Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT4 activation in bovine lateral saphenous vein.

To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists. Vessels were pre-contracted with 1 × 10-4 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT1B, 5-HT2B, 5-HT4, and 5-HT7. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. At 1 × 10-7 M 5-HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10-4 M 5-HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5-HT2B, 5-HT4, or 5-HT7 resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5-HT receptor agonists, the selective 5-HT4 receptor agonist resulted in the greatest potency (-log EC50) value (6.30) compared with 5-HT2B and 5-HT7 receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT4 in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5-HT4 antagonist (1 × 10-5 M) for 5-min prior to the phenylephrine pre-contraction and 5-HT additions. Antagonism of the 5-HT4 receptor attenuated the vasorelaxation caused by 5-HT. Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT4, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT4 activation in bovine peripheral vasculature.

Unveiling serotonergic dysfunction of obsessive-compulsive disorder on prefrontal network dynamics: a computational perspective.

Serotonin (5-HT) regulates working memory within the prefrontal cortex network, which is crucial for understanding obsessive-compulsive disorder. However, the mechanisms how network dynamics and serotonin interact in obsessive-compulsive disorder remain elusive. Here, we incorporate 5-HT receptors (5-HT1A, 5-HT2A) and dopamine receptors into a multistable prefrontal cortex network model, replicating the experimentally observed inverted U-curve phenomenon. We show how the two 5-HT receptors antagonize neuronal activity and modulate network multistability. Reduced binding of 5-HT1A receptors increases global firing, while reduced binding of 5-HT2A receptors deepens attractors. The obtained results suggest reward-dependent synaptic plasticity mechanisms may attenuate 5-HT related network impairments. Integrating serotonin-mediated dopamine release into circuit, we observe that decreased serotonin concentration triggers the network into a deep attractor state, expanding the domain of attraction of stable nodes with high firing rate, potentially causing aberrant reverse learning. This suggests a hypothesis wherein elevated dopamine concentrations in obsessive-compulsive disorder might result from primary deficits in serotonin levels. Findings of this work underscore the pivotal role of serotonergic dysregulation in modulating synaptic plasticity through dopamine pathways, potentially contributing to learned obsessions. Interestingly, serotonin reuptake inhibitors and antidopaminergic potentiators can counteract the over-stable state of high-firing stable points, providing new insights into obsessive-compulsive disorder treatment.

Collaborative action between noradrenergic and serotoninergic systems in peripheral antinociception in mice.

Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.

Novel 5-HT7 receptor antagonists modulate intestinal immune responses and reduce severity of colitis.

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD.NEW & NOTEWORTHY This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease.

Prolonged intermittent hypoxia differentially regulates phrenic motor neuron serotonin receptor expression in rats following chronic cervical spinal cord injury.

Low-dose (< 2 h/day), acute intermittent hypoxia (AIH) elicits multiple forms of serotonin-dependent phrenic motor plasticity and is emerging as a promising therapeutic strategy to restore respiratory and non-respiratory motor function after spinal cord injury (SCI). In contrast, high-dose (> 8 h/day), chronic intermittent hypoxia (CIH) undermines some forms of serotonin-dependent phrenic motor plasticity and elicits pathology. CIH is a hallmark of sleep disordered breathing, which is highly prevalent in individuals with cervical SCI. Interestingly, AIH and CIH preconditioning differentially impact phrenic motor plasticity. Although mechanisms of AIH-induced plasticity in the phrenic motor system are well-described in naïve rats, we know little concerning how these mechanisms are affected by chronic SCI or intermittent hypoxia preconditioning. Thus, in a rat model of chronic, incomplete cervical SCI (lateral spinal hemisection at C2 (C2Hx), we assessed serotonin type 2A, 2B and 7 receptor expression in and near phrenic motor neurons and compared: 1) intact vs. chronically injured rats; and 2) the impact of preconditioning with varied "doses" of intermittent hypoxia (IH). While there were no effects of chronic injury or intermittent hypoxia alone, CIH affected multiple receptors in rats with chronic C2Hx. Specifically, CIH preconditioning (8 h/day; 28 days) increased serotonin 2A and 7 receptor expression exclusively in rats with chronic C2Hx. Understanding the complex, context-specific interactions between chronic SCI and CIH and how this ultimately impacts phrenic motor plasticity is important as we leverage AIH-induced motor plasticity to restore breathing and other non-respiratory motor functions in people with chronic SCI.

