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1.
FASEB J ; 38(11): e23648, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38822661

ABSTRACT

Previous studies on germ-free (GF) animals have described altered anxiety-like and social behaviors together with dysregulations in brain serotonin (5-HT) metabolism. Alterations in circulating 5-HT levels and gut 5-HT metabolism have also been reported in GF mice. In this study, we conducted an integrative analysis of various behaviors as well as markers of 5-HT metabolism in the brain and along the GI tract of GF male mice compared with conventional (CV) ones. We found a strong decrease in locomotor activity, accompanied by some signs of increased anxiety-like behavior in GF mice compared with CV mice. Brain gene expression analysis showed no differences in HTR1A and TPH2 genes. In the gut, we found decreased TPH1 expression in the colon of GF mice, while it was increased in the cecum. HTR1A expression was dramatically decreased in the colon, while HTR4 expression was increased both in the cecum and colon of GF mice compared with CV mice. Finally, SLC6A4 expression was increased in the ileum and colon of GF mice compared with CV mice. Our results add to the evidence that the microbiota is involved in regulation of behavior, although heterogeneity among studies suggests a strong impact of genetic and environmental factors on this microbiota-mediated regulation. While no impact of GF status on brain 5-HT was observed, substantial differences in gut 5-HT metabolism were noted, with tissue-dependent results indicating a varying role of microbiota along the GI tract.


Subject(s)
Behavior, Animal , Germ-Free Life , Serotonin , Animals , Serotonin/metabolism , Mice , Male , Gastrointestinal Microbiome/physiology , Brain/metabolism , Tryptophan Hydroxylase/metabolism , Tryptophan Hydroxylase/genetics , Anxiety/metabolism , Anxiety/microbiology , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Mice, Inbred C57BL , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/genetics , Colon/metabolism , Colon/microbiology
2.
BMC Complement Med Ther ; 24(1): 198, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773460

ABSTRACT

BACKGROUND: Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. METHODS: A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. RESULTS: Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. CONCLUSION: This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia.


Subject(s)
Analgesics , Disease Models, Animal , Drugs, Chinese Herbal , Pain, Postoperative , Animals , Mice , Drugs, Chinese Herbal/pharmacology , Male , Pain, Postoperative/drug therapy , Analgesics/pharmacology , Serotonin/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/drug effects , Administration, Oral , Mice, Inbred ICR
3.
Behav Brain Res ; 469: 115051, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38777263

ABSTRACT

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.


Subject(s)
Dopamine Plasma Membrane Transport Proteins , Exploratory Behavior , Recognition, Psychology , Animals , Dopamine Plasma Membrane Transport Proteins/metabolism , Male , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/drug effects , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2A/drug effects , Motor Activity/drug effects , Motor Activity/physiology , Brain/metabolism , Brain/drug effects , Emotions/drug effects , Emotions/physiology , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Agonists/pharmacology , Rats, Wistar
4.
Nature ; 630(8015): 237-246, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38720072

ABSTRACT

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.


Subject(s)
Cryoelectron Microscopy , Hallucinogens , Receptor, Serotonin, 5-HT1A , Animals , Mice , Hallucinogens/pharmacology , Hallucinogens/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/chemistry , Humans , Male , Models, Molecular , 5-Methoxytryptamine/pharmacology , 5-Methoxytryptamine/chemistry , 5-Methoxytryptamine/analogs & derivatives , Female , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2A/chemistry , Structure-Activity Relationship , Lysergic Acid Diethylamide/pharmacology , Lysergic Acid Diethylamide/chemistry , Lysergic Acid Diethylamide/analogs & derivatives , Behavior, Animal/drug effects
5.
Elife ; 132024 Apr 04.
Article in English | MEDLINE | ID: mdl-38573820

ABSTRACT

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.


