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To examine the effect of ketanserin and naloxone on fentanyl-induced motor activity in isoflurane-anaesthetized pigs. Randomized, blinded, prospective two-group study. A group of 12 crossbred pigs weighing 22–31 kg. Fentanyl was administered to isoflurane-anaesthetized pigs at 7.5 μg kg–1 hour–1 for 40 minutes intravenously, followed by an intravenous injection of naloxone 0.1 mg kg–1 or ketanserin 1 mg kg–1. Electromyography (EMG) and accelerometry were used to record motor unit activity and tremors, respectively. To test the effect of drug administration on motor activity, data from a 5 minute period at baseline, immediately before and after antagonist injection were compared in a mixed model; p < 0.05. Results are reported with the median difference, 95% confidence intervals and corresponding p- values in brackets. Fentanyl significantly increased EMG activity [30.51 (1.84–81.02) μV, p = 0.004] and induced tremors [0.09 (0.02–0.18) m s–2, p < 0.001] in 10 of 12 pigs. Ketanserin significantly reduced EMG [32.22 (6.29–136.80) μV, p = 0.001] and tremor [0.10 (0.03–0.15) m s–2, p = 0.007] activity. No significant effect was found for naloxone on EMG [26.76 (–13.28–91.17) μV, p = 0.4] or tremors [0.08 (–0.01–0.19) m s–2, p = 0.08]. Fentanyl can induce motor activity in anaesthetized pigs, with a suggested link to the serotonergic system. This study shows that ketanserin can antagonize this activity, which supports the role of serotonin. This knowledge contributes to the general understanding of the motor effects of fentanyl and especially the problem of tremors in anaesthetized pigs. [ABSTRACT FROM AUTHOR]

Stanhopea tigrina Bateman ex Lindl. (Orchidaceae) is an orchid endemic to Mexico, known as "Calavera" or "calaverita", in the Huasteca Potosina (central region of Mexico). This plant species is used for the folk treatment of mental disorders and urological kidney disorders, according to the ethnomedicinal information obtained in this study. Ethanolic extracts of leaves (HE) and pseudobulb (PE) were obtained by microwave-assisted extraction (MAE). Gas Chromatography coupled with Mass Spectrometry (GC-MS) was used to carry out the chemical characterization of HE and PE. The pharmacological effects (antioxidant, diuretic, anxiolytic, locomotor, hypnotic, and sedative) of HE and PE were evaluated. The possible mechanism of action of the anxiolytic-like activity induced by HE was assessed using inhibitors of the GABAergic, adrenergic, and serotonergic systems. The possible mechanism of the diuretic action of HE was assessed using prostaglandin inhibitory antagonists and nitric oxide synthase (NOS) blockers. HE at 50 and 100 mg/kg exerted anxiolytic-like activity without inducing hypnosis or sedation. Flumazenil, prazosin, and ketanserin inhibited the anxiolytic-like activity shown by HE, which suggests the participation of GABA, α1-adrenergic receptors, and 5-HT2 receptors, respectively. The diuretic effect was reversed by the non-selective NOS inhibitor L-NAME, which caused the reduction in nitric oxide (NO). These results demonstrate that the ethanolic extract of S. tigrina leaves exhibited anxiolytic-like activity and diuretic effects without inducing hypnosis or sedation. This work validates the medicinal uses of this orchid species. [ABSTRACT FROM AUTHOR]

Inflammation plays a pivotal role in the development and progression of inflammatory bowel disease (IBD), by contributing to tissue damage and exacerbating the immune response. The investigation of serotonin receptor 2A (5-HT2A) ligands and transient receptor potential (TRP) channel ligands is of significant interest due to their potential to modulate key inflammatory pathways, mitigate the pathological effects of inflammation, and offer new avenues for therapeutic interventions in IBD. This study investigates the anti-inflammatory effects of 5-HT2A ligands, including psilocybin, 4-AcO-DMT, and ketanserin, in combination with TRP channel ligands, including capsaicin, curcumin, and eugenol, on the inflammatory response induced by tumor necrosis factor (TNF)-α and interferon (IFN)-γ in human 3D EpiIntestinal tissue. Enzyme-linked immunosorbent assay was used to assess the expression of pro-inflammatory markers TNF-α, IFN-γ, IL-6, IL-8, MCP-1, and GM-CSF. Our results show that psilocybin, 4-AcO-DMT, and eugenol significantly reduce TNF-α and IFN-γ levels, while capsaicin and curcumin decrease these markers to a lesser extent. Psilocybin effectively lowers IL-6 and IL-8 levels, but curcumin, capsaicin, and 4-AcO-DMT have limited effects on these markers. In addition, psilocybin can significantly decrease MCP-1 and GM-CSF levels. While ketanserin lowers IL-6 and GM-CSF levels, there are no effects seen on TNF-α, IFN-γ, IL-8, or MCP-1. Although synergistic effects between 5-HT2A and TRP channel ligands are minimal in this study, the results provide further evidence of the anti-inflammatory effects of psilocybin and eugenol. Further research is needed to understand the mechanisms of action and the feasibility of using these compounds as anti-inflammatory therapies for conditions like IBD. [ABSTRACT FROM AUTHOR]

