, DOPAC/DA, and 5-HIAA/5-HT ratios, and an altered pattern of correlations within and between monoamine systems. We therefore conclude that the chronic administration of FPN in rats induces massive and inhomogeneous changes in the DA and 5-HT systems in the brain. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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Review

Jump to: Editorial, Research

12 pages, 24950 KiB  
Review
Hyperthermia and Serotonin: The Quest for a “Better Cyproheptadine”
by Georg A. Petroianu
Int. J. Mol. Sci. 2022, 23(6), 3365; https://doi.org/10.3390/ijms23063365 - 20 Mar 2022
Cited by 4 | Viewed by 5567
Abstract
Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and [...] Read more.
Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and the neurotransmitters involved are reviewed. The GABAergic inhibitory output from the brain thermostat in the preoptic area POA to subaltern neural circuitry of temperature control (Nucleus Raphe Dorsalis and Nucleus Raphe Pallidus) is a function of the balance between the (opposite) effects mediated by the transient receptor potential receptor TRPM2 and EP3 prostaglandin receptors. Activation of TRPM2-expressing neurons in POA favors hypothermia, while inhibition has the opposite effect. Conversely, EP3 receptors induce elevation in body temperature. Activation of EP3-expressing neurons in POA results in hyperthermia, while inhibition has the opposite effect. Agonists at TRPM2 and/or antagonists at EP3 could be beneficial in hyperthermia control. Activity of the neural circuitry of temperature control is modulated by a variety of 5-HT receptors. Based on the theoretical model presented the “ideal” antidote against serotonin syndrome hyperthermia appears to be an antagonist at the 5-HT receptor subtypes 2, 4 and 6 and an agonist at the receptor subtypes 1, 3 and 7. Very broadly speaking, such a profile translates in a sympatholytic effect. While a compound with such an ideal profile is presently not available, better matches than the conventional antidote cyproheptadine (used off-label in severe serotonin syndrome cases) appear to be possible and need to be identified. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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24 pages, 1835 KiB  
Review
Memory Disorders Related to Hippocampal Function: The Interest of 5-HT4Rs Targeting
by Candice M. Roux, Marianne Leger and Thomas Freret
Int. J. Mol. Sci. 2021, 22(21), 12082; https://doi.org/10.3390/ijms222112082 - 08 Nov 2021
Cited by 7 | Viewed by 5284
Abstract
The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic [...] Read more.
The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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19 pages, 2092 KiB  
Review
Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome
by Yoshiyuki Mishima and Shunji Ishihara
Int. J. Mol. Sci. 2021, 22(19), 10235; https://doi.org/10.3390/ijms221910235 - 23 Sep 2021
Cited by 39 | Viewed by 6498
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder that affects the gastrointestinal tract. Details regarding the pathogenesis of IBS remain largely unknown, though the dysfunction of the brain-gut-microbiome (BGM) axis is a major etiological factor, in which neurotransmitters serve as a key [...] Read more.
Irritable bowel syndrome (IBS) is a chronic functional disorder that affects the gastrointestinal tract. Details regarding the pathogenesis of IBS remain largely unknown, though the dysfunction of the brain-gut-microbiome (BGM) axis is a major etiological factor, in which neurotransmitters serve as a key communication tool between enteric microbiota and the brain. One of the most important neurotransmitters in the pathology of IBS is serotonin (5-HT), as it influences gastrointestinal motility, pain sensation, mucosal inflammation, immune responses, and brain activity, all of which shape IBS features. Genome-wide association studies discovered susceptible genes for IBS in serotonergic signaling pathways. In clinical practice, treatment strategies targeting 5-HT were effective for a certain portion of IBS cases. The synthesis of 5-HT in intestinal enterochromaffin cells and host serotonergic signaling is regulated by enteric resident microbiota. Dysbiosis can trigger IBS development, potentially through aberrant 5-HT signaling in the BGM axis; thus, the manipulation of the gut microbiota may be an alternative treatment strategy. However, precise information regarding the mechanisms underlying the microbiota-mediated intestinal serotonergic pathway related to the pathogenesis of IBS remains unclear. The present review summarizes current knowledge and recent progress in understanding microbiome–serotonin interaction in IBS cases. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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13 pages, 1142 KiB  
Review
The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects
by Dasiel O. Borroto-Escuela, Patrizia Ambrogini, Barbara Chruścicka, Maria Lindskog, Minerva Crespo-Ramirez, Juan C. Hernández-Mondragón, Miguel Perez de la Mora, Harriët Schellekens and Kjell Fuxe
Int. J. Mol. Sci. 2021, 22(4), 1927; https://doi.org/10.3390/ijms22041927 - 15 Feb 2021
Cited by 51 | Viewed by 7274
Abstract
Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression [...] Read more.
Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor–receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor–receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor–receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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19 pages, 1350 KiB  
Review
Pathological Insight into 5-HT2B Receptor Activation in Fibrosing Interstitial Lung Diseases
by Anna Löfdahl, Göran Tornling, Jenny Wigén, Anna-Karin Larsson-Callerfelt, Christina Wenglén and Gunilla Westergren-Thorsson
Int. J. Mol. Sci. 2021, 22(1), 225; https://doi.org/10.3390/ijms22010225 - 28 Dec 2020
Cited by 13 | Viewed by 3858
Abstract
Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology [...] Read more.
Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)2 receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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