Subject(s)
Thrombocytopenia , Vilazodone Hydrochloride , Mice , Animals , Vilazodone Hydrochloride/adverse effects , Vilazodone Hydrochloride/metabolism , Zebrafish , Receptor, Serotonin, 5-HT1A/metabolism , Blood Platelets/metabolism , Thrombocytopenia/drug therapy , Thrombocytopenia/metabolism , Megakaryocytes/metabolism , Thrombopoiesis
6.
Sci Rep ; 14(1): 9878, 2024 04 30.
Article in English | MEDLINE | ID: mdl-38684848

ABSTRACT

Chronic stress is associated with major depressive disorder (MDD). Increased glucocorticoid levels caused by uncontrolled release through the hypothalamic‒pituitary‒adrenal (HPA) axis can cause changes in the lipid content of the cellular plasma membrane. These changes are suspected to be involved in the development of depressive disorders. St. John's wort extract (SJW) Ze 117 has long been used as an alternative to synthetic antidepressants. Part of its effect may be due to an effect on the cellular lipid composition and thus on the properties of plasma membranes and receptor systems embedded therein. In this study, we investigated the effect of Ze 117 on that of dexamethasone and simvastatin. Dexamethasone increases the fluidity of C6 cell plasma membranes. This effect is counteracted by administration of Ze 117. Here we demonstrate that this is not due to a change in C16:1/16:0 and C18:1/18:0 ratios in C6 cell fatty acids. On the other hand, Ze 117 increased the cellular cholesterol content by 42.5%, whereas dexamethasone reduced cholesterol levels similarly to simvastatin. Lowering cholesterol levels by dexamethasone or simvastatin resulted in decreased ß-arrestin 2 recruitment to the 5-HT1a receptor. This effect was counterbalanced by Ze 117, whereas the SJW extract had little effect on ß-arrestin 2 recruitment in non-stressed cells. Taken together, in C6 cells, Ze 117 induces changes in membrane fluidity through its effect on cellular cholesterol metabolism rather than by affecting fatty acid saturation. This effect is reflected in an altered signal transduction of the 5-HT1a receptor under Ze 117 administration. The current in vitro results support the hypothesis that Ze 117 addresses relevant parts of the cellular lipid metabolism, possibly explaining some of the antidepressant actions of Ze 117.


Subject(s)
Cholesterol , Dexamethasone , Hypericum , Membrane Fluidity , Plant Extracts , Simvastatin , Hypericum/chemistry , Plant Extracts/pharmacology , Cholesterol/metabolism , Membrane Fluidity/drug effects , Dexamethasone/pharmacology , Cell Line, Tumor , Simvastatin/pharmacology , Glioma/metabolism , Glioma/drug therapy , Glioma/pathology , Animals , Rats , Cell Membrane/metabolism , Cell Membrane/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Fatty Acids/metabolism
7.
Cell Rep ; 43(5): 114140, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38656873

ABSTRACT

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.


Subject(s)
Hippocampus , Neural Stem Cells , Receptors, Serotonin , Stress, Psychological , Animals , Neural Stem Cells/metabolism , Female , Hippocampus/metabolism , Male , Mice , Receptors, Serotonin/metabolism , Receptors, Serotonin/genetics , Stress, Psychological/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Sex Characteristics , Mice, Inbred C57BL , Serotonin/metabolism
8.
Int J Mol Sci ; 25(8)2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38673988

ABSTRACT

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.


Subject(s)
Hypercapnia , Parkinson Disease , Receptor, Serotonin, 5-HT1A , Receptor, Serotonin, 5-HT2A , Animals , Male , Rats , Disease Models, Animal , Dopamine/metabolism , Hypercapnia/metabolism , Hypercapnia/physiopathology , Norepinephrine/metabolism , Norepinephrine/pharmacology , Oxidopamine/pharmacology , Parkinson Disease/metabolism , Rats, Wistar , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Respiration/drug effects , Serotonin/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Agonists/pharmacology
9.
Environ Sci Technol ; 58(17): 7577-7587, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38630542