Intestinal inflammation and dysbiosis can lead to inflammatory bowel diseases (IBD) and systemic inflammation, affecting multiple organs. Developing novel anti-inflammatory therapeutics is crucial for preventing IBD progression. Serotonin receptor type 2A (5-HT2A) ligands, including psilocybin (Psi), 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), and ketanserin (Ket), along with transient receptor potential (TRP) channel ligands like capsaicin (Cap), curcumin (Cur), and eugenol (Eug), show promise as anti-inflammatory agents. In this study, we investigated the cytotoxic and anti-inflammatory effects of Psi, 4-AcO-DMT, Ket, Cap, Cur, and Eug on human small intestinal epithelial cells (HSEIC). HSEIC were exposed to tumor necrosis factor (TNF)-α and interferon (IFN)-γ for 24 h to induce an inflammatory response, followed by treatment with each compound at varying doses (0–800 μM) for 24 to 96 h. The cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and protein expression by Western blot (WB) analysis. As single treatments, Psi (40 μM), Cur (0.5 μM), and Eug (50 μM) significantly reduced COX-2 levels without cytotoxic effects. When combined, Psi (40 μM) and Cur (0.5 μM) exhibited synergy, resulting in a substantial decrease in COX-2 protein levels (−28× fold change), although the reduction in IL-6 was less pronounced (−1.6× fold change). Psi (20 μM) and Eug (25 μM) demonstrated the most favorable outcomes, with significant decreases in COX-2 (−19× fold change) and IL-6 (−10× fold change) protein levels. Moreover, the combination of Psi and Eug did not induce cytotoxic effects in vitro at any tested doses. This study is the first to explore the anti-inflammatory potential of psilocybin and 4-AcO-DMT in the intestines while highlighting the potential for synergy between the 5-HT2A and TRP channel ligands, specifically Psi and Eug, in alleviating the TNF-α/IFN-γ-induced inflammatory response in HSEIC. Further investigations should evaluate if the Psi and Eug combination has the therapeutic potential to treat IBD in vivo.

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The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT1A receptors and upregulated 5-HT1A gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced the pro-depressive effect in a forced swim test. Since 5-HT2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT1A and 5-HT2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine, while fluoxetine, ketanserin, and fluoxetine + ketanserin decreased the functional activity of 5-HT1A receptors and Htr1a gene transcription in the midbrain and hippocampus. All tested drug regimens decreased the mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

Simple Summary: Pigs used in research are often subjected to procedures for which pain relief is crucial. However, the literature indicates that analgesics are under-reported and under-used in experiments involving pigs. Fentanyl is one of the opioids used to provide post-operative pain relief in experimental pigs. Analgesic requirements are often assessed using behavioral indicators such as activity. However, the effects of fentanyl on behavior in pigs are largely unknown. The aims of the current study were to investigate how fentanyl influences behavior in pigs, and if serotonin could be involved in fentanyl-induced behavioral side effects. The results of this study demonstrate that fentanyl can influence activity level, and induce different repetitive behaviors in pigs. Some of the behavioral changes induced by fentanyl seem to involve the serotonergic system. In conclusion fentanyl might influence behavior through mechanisms unrelated to analgesia. This is important for experimental pigs as it could interfere with pain assessment and determination of analgesic requirements. Analgesic effects of fentanyl have been investigated using behavior. The behavioral effects of fentanyl and possible serotonergic influence are largely unknown. We therefore investigated behavioral effects of fentanyl, with or without the serotonin antagonist ketanserin, in pigs. Fourteen mixed-breed pigs, weighing 17–25 kg were included in a randomised blinded prospective, balanced three-group study. Ten pigs received first 5 and then 10 µg/kg of fentanyl intravenously. Ketanserin at 1 mg/kg or saline was given intravenously as a third injection. Four control pigs received three injections of saline. Behavior was video-recorded. The distance moved was automatically measured by commercially available software, and behaviors manually scored in retrospect. Fentanyl inhibited resting and playing, and induced different repetitive behaviors. The mean (SD) distance moved in the control group and fentanyl group was 21.3 (13.0) and 57.8 (20.8) metres respectively (p < 0.05 for pairwise comparison). A stiff gait pattern was seen after fentanyl injection for median (range) 4.2 (2.8–5.1) minutes per 10 min, which was reduced to 0 (0–4) s after ketanserin administration. Conclusion: fentanyl-induced motor and behavioral effects, and serotonergic transmission may be involved in some of them. The psychomotor side effects of fentanyl could potentially interfere with post-operative pain evaluation in pigs. [ABSTRACT FROM AUTHOR]