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice.

Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) contributes importantly to sudden unexpected death in epilepsy (SUDEP). It has been shown that enhancing serotonin (5-HT) function relieves S-IRA in animal models of SUDEP, including DBA/1 mice. Direct activation of 5-HT3 and 5-HT4 receptors suppresses S-IRA in DBA/1 mice, indicating that these receptors are involved in S-IRA. However, it remains unknown if other subtypes of 5-HT receptors are implicated in S-IRA in DBA/1 mice. In this study, we investigated the action of an agonist of the 5-HT1A (8-OH-DPAT), 5-HT2A (TCB-2), 5-HT2B (BW723C86), 5-HT2C (MK-212), 5-HT6 (WAY-208466) and 5-HT7 (LP-211) receptor on S-IRA in DBA/1 mice. An agonist of the 5-HT receptor or a vehicle was intraperitoneally administered 30 min prior to acoustic simulation, and the effect of each drug/vehicle on the incidence of S-IRA was videotaped for offline analysis. We found that the incidence of S-IRA was significantly reduced by TCB-2 at 10 mg/kg (30%, n = 10; p < 0.01, Fisher's exact test) but was not altered by other agonists compared with the corresponding vehicle controls in DBA/1 mice. Our data demonstrate that 5-HT2A receptors are implicated in S-IRA, and 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors are not involved in S-IRA in DBA/1 mice.

Optogenetic activation of dorsal raphe serotonin neurons induces brain-wide activation.

Serotonin is a neuromodulator that affects multiple behavioral and cognitive functions. Nonetheless, how serotonin causes such a variety of effects via brain-wide projections and various receptors remains unclear. Here we measured brain-wide responses to optogenetic stimulation of serotonin neurons in the dorsal raphe nucleus (DRN) of the male mouse brain using functional MRI with an 11.7 T scanner and a cryoprobe. Transient activation of DRN serotonin neurons caused brain-wide activation, including the medial prefrontal cortex, the striatum, and the ventral tegmental area. The same stimulation under anesthesia with isoflurane decreased brain-wide activation, including the hippocampal complex. These brain-wide response patterns can be explained by DRN serotonergic projection topography and serotonin receptor expression profiles, with enhanced weights on 5-HT1 receptors. Together, these results provide insight into the DR serotonergic system, which is consistent with recent discoveries of its functions in adaptive behaviors.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Serotonin receptor 2B (5-HT2B receptor) plays a critical role in many chronic pain conditions. The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea (IBS-D) was investigated in the present study. AIM: To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D. METHODS: Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls. The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores. The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint. Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1 (TRPV1) expression were examined following 5-HT2B receptor antagonist administration. Changes in visceral sensitivity after administration of the TRPV1 antagonist were recorded. RESULTS: Here, we observed greater expression of the 5-HT2B receptor in the colonic mucosa of patients with IBS-D than in that of controls, which was correlated with abdominal pain scores. Intracolonic instillation of acetic acid and wrap restraint induced obvious chronic visceral hypersensitivity and increased fecal weight and fecal water content. Exogenous 5-HT2B receptor agonist administration increased visceral hypersensitivity, which was alleviated by successive administration of a TRPV1 antagonist. IBS-D rats receiving the 5-HT2B receptor antagonist exhibited inhibited visceral hyperalgesia.Moreover, the percentage of 5-HT2B receptor-immunoreactive (IR) cells surrounded by TRPV1-positive cells (5-HT2B receptor I+) and total 5-HT2B receptor IR cells (5-HT2B receptor IT) in IBS-D rats was significantly reduced by the administration of a 5-HT2B receptor antagonist. CONCLUSION: Our finding that increased expression of the 5-HT2B receptor contributes to visceral hyperalgesia by inducing TRPV1 expression in IBS-D patients provides important insights into the potential mechanisms underlying IBS-D-associated visceral hyperalgesia.

Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice.

Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood. Here, we report that adult hippocampal neural stem cells (NSCs) of the Ascl1 lineage (Ascl1-NSCs) in female mice express functional 5HT1A receptors (5HT1ARs), and selective deletion of 5HT1ARs in Ascl1-NSCs decreases the Ascl1-NSC pool only in females. Mechanistically, 5HT1AR deletion in Ascl1-NSCs of females leads to 5HT-induced depolarization mediated by upregulation of 5HT7Rs. Furthermore, repeated restraint stress (RRS) impairs Ascl1-NSC maintenance through a 5HT1AR-mediated mechanism. By contrast, Ascl1-NSCs in males express 5HT7R receptors (5HT7Rs) that are downregulated by RRS, thus maintaining the Ascl1-NSC pool. These findings suggest that sex-specific expression of distinct 5HTRs and their differential interactions with stress may underlie sex differences in stress vulnerability.

Serotonin Receptors in Myocardial Infarction: Friend or Foe?

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide and treatment costs pose a major burden on the global health care system. Despite the variety of treatment options, individual recovery can be still poor and the mortality rate, especially in the first few years after the event, remains high. Therefore, intense research is currently focused on identifying novel target molecules to improve the outcome following AMI. One of the potentially interesting targets is the serotonergic system (5-HT system), not at least because of its connection to mental disorders. It is known that patients suffering from AMI have an increased risk of developing depression and vice versa. This implicates that the 5-HT system can be affected in response to AMI and might thus represent a target structure for patients' treatment. This review aims to highlight the importance of the 5-HT system after AMI by describing the role of individual serotonin receptors (5-HTR) in the regulation of physiological and pathophysiological responses. It particularly focuses on the signaling pathways of the serotonin receptors 1, 2, 4, and 7, which are expressed in the cardiovascular system, during disease onset, and the following remodeling process. This overview also emphasizes the importance of the 5-HT system in AMI etiology and highlights 5-HTRs as potential treatment targets.

Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT1eR and 5-HT1FR.

Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT1eR have confirmed roles in native tissue and are validated drug targets. Despite 5-HT1eR's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT1eR's pharmacology in relation to the highly homologous 5-HT1FR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT1eR/5-HT1FR agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT1eR distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT1eR and 5-HT1FR contribute to the agonist activity of these antidepressants.

The 5-HT7 receptor antagonist SB 269970 ameliorates maternal fluoxetine exposure-induced impairment of synaptic plasticity in the prefrontal cortex of the offspring female mice.

The use of a selective serotonin reuptake inhibitor fluoxetine in depression during pregnancy and the postpartum period might increase the risk of affective disorders and cognitive symptoms in progeny. In animal models, maternal exposure to fluoxetine throughout gestation and lactation negatively affects the behavior of the offspring. Little is known about the effects of maternal fluoxetine on synaptic transmission and plasticity in the offspring cerebral cortex. During pregnancy and lactation C57BL/6J mouse dams received fluoxetine (7.5 mg/kg/day) with drinking water. Female offspring mice received intraperitoneal injections of the selective 5-HT7 receptor antagonist SB 269970 (2.5 mg/kg) for 7 days. Whole-cell and field potential electrophysiological recordings were performed in the medial prefrontal cortex (mPFC) ex vivo brain slices. Perinatal exposure to fluoxetine resulted in decreased field potentials and impaired long-term potentiation (LTP) in layer II/III of the mPFC of female young adult offspring. Neither the intrinsic excitability nor spontaneous excitatory postsynaptic currents were altered in layer II/III mPFC pyramidal neurons. In mPFC slices obtained from fluoxetine-treated mice that were administered SB 269970 both field potentials and LTP magnitude were restored and did not differ from controls. Treatment of fluoxetine-exposed mice with a selective 5-HT7 receptor antagonist, SB 269970, normalizes synaptic transmission and restores the potential for plasticity in the mPFC of mice exposed in utero and postnatally to fluoxetine.

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R.

BACKGROUND: Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology. METHODS: Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex. RESULTS: We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model. CONCLUSIONS: Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer's disease.

5HT2A modulation attenuates pancreatic cancer induced pain mouse model by inhibiting HDAC.