ABSTRACT

The serotonin signaling system plays a crucial role in regulating the ontogeny of crustaceans. Here, we describe the effects of different concentrations of the 5-hydroxytryptamine 1A receptor antagonist (WAY-100635) on the induced antipredation (Rhodeus ocellatus as the predator), morphological, behavioral, and life-history defenses of Daphnia magna and use transcriptomics to analyze the underlying molecular mechanisms. Our results indicate that exposure to WAY-100635 leads to changes in the expression of different defensive traits in D. magna when faced with fish predation risks. Specifically, as the length of exposure to WAY-100635 increases, high concentrations of WAY-100635 inhibit defensive responses associated with morphological and reproductive activities but promote the immediate negative phototactic behavioral defense of D. magna. This change is related to the underlying mechanism through which WAY-100635 interferes with gene expression of G-protein-coupled GABA receptors by affecting GABBR1 but promotes serotonin receptor signaling and ecdysteroid signaling pathways. In addition, we also find for the first time that fish kairomone can significantly activate the HIF-1α signaling pathway, which may lead to an increase in the rate of immediate movement. These results can help assess the potential impacts of serotonin-disrupting psychotropic drugs on zooplankton in aquatic ecosystems.


Subject(s)
Daphnia , Transcriptome , Animals , Daphnia/drug effects , Transcriptome/drug effects , Predatory Behavior/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Daphnia magna
10.
Cells ; 13(6)2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38534310

ABSTRACT

Cannabinoids have shown potential in drug-resistant epilepsy treatment; however, we lack knowledge on which cannabinoid(s) to use, dosing, and their pharmacological targets. This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC), as well as (iii) the serotonin (5-HT)1A receptor's role in CBD's mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 µM CBD alone and combined with Δ9-THC was evaluated. To examine CBD's mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD's effect was evaluated. An amount of ≥30 µM CBD alone exerted significant anticonvulsant effects while 10 µM CBD did not. However, 10 µM CBD combined with low-dose Δ9-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD's effects. Thus, our results demonstrate the efficacy of low-dose CBD and Δ9-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD's mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.


Subject(s)
Cannabidiol , Cannabinoids , Neocortex , Mice , Animals , Cannabidiol/pharmacology , Anticonvulsants/therapeutic use , Dronabinol , Receptor, Serotonin, 5-HT1A , Cannabinoids/therapeutic use , Serotonin
11.
Neurobiol Dis ; 193: 106465, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38460800

ABSTRACT

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.


Subject(s)
Selective Serotonin Reuptake Inhibitors , Serotonin , Humans , Child , Mice , Animals , Serotonin/metabolism , Receptor, Serotonin, 5-HT1A , Asphyxia , Fluoxetine/pharmacology , Serotonin Receptor Agonists/pharmacology , Receptors, Serotonin , Cognition , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Hypoxia
12.
Bioorg Med Chem ; 104: 117698, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38552597

ABSTRACT

Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC50 of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.


Subject(s)
Selective Serotonin Reuptake Inhibitors , Serotonin , Mice , Animals , Piperazine/pharmacology , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Piperidines/pharmacology , Piperazines/chemistry , Receptor, Serotonin, 5-HT1A
13.
Cell ; 187(9): 2194-2208.e22, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38552625

ABSTRACT

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.


Subject(s)
Cheminformatics , Drug Design , Polypharmacology , Animals , Mice , Humans , Cheminformatics/methods , Ligands , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/chemistry , Male , Binding Sites
14.
Neurol Res ; 46(5): 398-405, 2024 May.
Article in English | MEDLINE | ID: mdl-38555524

ABSTRACT

OBJECTIVES: The serotonin (5-hydroxytryptamine, 5-HT) receptor 1A (5-HT1AR) is closely associated with serotonergic neurotransmission in the brain, being the most prevalent and widely distributed receptor of its kind. The purpose of this study is to investigate the regulation mechanism of 5-HT1AR by GSK4716. METHODS: To investigate the mechanism of GSK4716-mediated 5-HT1AR regulation, we used hippocampus-derived HT22 cells expressing 5-HT1AR. The expression level of 5-HT1AR and associated proteins, were detected by reporter gene assay and western blotting. RESULTS: GSK4716, an estrogen-related receptor gamma agonist increased 5-HT1AR expression by interacting with the GR, a repressor of 5-HT1AR transcription. Dexamethasone, a GR agonist, decreased the GSK4716-induced increase in 5-HT1AR, which was associated with an alteration in nuclear GR. Furthermore, GR antagonist RU486 reversed the effects induced by dexamethasone, including the elevation of nuclear GR levels and the reduction of 5-HT1AR transcription and expression. CONCLUSION: The results could provide insight into the potential applications of small molecules, such as GSK4716, in the regulation of 5-HT1AR expression, which plays a role in serotonergic neurotransmission.