Focusing on a reliable supramolecular synthon approach, novel molecular salts of the antihypertensive medication ketanserin (KTS) with aromatic carboxylic acid derivatives (benzoic acid (BA), 2-hydroxybenzoic acid (2-HBA), and 2,5-dihydroxybenzoic acid (2,5-DHBA)) are reported. Binary salts of KTS with the respective salt former were obtained via solvent-assisted grinding followed by solution crystallization. Salt production was confirmed through crystal structure investigations that revealed proton transfer from the carboxylic acid group of the salt former to the piperidine nitrogen atom of KTS. A rigorous investigation of the crystal packing of novel binary salts of KTS inspired the construction of ternary adducts, and a ternary crystalline product was subsequently identified using milrinone (MLN), another cardiotonic drug. According to our knowledge, this is the first instance of a dual-drug ternary co-crystal combining both antihypertensive drugs. In order to evaluate the impacts of co-crystallization on the in vitro release behaviour of binary and ternary adducts, solubility tests for the cocrystal were carried out under a variety of physiological pH conditions. The results indicate that, in contrast to the parent drug and binary adducts, the solubility rate of the ternary adducts is significantly increased. Finally, the stability of the synthesised adduct was evaluated under a range of conditions, including temperature (40 ± 1 °C), humidity (90% ± 5% RH, 25 °C) and various solvents media, and it was established that they have good stability. We anticipate that the present findings will work with a wide range of medication combinations, providing a potential new approach to create multi-drug systems for cardiovascular disease. [ABSTRACT FROM AUTHOR]

The dopaminergic and serotonergic systems are two of the most important neuronal pathways in the human brain. Almost all psychotropic medications impact at least one neurotransmitter system. As a result, investigating how they affect memory could yield valuable insights into potential therapeutic applications or unanticipated side effects. The aim of this literature review was to collect literature data from animal studies regarding the effects on memory of four drugs known to act on the serotonergic and dopaminergic systems. The studies included in this review were identified in the PubMed database using selection criteria from the PRISMA protocol. We analyzed 29 articles investigating one of four different dopaminergic or serotonergic compounds. Studies conducted on bromocriptine have shown that stimulating D2 receptors may enhance working memory in rodents, whereas inhibiting these receptors could have the opposite effect, reducing working memory performance. The effects of serotonin on working memory are not clearly established as studies on fluoxetine and ketanserin have yielded conflicting results. Further studies with better-designed methodologies are necessary to explore the impact of compounds that affect both the dopaminergic and serotonergic systems on working memory. [ABSTRACT FROM AUTHOR]

Background Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8–11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD. Methods We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours. Results Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD. Conclusions These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy. Trial registry ClinicalTrials.gov (NCT04558294) [ABSTRACT FROM AUTHOR]

Inflammation plays a pivotal role in the development and progression of inflammatory bowel disease (IBD), by contributing to tissue damage and exacerbating the immune response. The investigation of serotonin receptor 2A (5-HT2A) ligands and transient receptor potential (TRP) channel ligands is of significant interest due to their potential to modulate key inflammatory pathways, mitigate the pathological effects of inflammation, and offer new avenues for therapeutic interventions in IBD. This study investigates the anti-inflammatory effects of 5-HT2A ligands, including psilocybin, 4-AcO-DMT, and ketanserin, in combination with TRP channel ligands, including capsaicin, curcumin, and eugenol, on the inflammatory response induced by tumor necrosis factor (TNF)-α and interferon (IFN)-γ in human 3D EpiIntestinal tissue. Enzyme-linked immunosorbent assay was used to assess the expression of pro-inflammatory markers TNF-α, IFN-γ, IL-6, IL-8, MCP-1, and GM-CSF. Our results show that psilocybin, 4-AcO-DMT, and eugenol significantly reduce TNF-α and IFN-γ levels, while capsaicin and curcumin decrease these markers to a lesser extent. Psilocybin effectively lowers IL-6 and IL-8 levels, but curcumin, capsaicin, and 4-AcO-DMT have limited effects on these markers. In addition, psilocybin can significantly decrease MCP-1 and GM-CSF levels. While ketanserin lowers IL-6 and GM-CSF levels, there are no effects seen on TNF-α, IFN-γ, IL-8, or MCP-1. Although synergistic effects between 5-HT2A and TRP channel ligands are minimal in this study, the results provide further evidence of the anti-inflammatory effects of psilocybin and eugenol. Further research is needed to understand the mechanisms of action and the feasibility of using these compounds as anti-inflammatory therapies for conditions like IBD.

Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Ceiba aesculifolia (Kunth) Britten & Baker f (Malvaceae) is used for the folk treatment of mood disorders. C. aesculifolia bark was extracted in ethanol, and the extract (CAE) was chemically standardized using gas chromatography–mass spectrometry (GC-MS). This study evaluated the effects of CAE (10–100 mg/kg p.o.) on anxiolytic-like activity, sedation, locomotor activity, depression-like activity, and spatial working memory using in vivo rodent models. A possible mechanism for the anxiolytic-like and antidepressant-like actions induced by CAE was assessed using neurotransmission pathway inhibitors. Myristic acid was one of the compounds found in CAE using GC-MS. This study also evaluated the anxiolytic-like activity and the sedative actions of myristic acid and assessed a possible mechanism of action using neurotransmission pathway inhibitors and an in silico analysis. CAE elicited anxiolytic-like activity and antidepressant-like effects (ED50 = 57 mg/kg). CAE (10–100 mg/kg) did not affect locomotor coordination or induce sedation. The anxiolytic-like and antidepressant-like actions of CAE were reverted by prazosin, suggesting a possible participation of the noradrenergic system. The anxiolytic-like activity of myristic acid was reverted by the co-administration of prazosin and partially reverted by ketanserin. The docking study revealed that myristic acid can form favorable interactions within 5-HT2A and α1A-adrenoreceptor binding pockets. [ABSTRACT FROM AUTHOR]

