5-HT1A Agonist Research Articles

THC-O-Acetate: Scarce Evidence for a Psychedelic Cannabinoid

ABSTRACT There is a growing interest in semi-synthetic cannabinoids, including THC-O-acetate (THC-Oac). Some cannabis marketers and users have claimed that THC-Oac produces psychedelic effects; the current study is the first to examine this claim. Researchers developed an online survey for THC-Oac consumers based on previous cannabis and psychedelic use surveys and in consultation with the moderator of an online forum. The survey assessed the experiential profile of THC-Oac and included items from the Mystical Experience Questionnaire (MEQ), an instrument for assessing psychedelic experiences. Participants reported a low to moderate level of cognitive distortions (altered sense of time, difficulties concentrating, difficulties with short-term memory) and few visuals or hallucinations. Participants’ responses were significantly below the threshold for a complete mystical experience on all four MEQ dimensions. Participants who had used classic (5-HT2A agonist) psychedelics had lower scores on all MEQ dimensions. When asked directly, 79% responded that using THC-Oac is “not at all” or “a little” of a psychedelic experience. Some reports of psychedelic experiences may be due to expectations or contaminants. Those having prior experience with classic psychedelics had lower ratings of mystical experiences.

Opposing effects of 5-HT1A receptor agonist buspirone on supraspinal abdominal pain transmission in normal and visceral hypersensitive rats.

The serotonergic 5-HT1A receptors are implicated in the central mechanisms of visceral pain, but their role in these processes is controversial. Considering existing evidences for organic inflammation-triggered neuroplastic changes in the brain serotonergic circuitry, the ambiguous contribution of 5-HT1A receptors to supraspinal control of visceral pain in normal and post-inflammatory conditions can be assumed. In this study performed on male Wistar rats, we used microelectrode recording of the caudal ventrolateral medulla (CVLM) neuron responses to colorectal distension (CRD) and electromyography recording of CRD-evoked visceromotor reactions (VMRs) to evaluate post-colitis changes in the effects of 5-HT1A agonist buspirone on supraspinal visceral nociceptive transmission. In rats recovered from trinitrobenzene sulfonic acid colitis, the CRD-induced CVLM neuronal excitation and VMRs were increased compared with those in healthy animals, revealing post-inflammatory intestinal hypersensitivity. Intravenous buspirone (2 and 4 mg/kg) under urethane anesthesia dose-dependently suppressed CVLM excitatory neuron responses to noxious CRD in healthy rats, but caused dose-independent increase in the already enhanced nociceptive activation of CVLM neurons in post-colitis animals, losing also its normally occurring faciliatory effect on CRD-evoked inhibitory medullary neurotransmission and suppressive action on hemodynamic reactions to CRD. In line with this, subcutaneous injection of buspirone (2 mg/kg) in conscious rats, which attenuated CRD-induced VMRs in controls, further increased VMRs in hypersensitive animals. The data obtained indicate a shift from anti- to pronociceptive contribution of 5-HT1A-dependent mechanisms to supraspinal transmission of visceral nociception in intestinal hypersensitivity conditions, arguing for the disutility of buspirone and possibly other 5-HT1A agonists for relieving post-inflammatory abdominal pain.

Formulation and evaluation of Transdermal Patch for the treatment of Migraine

A migraine is a specific kind of headache disorder that primarily affects the head. It can range in severity from mild to severe and is often accompanied by other symptoms like vomiting, nausea, illness, dizziness that gets worse with movement, photophobia, sonophobia, severe disability, or other types of nature. Triptans that are administered intravenously can be used to treat migraines and irritated injection sites. Transdermal delivery means that the medications will be administered through the skin in a precise, regulated manner. Our study aims to identify all possible transdermal patch combination and application for the treatment of migraines. The drug rizatriptan belongs to a group of drugs known as selective serotonin receptor agonists. It functions by constricting blood vessels in the brain, preventing the transmission of pain signals to the brain, and preventing the production of several naturally occurring compounds that produce pain, nausea, and other migraine symptoms. Verapamil belongs to the group of drugs known as calcium-channel blockers. It works by relaxing the blood vessels in order to reduce the workload of the heart. The Lambda max Rizatriptan and Verapamil is 278.9nm and 228nm respectively. They are soluble in most of the solvents. When used with verapamil, rizatriptan's transdermal patch improves patient compliance in those with hypertension. P2 patch shows the optimized results.
 Keywords: Migraine, Rizatriptan, Verapamil, Bioavailability, Transdermal patch.