Subject(s)
Hippocampus , Receptor, Serotonin, 5-HT1A , Receptors, Glucocorticoid , Animals , Mice , Cell Line , Dexamethasone/pharmacology , Estrogens/pharmacology , Hippocampus/metabolism , Hippocampus/drug effects , Mifepristone/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology
15.
Pharmacol Biochem Behav ; 238: 173749, 2024 May.
Article in English | MEDLINE | ID: mdl-38462045

ABSTRACT

BACKGROUND: Muscarinic or 5-HT1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits. METHODS: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals. RESULTS: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice. CONCLUSION: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.


Subject(s)
Dizocilpine Maleate , Serotonin , Mice , Animals , Dizocilpine Maleate/pharmacology , Receptors, Muscarinic , Brain , Cholinergic Agents/pharmacology , Receptor, Serotonin, 5-HT1A
16.
Food Funct ; 15(9): 4773-4784, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38469873

ABSTRACT

Raphanus sativus L. cv. Sango, commonly known as red radish, is widely consumed around the world as a vegetable, but its benefit in pain relief is not sufficiently investigated. This study aimed to evaluate the antinociceptive effects of R. sativus and a possible mechanism of action. An aqueous extract of R. sativus sprouts (AERSS) was investigated by parenteral (10, 30, and 100 mg kg-1, i.p.) and enteral (500 mg kg-1, p.o.) administration in the neurogenic and inflammatory phases of the formalin test, where gastric damage was also evaluated as a possible adverse effect. Ketorolac (5 mg kg-1, i.p.) was used as the reference drug. Endogenous opioid and 5-HT1A serotonin receptors, as well as the cAMP/NO-cGMP pathways, were explored in the study of a possible mechanism of action by using their corresponding antagonists: naloxone, 1 mg kg-1, i.p., WAY100635, 1 mg kg-1, i.p., and enzymatic activators or inhibitors, respectively. Sulforaphane (SFN), a known bioactive metabolite, was analyzed using electroencephalography (EEG) to evidence its central involvement. A significant and dose-dependent antinociceptive activity was observed with the AERSS resembling the antinociceptive effect of the reference drug, with an equivalent significant response with a dose of 500 mg kg-1, p.o. without causing gastric damage. The participation of the endogenous opioid and 5-HT1A serotonin receptors at central and peripheral levels was also observed, with a differential participation of cAMP/NO-cGMP. SFN as one metabolite produced significant changes in the EEG analysis, reinforcing its effects on the CNS. Our preclinical evidence supports the benefits of consuming Raphanus sativus cv. Sango sprouts for pain relief.


Subject(s)
Analgesics , Isothiocyanates , Plant Extracts , Raphanus , Signal Transduction , Animals , Humans , Male , Mice , Analgesics/pharmacology , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Isothiocyanates/pharmacology , Pain/drug therapy , Plant Extracts/pharmacology , Raphanus/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Opioid/metabolism , Signal Transduction/drug effects , Sulfoxides/pharmacology
17.
Basic Clin Pharmacol Toxicol ; 134(5): 574-601, 2024 May.
Article in English | MEDLINE | ID: mdl-38477419

ABSTRACT

Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.


Subject(s)
Cannabidiol , Cannabinoids , Epilepsy , Mental Disorders , Multiple Sclerosis , Parkinson Disease , Humans , Cannabidiol/pharmacology , Cannabidiol/therapeutic use , Parkinson Disease/drug therapy , Multiple Sclerosis/drug therapy , Receptor, Serotonin, 5-HT1A/therapeutic use , Cannabinoids/pharmacology , Cannabinoids/therapeutic use , Epilepsy/drug therapy , Mental Disorders/drug therapy , Comorbidity
18.
Behav Brain Res ; 466: 114975, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38552745

ABSTRACT

Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.