Rationale: We have discovered that rats at the age of 18 months begin to twitch their heads spontaneously (spontaneous head twitching, SHT). To date, no one has described this phenomenon. Objectives: The purpose of this study was to characterize SHT pharmacologically and to assess some possible mechanisms underlying SHT. Methods: Wistar male rats were used in the study. Animals at the age of 18 months were qualified as HSHT (SHT ≥ 7/10 min observations) or LSHT (SHT < 7/10 min observations). Quantitative real-time PCR with TaqMan low-density array (TLDA) approach was adopted to assess the mRNA expression of selected genes in rat's hippocampus. Results: HSHT rats did not differ from LSHT rats in terms of survival time, general health and behavior, water intake, and spontaneous locomotor activity. 2,5-dimethoxy-4-iodoamphetamine (DOI) at a dose of 2.5 mg/kg increased the SHT in HSHT and LSHT rats, while ketanserin dose-dependently abolished the SHT in the HSHT rats. The SHT was reduced or abolished by olanzapine, clozapine, risperidone, and pimavanserin. All these drugs have strong 5-HT2A receptor–inhibiting properties. Haloperidol and amisulpride, as antipsychotic drugs with a mostly dopaminergic mechanism of action, did not influence SHT. Similarly, escitalopram did not affect SHT. An in-depth gene expression analysis did not reveal significant differences between the HSHT and the LSHT rats. Conclusions: SHT appears in some aging rats (about 50%) and is permanent over time and specific to individuals. The 5-HT2A receptor strongly controls SHT. HSHT animals can be a useful animal model for studying 5-HT2A receptor ligands. [ABSTRACT FROM AUTHOR]

The effect of ketanserin on inflammation, liver fibrosis, and microviscosity of the plasma and mitochondrial membranes of hepatocytes was studied on young (3 months) and old (9 months) male Wistar rats with experimental liver cirrhosis. Ketanserin reduced inflammation, area of the connective tissue, and liver damage and improved serum biochemical parameters in rats of both age groups; in old rats, the effects were more pronounced than in young animals. In old rats, ketanserin reduced polarity of hepatocyte plasma and mitochondrial membranes in the area of protein-lipid contacts, which determined higher effectiveness of ketanserin during the treatment of liver cirrhosis in aged animals. [ABSTRACT FROM AUTHOR]

Rationale: The 5-HT2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). Objectives: The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. Methods: Impulsive decision-making was evaluated in male Sprague–Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32 s) across one session. Results: DOI (0.5 and 1.0 mg/kg) increased impulsive decision-making, and the effects of DOI (1.0 mg/kg) were blocked by the 5-HT2A receptor antagonist ketanserin (1.0 mg/kg) rather than the 5-HT2C receptor antagonist SB-242084 (1.0 mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5 mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3 mg/kg) were not antagonized by ketanserin (1.0 mg/kg), selective 5-HT1A antagonist WAY-100635 (1.0 mg/kg), or selective dopamine D4 receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D2/D3 receptor antagonist tiapride (40 mg/kg). Conclusions: DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptorsDOI-induced increase of impulsivity is mediated by the 5-HT2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor. [ABSTRACT FROM AUTHOR]

• Knockdown of 5-HT 2A R in the ventrolateral orbital cortex (VLO) aggravated pain in a mouse model of trigeminal neuralgia (TN). • Knockdown or inhibition of 5-HT 2A R decreased neuronal glutamatergic activity in the VLO. • Activation of 5-HT 2A R increased neuronal glutamatergic activity in the VLO. 5-HT 2A receptors (5-HT 2A Rs) are widely expressed in the central nervous system, including in the ventrolateral orbital cortex (VLO). The VLO is an important cortical component for pain processing. Brain 5-HT 2A Rs are implicated in both pro- and anti- nociceptive functions. However, the roles of 5-HT 2A Rs in the VLO in trigeminal neuralgia and neuronal synaptic function remain to be understood. We used chronic constriction injury of infraorbital nerve (IoN-CCI) model and shRNA mediated gene knockdown in mice to investigate the role of 5-HT 2A Rs in the VLO in trigeminal neuralgia. We found that knockdown of 5-HT 2A Rs in the VLO aggravated spontaneous pain and mechanical allodynia in mice after IoN-CCI. At the synaptic level, decreasing 5-HT 2A R expression by shRNA or inhibition of 5-HT 2A R activity by its antagonist ketanserin decreased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of the neurons in the VLO, whereas 5-HT 2A R partial agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) enhanced sEPSCs of the neurons in the VLO. In summary, 5-HT 2A Rs in the VLO modulate the trigeminal pain by regulating neuronal glutamatergic activity. [ABSTRACT FROM AUTHOR]