PURPOSE: Patients have been severely suffered from cancer associated pain, and pancreatic cancer is the most severe form of cancer associated with pain. There are very few options available to manage it. The present report evaluated the effect of 5HT2A on pancreatic cancer associated pain. METHODS: Pancreatic cancer was induced by injecting SW 1,990 cells (~3×106 in a 20 µL suspension) into the pancreas and formed a 2-3-mm vesicle using an inoculator fitted with a 26-gauge needle in BALB/c-nu mice. Survival rate and body weight of the mice were observed. Pain behaviour testing was performed at the end of each week (third and fourth week) after surgery. Inflammatory mediators and HDAC 2 proteins were determined in the spinal tissue using quantitative real-time polymerase chain reaction. RESULTS: There was improvement in the survival rate and body weight in 5HT2A antagonist treated group than pancreatic cancer group of mice. Moreover, 5HT2A antagonist ameliorated the alteration in pain behaviour of pancreatic cancer mice. mRNA expression of HDAC2 and level of inflammatory cytokines were reduced in the spinal tissue of 5HT 2A antagonist treated group than pancreatic cancer group of mice. CONCLUSIONS: Data revealed that 5HT2A antagonist ameliorates pain associated with pancreatic cancer mice by HDAC inhibition and inflammatory cytokines. The result of investigation supports that modulation of 5HT2A receptor could be used clinically to protects neuropathic pain in pancreatic cancer.

Alterations in the brain serotonin system and serotonin-regulated behavior during aging in zebrafish males and females.

The brain serotonin (5-HT) system performs a neurotrophic function and supports the plasticity of the nervous system, while its age-related changes can increase the risk of senile neurodegeneration. Zebrafish brain is highly resistant to damage and neurodegeneration due to its high regeneration potential and it is a promising model object in searching for molecular factors preventing age-related neurodegeneration. In the present study alterations in 5-HT-related behavior in the home tank and the novel tank diving test, as well as 5-HT, 5-HIAA levels, tryptophan hydroxylase (TPH), monoamine oxidase (MAO) activity and the expression of genes encoding TPH, MAO, 5-HT transporter and 5-HT receptors in the brain of 6, 12, 24 and 36 month old zebrafish males and females are investigated. Marked sexual dimorphism in the locomotor activity in the novel tank test is revealed: females of all ages move slower than males. No sexual dimorphism in 5-HT-related traits is observed. No changes in 5-HT and 5-HIAA levels in zebrafish brain during aging is observed. At the same time, the aging is accompanied by a decrease in the locomotor activity, TPH activity, tph2 and htr1aa genes expression as well as an increase in the MAO activity and slc6a4a gene expression in their brain. These results indicate that the brain 5-HT system in zebrafish is resistant to age-related alterations.

Serotonin regulation of mitochondria in kidney diseases.

Serotonin, while conventionally recognized as a neurotransmitter in the CNS, has recently gained attention for its role in the kidney. Specifically, serotonin is not only synthesized in the kidney, but it also regulates glomerular function, vascular resistance, and mitochondrial homeostasis. Because of serotonin's importance to mitochondrial health, this review is focused on the role of serotonin and its receptors in mitochondrial function in the context of acute kidney injury, chronic kidney disease, and diabetic kidney disease, all of which are characterized by mitochondrial dysfunction and none of which has approved pharmacological treatments. Evidence indicates that activation of certain serotonin receptors can stimulate mitochondrial biogenesis (MB) and restore mitochondrial homeostasis, resulting in improved renal function. Serotonin receptor agonists that induce MB are therefore of interest as potential therapeutic strategies for renal injury and disease. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is associated with many human renal diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease, which are associated with increased morbidity and mortality. Unfortunately, none of these pathologies has an FDA-approved pharmacological intervention, underscoring the urgency of identifying new therapeutics for such disorders. Studies show that induction of mitochondrial biogenesis via serotonin (5-hydroxytryptamine, 5-HT) receptors reduces kidney injury markers, restores mitochondrial and renal function after kidney injury, and decreases mortality, suggesting that targeting 5-HT receptors may be a promising therapeutic avenue for mitochondrial dysfunction in kidney diseases. While numerous reviews describe the importance of mitochondria and mitochondrial quality control mechanisms in kidney disease, the relevance of 5-HT receptor-mediated mitochondrial metabolic modulation in the kidney has yet to be thoroughly explored.

Neonatal hypoxia impairs serotonin release and cognitive functions in adult mice.

Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.