Subject(s)
Animals, Newborn , Hippocampus , Pain Threshold , Receptor, Serotonin, 5-HT1A , Animals , Female , Male , Rats , Behavior, Animal/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Freund's Adjuvant , Hippocampus/metabolism , Nociception/physiology , Pain/metabolism , Pain/physiopathology , Pain Threshold/physiology , Rats, Wistar , Receptor, Serotonin, 5-HT1A/metabolism
19.
Article in English | MEDLINE | ID: mdl-38354893

ABSTRACT

Chronic stress is a major risk factor for psychiatric disorders. However, certain individuals may be at higher risk due to greater stress susceptibility. Elucidating the neurobiology of stress resilience and susceptibility may facilitate the development of novel strategies to prevent and treat stress-related disorders such as depression. Mounting evidence suggests that the serotonin (5-HT) system is a major regulator of stress sensitivity. In this study, we assessed the functions of 5-HT1A and 5-HT2A receptors within the lateral septum (LS) in regulating stress vulnerability. Among a group of male mice exposed to chronic social defeat stress (CSDS), 47.2% were classified as stress-susceptible, and these mice employed more passive coping strategies during the defeat and exhibited more severe anxiety- and depression-like behaviors during the following behavioral tests. These stress-susceptible mice also exhibited elevated neuronal activity in the LS as evidenced by greater c-Fos expression, greater activity of 5-HT neurons in both the dorsal and median raphe nucleus, and downregulated expression of the 5-HT1A receptor in the intermediate LS (LSi). Finally, we found the stress-induced social withdrawal symptoms could be rapidly relieved by LSi administration of 8-OH-DPAT, a 5-HT1A receptor agonist. These results indicate that 5-HT1A receptors within the LSi play an important role in stress vulnerability in mice. Therefore, modulation of stress vulnerable via 5-HT1A receptor activation in the LSi is a potential strategy to treat stress-related psychiatric disorders.


Subject(s)
Receptor, Serotonin, 5-HT1A , Serotonin , Animals , Male , Mice , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Neurons/metabolism , Raphe Nuclei/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology
20.
Br J Pharmacol ; 181(11): 1671-1689, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38320596

ABSTRACT

BACKGROUND AND PURPOSE: Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in AYA-treated rats. EXPERIMENTAL APPROACH: We focused on the 5-HT1A and 5-HT2A receptors, as DMT exhibits a high affinity for both of them, along with the infralimbic cortex in which activity and plasticity play crucial roles in regulating the mnemonic process under analysis. KEY RESULTS: A single oral treatment with AYA containing 0.3 mg·kg-1 of DMT increased the within-session extinction of contextual freezing behaviour without affecting its recall. This protocol, when repeated twice on consecutive days, enhanced extinction recall. These effects were consistent for both 1- and 21-day-old memories in males and females. AYA effects on fear extinction were independent of changes in anxiety and general exploratory activity: AYA- and vehicle-treated animals showed no differences when tested in the elevated plus-maze. The 5-HT2A receptor antagonist MDL-11,939 and the 5-HT1A receptor antagonist WAY-100635 infused into the infralimbic cortex respectively blocked within- and between-session fear extinction effects resulting from repeated oral administration of AYA. CONCLUSION AND IMPLICATIONS: Our findings highlight complementary mechanisms by which AYA facilitates the behavioural suppression of aversive memories in the rat infralimbic cortex. These results suggest potential beneficial effects of AYA or DMT in stress-related disorders.


Subject(s)
Banisteriopsis , Extinction, Psychological , Fear , Receptor, Serotonin, 5-HT1A , Receptor, Serotonin, 5-HT2A , Animals , Fear/drug effects , Fear/physiology , Male , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/drug effects , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2A/drug effects , Extinction, Psychological/drug effects , Rats , Banisteriopsis/chemistry , Hallucinogens/pharmacology , Hallucinogens/administration & dosage , Rats, Sprague-Dawley , Behavior, Animal/drug effects , Pyridines/pharmacology
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