Caffeine, a methylxanthine alkaloid, works as a nonselective adenosine receptor antagonist. It is the most widely used psychostimulant drug worldwide. However, caffeine overdose can lead to acute intoxication, posing a clinical problem. Hyperthermia and hyperactivity are associated issues with acute caffeine intoxication; however, no definitive treatment exists. This study aimed to assess the ability of risperidone to attenuate caffeine-induced hyperthermia and hyperactivity while elucidating the unknown mechanisms of caffeine intoxication. The rats received intraperitoneal injections of saline, risperidone (0.25 mg/kg, 0.5 mg/kg), WAY-100635, ketanserin, haloperidol, sulpiride, or SCH 23390, 5 min after the administration of caffeine (25 mg/kg). Subcutaneous temperature and activity counts were measured using nano tag ® for up to 90 min. In vivo microdialysis was used to determine the effect of risperidone on caffeine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline (NA) concentrations in the anterior hypothalamus. Rats were injected with caffeine (25 mg/kg), followed by saline or risperidone (0.5 mg/kg) 5 min later. The levels of DA, 5-HT, and noradrenaline were measured every 15 min for up to 90 min after caffeine administration. Risperidone and 5-HT2A receptor antagonist ketanserin attenuated caffeine-induced hyperthermia and hyperactivity. Haloperidol and dopamine D1 antagonist SCH-23390 exacerbated hyperthermia without any effect on the hyperactivity. In the microdialysis study, risperidone treatment further attenuated caffeine-induced 5-HT elevation, but not DA and NA. Our results indicate that risperidone attenuates caffeine-induced hyperthermia and hyperactivity by blocking 5-HT2A receptor activity and may be potentially useful for treating caffeine intoxication. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT 2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT 2A, 5-HT 6 , and 5-HT 7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se , supporting the concept that 5-HT 2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT 2A and 5-HT 6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT 7 receptor. Considering previous studies showing that 5-HT 6 receptor inhibition, but not activation, and 5-HT 7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT 2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT 2A receptor activation. [Display omitted] • Ibogalogs such as DM506 and IBG decrease neuropathic and visceral pain in mice. • Ibogalogs activate both 5-HT 2A and 5-HT 6 receptor subtypes. • DM506 and IBG, but not TBG, act as inverse agonists of the 5-HT 7 receptor. • Pain-relieving effects of ibogalogs are mainly mediated by 5-HT 2A receptor activation. • Pain-relieving effects of ibogalogs are blocked by the 5-HT 2 receptor antagonist ketanserin. [ABSTRACT FROM AUTHOR]

Matricaria chamomilla L. is a well-known plant, which has decreased morphine dependence and withdrawal. The aim of the present study was to investigate the effects of the hydroalcoholic extract of Matricaria chamomile and the role of serotonergic receptor on the rewarding effects of morphine using a conditioned place preference (CPP) paradigm in rats. In this study, adult male Wistar rats received intraperitoneal injection of Matricaria chamomile (30 mg/kg) to assess of the acquisition and expression of the morphine-induced CPP and also received intraperitoneal injection of ketanserin (1 mg/kg) to assess of the extinction and reinstatement of CPP following Matricaria chamomile and as well as measurement of CSF serotonin levels. The results indicated that the Matricaria chamomile extract significantly attenuated the acquisition and expression of morphine reward memory in CPP paradigm. While the Matricaria chamomile had no effect on the extinction of reward memory, despite a significant increase in the CSF serotonin levels in the rats receiving ketanserin/chamomile. Also, Matricaria chamomile had no effect on the reinstatement and the CSF serotonin levels, while ketanserin reduced the CSF serotonin level and increased the CPP score in the reinstatement of reward memory for morphine. We conclude that the Matricaria chamomile attenuated the acquisition and expression of morphine reward memory, while could not maintain the extinguished memory and had no effect on the reinstatement of reward memory. Also, the blocking of serotonin receptor reduced the CSF serotonin level and increased the CPP score in both extinction and reinstatement phases. Therefore, Matricaria chamomile as a useful adjunctive therapeutic strategy may exert a protective effect against opiate-induced reward and incentive motivation during drug craving in opiate-addicted individuals. • Chamomile attenuated the acquisition and expression of morphine reward memory. • Chamomile did not affect the extinction learning of morphine reward. • Chamomile did not affect the extinction and reinstatement morphine reward memory. • Chamomile did not affect the CSF serotonin levels following morphine CPP. • Ketaserine increased the score of morphine CPP in rats receiving chamomile. [ABSTRACT FROM AUTHOR]

Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A–TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A–TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Background: Depression is a psychiatric disorder with limited therapy options. Psychedelics are new antidepressant candidates, being the ayahuasca one of the most promising ones. A synergistic combination of N,N -dimethyltryptamine (DMT) and β-carbolines allows ayahuasca antidepressant properties. Another psychedelic and DMT-containing beverage is the jurema wine used religiously by indigenous people from Northeastern Brazil. Aims: To evaluate the antidepressant-like effect of standardized extract of Mimosa tenuiflora (SEMT), associated or not with harmine (β-carboline), in behavioral models of depression. Methods: The SEMT was submitted to (+) ESI-IT-LC/MS analysis for DMT quantification. To assess the antidepressant-like effect of SEMT, the open field (OFT), tail suspension (TST), and forced swim (FST) tests were performed. To verify the participation of serotonergic systems, the 5-hydroxytryptophan (5-HTP)-induced head twitch test was performed. Results: The content of DMT found in SEMT was 24.74 ± 0.8 mg/g. Yuremamine was also identified. SEMT presented an antidepressant-like effect in mice submitted to the TST and FST, independent from harmine, with no significant alterations on the OFT. The sub-dose interaction between SEMT and ketamine also produced an anti-immobility effect in the TST, with no changes in the OFT. SEMT potentiated the head twitch behavior induced by 5-HTP and ketanserin prevented its antidepressant-like effect in the TST (p < 0.05). Conclusions: SEMT presented a harmine-independent antidepressant-like effect in mice submitted to the TST and FST. This effect occurs possibly via activation of serotonergic systems, particularly the 5-HT2A/2C receptors. [ABSTRACT FROM AUTHOR]

Death-associated protein kinase 3 (DAPK3) is a serine/threonine protein kinase that regulates apoptosis, autophagy, transcription, and actin cytoskeleton reorganization. DAPK3 induces morphological alterations in apoptosis when overexpressed, and it is considered a potential drug target in antihypertensive and anticancer drug development. In this article, we report new findings from a structure-guided virtual screening for discovery of phytochemicals that could modulate the elevated expression of DAPK3, and with an eye to anticancer drug discovery. We used the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), a curated database, as part of the methodology. The potential initial hits were identified based on their physicochemical properties and binding affinity toward DAPK3. Subsequently, various filters for drug likeness followed by interaction analysis and molecular dynamics (MD) simulations for 100 nsec were performed to explore the conformational sampling and stability of DAPK3 with the candidate molecules. Notably, the data from all-atom MD simulations and principal component analysis suggested that DAPK3 forms stable complexes with ketanserin and rotenone. In conclusion, this study supports the idea that ketanserin and rotenone bind to DAPK3, and show stability, which can be further explored as promising scaffolds in drug development and therapeutics innovation in clinical contexts such as hypertension and various types of cancer. [ABSTRACT FROM AUTHOR]

The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor. Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [ 11 C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BP ND ), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region. Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC 50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg. These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience., Competing Interests: Declaration of competing interest MKM has received an honorarium as a speaker for Lundbeck Pharma and the Lundbeck Foundation. DSS has received an honorarium as a speaker for the Lundbeck Foundation. MEL is a consultant for Mind Medicine, Inc. GMK has received honoraria as a speaker for Compass Ltd. and H. Lundbeck and is a consultant for Onsero, Pangea, and Gilgamesh, PureTechHealth, and is a board member of Elsass Foundation. All other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Analgesic effects of fentanyl have been investigated using behavior. The behavioral effects of fentanyl and possible serotonergic influence are largely unknown. We therefore investigated behavioral effects of fentanyl, with or without the serotonin antagonist ketanserin, in pigs. Fourteen mixed-breed pigs, weighing 17–25 kg were included in a randomised blinded prospective, balanced three-group study. Ten pigs received first 5 and then 10 µg/kg of fentanyl intravenously. Ketanserin at 1 mg/kg or saline was given intravenously as a third injection. Four control pigs received three injections of saline. Behavior was video-recorded. The distance moved was automatically measured by commercially available software, and behaviors manually scored in retrospect. Fentanyl inhibited resting and playing, and induced different repetitive behaviors. The mean (SD) distance moved in the control group and fentanyl group was 21.3 (13.0) and 57.8 (20.8) metres respectively (p < 0.05 for pairwise comparison). A stiff gait pattern was seen after fentanyl injection for median (range) 4.2 (2.8–5.1) minutes per 10 min, which was reduced to 0 (0–4) s after ketanserin administration. Conclusion: fentanyl-induced motor and behavioral effects, and serotonergic transmission may be involved in some of them. The psychomotor side effects of fentanyl could potentially interfere with post-operative pain evaluation in pigs.

Introduction: The aim of the study was to assess the involvement of the monoaminergic system in the antidepressant effect of a new 3-substituted thietane-1,1-dioxide derivative (N-199/1) using tests with several pharmacological antagonists and agonists. Materials and methods: We conducted 3 sets of experiments in white outbred male mice. In Experiment 1, we assessed the antidepressant effect of N-199/1 in the forced swimming test (FST) and tail suspension test (TST) when administered repeatedly for 2 weeks intraperitoneally (i.p.). In Experiment 2, we evaluated the antidepressant effect of N-199/1 in FST and TST when co-administered with 5HT1A-(WAY100635, 0.1 mg/kg), 5HT2A/2C- (ketanserin, 5 mg/kg), 5HT3- (ondansetron, 1 mg/kg) serotonergic and α2-adrenergic (yohimbine, 1 mg/kg) receptors antagonists. In Experiment 3, we assessed the effect of N-199/1 on the hypothermia induced by i.p. injection of α2-adrenergic receptors agonist clonidine (0.3 mg/kg). Results and discussion: N-199/1 reduced immobility time (IT) and index of depression (ID) in FST, and did not affect IT in TST, either when administered repeatedly in Experiment 1, or acutely in Experiment 2. In Experiment 2, ketanserin enhanced the effect of N-199/1, decreasing ID by 36%, while WAY100635 and yohimbine antagonized it, increasing ID by 27% and IT by 115%, respectively, in comparison with N-199/1. N-199/1 attenuated the effect of ondansetron, increasing IT by 36%. In Experiment, 3 N-199/1 reduced clonidine-induced hypothermia 1 h after the injection of clonidine. N-199/1 exhibited pronounced antidepressant properties in FST, an agonism to 5HT1A-receptors and an antagonism to 5HT2A/2C- and α2-receptors in tests of neuropharmacological interaction, which indicates an atypical mechanism of its antidepressant action. Conclusion: The antidepressant effect of N-199/1 is due to the stimulation of 5HT1A-receptors and blockade of 5HT2A/2C- and α2-receptors. [ABSTRACT FROM AUTHOR]