Insights into the development of 99mTc-radioligands for serotonergic receptors imaging: Synthesis, labeling, In vitro, and In vivo studies.

Serotonergic (5-hydroxytryptamine; 5-HT) receptors play critical roles in neurological and psychological disorders such as schizophrenia, anxiety, depression, and Alzheimer's diseases. Therefore, it is particularly important to develop novel radioligands or modify the existing ones to identify the serotonergic receptors involved in psychiatric disorders. Among the 16 subtypes of serotonergic systems, only technetium-99m based radiopharmaceuticals have been evaluated for serotonin-1A (5-HT1A), serotonin-2A (5-HT2A), 5-HT1A/7 heterodimers and serotonin receptor neurotransmitter (SERT). This review focuses on recent efforts in the design, synthesis and evaluation of 99mTc-radioligands used for single photon emission computerized tomography (SPECT) imaging of serotonergic (5-HT) receptors. Additionally, the discussion will cover aspects such as chemical structure, in vitro/vivo stability, affinity toward serotonin receptors, blood-brain barrier permeation (BBB), and biodistribution study.

Living, Heat-Killed Limosilactobacillus mucosae and Its Cell-Free Supernatant Differentially Regulate Colonic Serotonin Receptors and Immune Response in Experimental Colitis.

Lactobacillus species have been shown to alleviate gut inflammation and oxidative stress. However, the effect of different lactobacilli components on gut inflammation has not been well studied. This study aims to identify the differences in the effect and mechanisms of different forms and components of Limosilactobacillus mucosae (LM) treatment in the alleviation of gut inflammation using a colitis mouse model that is induced by dextran sodium sulfate (DSS). Seventy-two C57BL/6 mice were divided into six groups: control, DSS, live LM+DSS (LM+DSS), heat-killed LM+DSS (HKLM+DSS), LM cell-free supernatant + DSS (LMCS+DSS), and MRS medium + DSS (MRS+DSS). The mice were treated with different forms and components of LM for two weeks before DSS treatment. After that, the mice were sacrificed for an assessment of their levels of inflammatory cytokines, serotonin (5-HT) receptors (HTRs), and tryptophan metabolites. The results showed that, compared to other treatments, LMCS was more effective (p < 0.05) in the alleviation of DSS-induced body weight loss and led to an increase in the disease activity index score. All three forms and components of LM increased (p < 0.05) the levels of indole-3-acetic acid but reduced (p < 0.05) the levels of 5-HT in the colon. HKLM or LMCS reduced (p < 0.05) the percentages of CD3+CD8+ cytotoxic T cells but increased (p < 0.05) the percentages of CD3+CD4+ T helper cells in the spleen. LM or HKLM increased (p < 0.05) abundances of CD4+Foxp3+ regulatory T cells in the spleen. The LM and LMCS treatments reduced (p < 0.05) the expression of the pro-inflammatory cytokines Il6 and Il17a. The mice in the HKLM+DSS group had higher (p < 0.05) mRNA levels of the anti-inflammatory cytokine Il10, the cell differentiation and proliferation markers Lgr5 and Ki67, the 5-HT degradation enzyme Maoa, and HTRs (Htr1a, Htr2a, and Htr2b) in the colon. All three forms and components of LM reduced the phosphorylation of STAT3. The above findings can help to optimize the functionality of probiotics and develop new dietary strategies that aid in the maintenance of a healthy gut.

SB-258585 reduces food motivation while blocking 5-HT6 receptors in the non-human primate striatum.

The interest in new 5-HT6 agents stems from their ability to modulate cognition processing, food motivation and anxiety-like behaviors. While these findings come primarily from rodent studies, no studies on primates have been published. Furthermore, our understanding of where and how they act in the brain remains limited. Although the striatum is involved in all of these processes and expresses the highest levels of 5-HT6 receptors, few studies have focused on it. We thus hypothesized that 5-HT6 receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT6 receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT6 receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT6 targets using PET imaging to measure 5-HT6 receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT6 receptor occupancy with the specific PET imaging [18F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT6 transmission, most likely through the striatum (the putamen and caudate nucleus), significantly reduces food motivation while exhibiting variable, weaker effects on behavior. While these results are consistent with the literature showing a decrease in food intake in rodents and proposing that 5-HT6 receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential.