Effects of psilocybin on body weight, body composition, and metabolites in male and female mice.

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.

Psilocybin and Eugenol Reduce Inflammation in Human 3D EpiIntestinal Tissue.

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.

Effects of Chronic Combined Treatment with Ketanserin and Fluoxetine in B6.CBA-D13Mit76C Recombinant Mice with Abnormal 5-HT1A Receptor Functional Activity.

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.

Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells.

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.

High and Hyper: Fentanyl Induces Psychomotor Side-Effects in Healthy Pigs.

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.

The Effects of Four Compounds That Act on the Dopaminergic and Serotonergic Systems on Working Memory in Animal Studies; A Literature Review.

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.

Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.

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).

Quemadura genital por producto químico: reporte de caso / Genital burn by chemical product: case report

Resumen ANTECEDENTES: Las quemaduras son la forma más severa de estrés que el cuerpo puede sufrir; pueden generarse por diferentes agentes térmicos y químicos. CASO CLÍNICO: Paciente de 25 años, con dolor intenso en la región genital de 12 horas de evolución, secundario a la introducción en la vagina de una piedra de alumbre. Se le hicieron múltiples irrigaciones con solución salina al 0.9% sin obtener el resto de la piedra de alumbre. Se le aplicó sulfadiazina de plata en la cavidad vaginal cada 12 horas, óvulos vaginales de ketanserina, miconazol y metronidazol cada 8 horas, ketorolaco por vía oral 10 mg cada 8 horas. Durante su estancia hospitalaria tuvo buena evolución, con disminución de la inflamación en la zona genital, epitelización adecuada. Al tercer día se dio de alta del hospital con cita para valoración a los siete días. CONCLUSIÓN: El tratamiento de las quemaduras en el área genital, por agentes químicos, tiene como piedra angular la identificación del agente causante de la lesión que permita actuar de forma inmediata y evitar las secuelas físicas, sexuales y psicológicas mediante el lavado exhaustivo con solución o agua estéril para remover el agente causal y disminuir que continúe actuando en el sitio afectado.

Abstract BACKGROUND: Burns are the most severe form of stress that the body can suffer; they can be caused by various thermal and chemical agents. CLINICAL CASE: A 25-year-old female patient presented with severe genital pain of 12 hours' duration, secondary to the introduction of an alum stone into the vagina. She underwent several irrigations with 0.9% saline without obtaining the rest of the alum stone. She was given vaginal silver sulfadiazine every 12 hours, vaginal ketanserin, miconazole and metronidazole every 8 hours and oral ketorolac 10 mg every 8 hours. During her stay in hospital, she progressed well, with a decrease in genital inflammation and adequate epithelialisation. She was discharged on the third day with an appointment for a seven-day follow-up. CONCLUSION: The management of genital burns caused by chemical agents is based on the identification of the agent causing the lesion, which allows immediate action and prevents physical, sexual and psychological sequelae by thorough washing with sterile solution or water to remove the causative agent and reduce its continued action in the affected area.

Death-Associated Protein Kinase 3 Inhibitors Identified by Virtual Screening for Drug Discovery in Cancer and Hypertension.

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.

Exploring the antiplatelet activity of serotonin 5-HT2A receptor antagonists bearing 6-fluorobenzo[d]isoxazol-3-yl)propyl) motif- as potential therapeutic agents in the prevention of cardiovascular diseases.

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.

Age-Related Features of Ketanserin Effects in Experimental Liver Cirrhosis.

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.

New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat.

Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg, i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT2 receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg, i.p.) and ketamine (3 mg/kg, i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT2 receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT2 receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action.

Role of the 5-HT2A Receptor in Acute Effects of LSD on Empathy and Circulating Oxytocin.

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.

LSD and ketanserin and their impact on the human autonomic nervous system.

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.

The antidepressant-like effects of Origanum majorana essential oil on mice through monoaminergic modulation using the forced swimming test.

Origanum majorana (L.) is an herb used in the treatment of diseases related to the nervous system in traditional medicine (e.g. as an anticonvulsant and sedative). The present study was conducted to investigate the antidepressant-like effects of Origanum majorana essential oil (OMEO) on mice in the forced swimming test (FST). The animals were intraperitoneally (i.p.) injected with OMEO (10-80 mg/kg) 1 h before the FST. To assess the involvement of the monoaminergic system in the antidepressant activity of OMEO, different pharmacological antagonists were administered 15 min before OMEO administration (80 mg/kg). The administration of OMEO (40 and 80 mg/kg, i.p.) decreased immobility time and increased swimming and climbing times significantly. OMEO did not cause any changes in spontaneous locomotor function in the open-field test (OFT). The pre-treatment of the animals with SCH23390, sulpiride, haloperidol, WAY100135, p-chlorophenylalanine (pCPA), ketanserin, prazosin, yohimbine, reserpine, but not propranolol, inhibited the anti-immobility effect of OMEO in the FST. A combination of sub-effective doses of fluoxetine (5 mg/kg, i.p.) or imipramine (5 mg/kg, i.p.) with OMEO (10 mg/kg, i.p.) increased the antidepressant-like effects. OMEO showed antidepressant-like effects through involvement with the dopaminergic (D1 and D2), serotonergic (5HT1A, 5-HT2A receptors) and noradrenergic (α1 and α2 adrenoceptors) systems.

Serotonin 5HT2A receptor antagonism mediated anti-inflammatory and anti-fibrotic effect in adriamycin-induced CKD in rats.

A selective 5-HT2A receptor antagonist ketanserin has been used preclinically to improve renal blood flow because of its beneficial effect on autoregulation in various chronic kidney disease models. Ketanserin might be able to turn down adriamycin-induced chronic kidney disease, which is characterized by renal fibrosis, inflammation and structural and functional changes in glomeruli. In the present study, we investigated whether ketanserin suppresses these renal alterations or not. Wistar rats were administered with a single dose of adriamycin (6 mg/kg/i.v), which leads to development of severe tubulointerstitial fibrosis with altered renal function. Subsequent ketanserin treatment (5 mg/kg/p.o) for 4 weeks shown significant change in oxidative stress, serum and urine parameters in adriamycin-induced chronic kidney disease rats. Additionally, results showed that mRNA expression of TGF-ß and collagen IV, which are known to promote fibrosis via various signaling pathways involved in the progression of renal disease, was suppressed by ketanserin treatment. Furthermore, expression levels of 5-HT2A and pro-inflammatory marker IL-6 have also been reduced significantly after ketanserin administration in adriamycin-treated animals. Moreover, histopathological studies also reveal the considerable structural changes after ketanserin treatment, and these results are further supported via data obtained from the percentage of glomeruli size changes. In conclusion, ketanserin reduces renal fibrosis and inflammation in adriamycin-induced chronic kidney disease by suppressing 5-HT2A, IL-6, TGF-ß and collagen IV expression in renal tissue.

In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation.

BACKGROUND: Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use. METHODS: We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively. RESULTS: Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT2A/2C antagonist ketanserin. CONCLUSION: These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA's interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted.

Differences between young and aged rats in voiding frequency and detrusor muscle serotonergic contraction.

INTRODUCTION: The involvement of serotonin (5-HT) in increased lower urinary tract symptoms in aging is unclear. We sought to compare voiding function and 5-HT induced detrusor contraction between young and aged rats. METHODS: This study used young (2- to 3-month-old) and aged (26- to 30-month-old) male Fischer 344 rats. 1. Rats were housed in individual metabolic cages, and then the total volume of urination, volume per micturition, voiding frequency, and voiding interval were analyzed. 2. Using urinary bladder body strips, developed tension was recorded after cumulative addition of 5-HT (1-100 nM) in the absence or presence of tetrodotoxin (1 µM), and in the presence of tetrodotoxin with ketanserin (0.3-3 µM) or naftopidil (1 and 3 µM). We examined the effects of atropine, ketanserin, and naftopidil on electrical field stimulation (EFS)-induced contraction. RESULTS: 1. Compared to young rats, aged rats exhibited decreased voiding frequency and increased volume per micturition, but total volume of urination (normalized to body weight) did not differ. Moreover, voiding interval was significantly prolonged in aged rats during the active period. 2. In the presence of tetrodotoxin, pEC50 of 5-HT were significantly lower in aged rats than in young rats (P < 0.01), but the maximal response to 5-HT was not altered in the aged bladder. Ketanserin inhibited 5-HT-induced contraction in both groups, while suppression by naftopidil was relatively limited, especially in aged rats. EFS induced neurogenic contraction in a frequency-dependent manner. Atropine-resistant contraction was not inhibited by naftopidil, but was potentiated by ketanserin. CONCLUSIONS: Urination intervals were extended in aged rats, indicating that urination rhythm changed. In the senescent rat bladder, 5-HT induced detrusor contraction, but the effect of 5-HT and the naftopidil-sensitive contractile force were weaker than those in young rats. Additionally, 5-HT did not contribute to the increase in atropine-resistant EFS-induced contractions in aged rats.

Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone.

RATIONALE: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. OBJECTIVE: Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1-3 receptor antagonists were examined in both groups. METHODS: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline. RESULTS: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. CONCLUSIONS: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.

5­Hydroxytryptamine 2A receptor inverse agonist pimavanserin impairs maternal behavior in postpartum female rats.

Maternal behavior is a highly motivated and well-organized social behavior. Although previous studies have shown that 5­hydroxytryptamine 2A/2C (5-HT2A/2C) receptors play an important role in mediating the expression of normal maternal behavior, the role of 5-HT2A receptors in maternal behavior remains unclear. In the present study, the homecage maternal behavior test paradigm was used to investigate whether the low or constitutive (i.e., intrinsic or basal) activity of 5-HT2A receptors influences the expression of normal maternal behavior. The inverse agonist pimavanserin (3, 6, and 12 mg/kg) and neural antagonist ketanserin (2.5 and 5 mg/kg) were used to induce the low or constitutive activity of 5-HT2A receptors, respectively. The results showed that inverse agonism of 5-HT2A receptors by pimavanserin slightly impaired maternal behavior in postpartum female rats, reflected by less time spent on nest building, and that ketanserin did not impair major components of maternal behavior. Furthermore, neither pimavanserin nor ketanserin impaired spontaneous locomotion. These data indicate that the reduced activity of 5-HT2A receptors may impair the expression of normal maternal behavior and this effect is not due to a nonspecific sedative effect. Nevertheless, the constitutive activity of 5-HT2A receptors in the absence of an endogenous agonist (i.e., serotonin) may be involved in the expression of normal maternal behavior.