• A single dose of psilocybin was associated with increased body weight. • Co-administration of ketanserin had no effect on this outcome. • Psilocybin treatment was associated with increased lean and water mass. • Psilocybin treatment increased CK, AST, and chloride. There is growing interest in the therapeutic potential of psilocybin for the treatment of a wide variety of medical problems, and even for the promotion of wellbeing among healthy individuals. Interestingly, among the many proposed indications, both obesity and anorexia nervosa (AN) have been discussed. However, the effect of psilocybin on appetitive behavior and metabolism is not well known. Here, we report the effects of psilocybin on body weight, intake and output, body composition, and metabolic function among lean male and female wild-type mice. In the days immediately following treatment, both male and female mice receiving a single intraperitoneal dose of psilocybin were consistently heavier than saline controls, with no effect of psilocybin on intake or output. Co-administration of the 5-HT2A/2C receptor antagonist ketanserin had no effect on this outcome. Body composition analysis revealed that psilocybin significantly increased lean and water mass among males, with a similar trend among females. A metabolic panel revealed increased creatine kinase (CK), aspartate aminotransferase (AST), and chloride among male and female psilocybin treated mice. Together, these findings begin to investigate the potential mechanisms of psilocybin's effects on body weight and metabolic measures. Such understanding will be critical for the safe, efficacious, and well-informed use of psilocybin in clinical and non-clinical settings. [ABSTRACT FROM AUTHOR]

The dopaminergic and serotonergic systems are two of the most important neuronal pathways in the human brain. Almost all psychotropic medications impact at least one neurotransmitter system. As a result, investigating how they affect memory could yield valuable insights into potential therapeutic applications or unanticipated side effects. The aim of this literature review was to collect literature data from animal studies regarding the effects on memory of four drugs known to act on the serotonergic and dopaminergic systems. The studies included in this review were identified in the PubMed database using selection criteria from the PRISMA protocol. We analyzed 29 articles investigating one of four different dopaminergic or serotonergic compounds. Studies conducted on bromocriptine have shown that stimulating D2 receptors may enhance working memory in rodents, whereas inhibiting these receptors could have the opposite effect, reducing working memory performance. The effects of serotonin on working memory are not clearly established as studies on fluoxetine and ketanserin have yielded conflicting results. Further studies with better-designed methodologies are necessary to explore the impact of compounds that affect both the dopaminergic and serotonergic systems on working memory.

Small drug-like molecules that can block the function of serotonin 5-HT2A receptors have garnered considerable attention due to their ability to inhibit platelet aggregation and the possible prevention of atherosclerotic lesions. Although clinical data provided compelling evidence for the efficacy of this approach in the prevention of various cardiovascular conditions, the chemical space of 5-HT2A receptor antagonists is limited to ketanserin and sarpogrelate. To expand the portfolio of novel chemical motifs with potential antiplatelet activity, we evaluated the antiplatelet activity of a series of 6-fluorobenzo[d]isoxazole derivatives that possess a high affinity for 5-HT2A receptor. Here we describe in vitro studies showing that 6-fluorobenzo[d]isoxazole derivatives exert promising antiplatelet activity in three various in vitro models of platelet aggregation, as well as limit serotonin-induced vasoconstriction. Compound AZ928 showed in vitro activity greater than the clinically approved drug sarpogrelate. In addition to promising antiplatelet activity, the novel series was characterized by a favorable safety profile. Our findings show that the novel series exerts promising antiplatelet efficacy while being deprived of potential side effects, such as hemolytic activity, which render these compounds as potential substances for further investigation in the field of cardiovascular research.

Biogenic amines play an important role in the regulation of appetitive responses in insects. Among them, serotonin (5-HT) regulates feeding-related processes in numerous insect species. In carpenter ants, 5-HT administration has been shown to depress feeding behavior, thus opening the possibility of using 5-HT modulation in control strategies against those species considered as pest. Here we studied if administration of a 5-HT antagonist, ketanserin, promotes feeding of a sucrose solution and a toxic bait in carpenter ants Camponotus mus. We found that 3 h after a single oral administration of ketanserin, the mass of sucrose solution consumed by carpenter ants increased significantly. A similar effect was found after a chronic administration that lasted 5 days. Yet, ketanserin did neither affect the intake rates nor the activity of the pharyngeal pump that mediates feeding dynamics. In addition, ketanserin promoted the consumption of a toxic bait based on boric acid. Our results thus show that feeding motivation and consumption of both sucrose solution and a toxic bait can be enhanced via prior administration of ketanserin. We discuss the possible mechanisms underlying these effects and conclude that understanding basic physiological and neural principles that underlie feeding motivation allows establishing more efficient control strategies for pest insects. [ABSTRACT FROM AUTHOR]

The psychedelic lysergic acid diethylamide (LSD) has experienced a revival in research, including clinical trials that evaluate LSD-assisted psychotherapy. LSD induces perceptual alterations and influences emotion processing in ways that may support psychotherapy. Here, we investigated the effects of LSD on emotional empathy and mediating role of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT2A receptor antagonist ketanserin (40 mg) using a placebo-controlled, double-blind, random-order, crossover design in 16 healthy subjects. The Multifaceted Empathy Test (MET) was used to assess the effects of LSD on emotional empathy. Plasma oxytocin levels were also measured. LSD dose-dependently increased implicit and explicit emotional empathy, with the highest 200 µg LSD dose having a significant effect compared with placebo. The 200 µg dose of LSD also moderately increased plasma oxytocin levels compared with placebo. Ketanserin reduced the LSD-induced elevations of oxytocin but not the LSD-induced increases in emotional empathy. These findings confirm that LSD enhances empathy, and this effect may be partially independent of its primary action on 5-HT2A receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT2A receptor stimulation, which is consistent with the psychedelic effect of LSD. Further studies are needed to investigate whether LSD may also enhance empathy and potentially produce therapeutic effects in patients who have deficits in empathy and impairments in social functioning. [ABSTRACT FROM AUTHOR]

The psychedelic lysergic acid diethylamide (LSD) has experienced a revival in research, including clinical trials that evaluate LSD-assisted psychotherapy. LSD induces perceptual alterations and influences emotion processing in ways that may support psychotherapy. Here, we investigated the effects of LSD on emotional empathy and mediating role of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT2A receptor antagonist ketanserin (40 mg) using a placebo-controlled, double-blind, random-order, crossover design in 16 healthy subjects. The Multifaceted Empathy Test (MET) was used to assess the effects of LSD on emotional empathy. Plasma oxytocin levels were also measured. LSD dose-dependently increased implicit and explicit emotional empathy, with the highest 200 µg LSD dose having a significant effect compared with placebo. The 200 µg dose of LSD also moderately increased plasma oxytocin levels compared with placebo. Ketanserin reduced the LSD-induced elevations of oxytocin but not the LSD-induced increases in emotional empathy. These findings confirm that LSD enhances empathy, and this effect may be partially independent of its primary action on 5-HT2A receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT2A receptor stimulation, which is consistent with the psychedelic effect of LSD. Further studies are needed to investigate whether LSD may also enhance empathy and potentially produce therapeutic effects in patients who have deficits in empathy and impairments in social functioning.

The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug‐induced effects in a randomized, placebo‐controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R‐peak‐based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD‐induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions. Knowledge on the impact of LSD and its antagonist ketanserin on the human autonomic nervous system is sparse. We show that the subjective effects of LSD are mainly driven by sympathetic activation and can be antagonized by ketanserin‐induced parasympathetic activity. The autonomic parameters further might serve as biomarkers for subjective LSD experiences and potentially as treatment markers, for example, in mood disorders. [ABSTRACT FROM AUTHOR]

Syringic acid presents various biological properties such as antioxidant, anti-inflammatory, anticancer, and other activities. The present experiment aimed to investigate the effect of the oral administration of syringic acid (10, 50, and 100 mg/kg) on its possible nociceptive response using hot-plate and tail-flick assay in the Balb-C mice model. The mice were pre-treated with 5 mg/kg atropine 15 min before, 1mg/kg mecamylamine 20 min before, 1mg/kg ketanserin 30 min before, 1 mg/kg ondansetron 30 min before, 1mg/kg yohimbine 30 min before, 1 mg/kg prazosin 30 min before and 5 mg/kg naloxone 15min before the administration of the Syringic acid. Dose-dependent antinociceptive activity of syringic acid was reported for 50 and 100 mg/kg doses in tail-flick and hot-plate assays, respectively. In further, mecamylamine, yohimbine, and naloxone significantly reversed syringic acid-induced response to thermal stimuli in tail-flick and hot-plate assays, respectively. From the data, it was confirmed that syringic acid presents central antinociceptive effects which may be coordinated by supraspinal/spinal mediated cholinergic, opioidergic, and adrenergic, inflection. [ABSTRACT FROM AUTHOR]

Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed malemice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus--a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin's efficacy. We conclude that psilocybin's mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression. [ABSTRACT FROM AUTHOR]

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5–4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80–90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT 2A , 5-HT 3 , H 1 , NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome. [ABSTRACT FROM AUTHOR]