Panic and depressive disorders: DAM related to symptom control

Panic attack is frightening and sudden episode, which coexists with major depressive disorders. Three classes of drugs to control panic and depressive disorders are benzodiazepines, tricyclic antidepressants, and selective serotonin reuptake inhibitors. In this investigation, the electron transfer capacity of these drugs was investigated. Benzodiazepines are good electron acceptors, while antidepressants are mostly good electron donors. Benzodiazepines bind to the receptor by accepting electrons and thus the receptor becomes more positive, increasing the affinity of GABA for the receptor. GABA binds to the positive receptor more easily because it is a good electron donor. Antidepressants are considered agonist of serotonin and they have an electron donating capacity similar to this neurotransmitter. Clonazepam and flunitrazepam are the best electron acceptor drugs among all the molecules studied, so they can be considered pro-oxidants. These drugs could contribute increasing the oxidative stress that may be related to side effects.

Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder

Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. However, the receptor mechanisms implicated in the putative anti-obsessional effect are not clear. On this background, we set out to explore (1) the role of serotonin 2A (5-HT2A) and serotonin 1A (5-HT1A) receptors in the effect of psilocybin on marble burying; (2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; (3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) 2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the marble burying test. HTR was examined in a magnetometer-based assay. The results show that (1) Psilocybin and escitalopram significantly reduced marble burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT, reduced marble burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin, but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. (2) Psilocybin injections over 3.5 h had no effect on marble burying and the effect of bolus injection was not persistent. (3) Co-administration of buspirone with psilocybin blocked its effect on HTR. These data suggest that neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects.

General Metadynamics Protocol To Simulate Activation/Deactivation of Class A GPCRs: Proof of Principle for the Serotonin Receptor.

We present a generally applicable metadynamics protocol for characterizing the activation free-energy profiles of class A G-protein coupled receptors and a proof-of-principle study for the 5HT1A-receptor. The almost universal A100 activation index, which depends on five inter-helix distances, is used as the single collective variable in well-tempered multiple-walker metadynamics simulations. Here, we show free-energy profiles for the serotonin receptor as binary (apo-receptor + G-protein-α-subunit and receptor + ligand) and ternary complexes with two prototypical orthosteric ligands: the full agonist serotonin and the partial agonist aripiprazole. Our results are not only compatible with previously reported experimental and computational data, but they also allow differences between active and inactive conformations to be determined in unprecedented atomic detail, and with respect to the so-called microswitches that have been suggested as determinants of activation, giving insight into their role in the activation mechanism.

Latest updates on the serotonergic system in depression and anxiety.

Psychiatric disorders are among the leading causes of global health burden, with depression and anxiety being the most disabling subtypes. The two common disorders, depression and anxiety, usually coexist and are pathologically polygenic with complicated etiologies. Current drug-based therapies include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and 5-hydroxytryptamine partial agonists. However, these modalities share common limitations, such as slow onset and low efficacy, which is why potential mechanistic insights for new drug targets are needed. In this review, we summarize recent advances in brain localization, pathology, and therapeutic mechanisms of the serotonergic system in depression and anxiety.

The 5-HT1A agonist 8-OH-DPAT reverses the suppression of breathing but not swallowing caused by opioid administration in female rats

The objective of our study was to determine the role of 5-HT1A receptors in modulating breathing and swallowing following opioid administration. Our previous experiments in anesthetized male and female Sprague Dawley rats demonstrated that swallow is suppressed by the opioid buprenorphine, and that female rats are more susceptible to buprenorphine-induced respiratory arrest (71% mortality at 0.3 mg/kg) than male rats (100% survival at 0.3 mg/kg). We hypothesized that following buprenorphine administration, intravenous administration of the 5-HT1A agonist 8-OH-DPAT would restore breathing and swallowing. Experiments were performed in spontaneously breathing female Sprague Dawley rats anesthetized with sodium pentobarbital ( n = 7). Bipolar electromyography (EMG) wires were inserted into various muscles to measure breathing and airway protective behaviors. Swallow was stimulated by oral water infusion. Intravenous buprenorphine was administered in doses that yield respiratory arrest in female rats. Sustained apnea occurred in 86% of animals following buprenorphine administration (one animal resisted respiratory depression). 8-OH-DPAT was then administered to effect (100, 300, or 1,000 μg/kg i.v.). 8-OH-DPAT did not restore swallow, but breathing was recovered in 100% of animals (33% at 100 μg/kg, 50% at 300 μg/kg, and 17% at 1,000 μg/kg). This effect of 8-OH-DPAT was reversed by the 5-HT1A antagonist WAY 100635 (1 mg/kg i.v.), which abolished breathing in all animals. These results indicate that 5-HT1A agonists may be utilized to restore breathing following respiratory arrest, and that opioid-induced depression of breathing and swallowing are mediated by potentially separate mechanisms. This work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, and the Commonwealth of Kentucky Challenge for Excellence. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Medical Therapy for Ineffective Esophageal Motility: A Systematic Review

Background: Ineffective esophageal motility (IEM) is a commonly identified disorder of peristalsis. Although often asymptomatic, IEM can be associated with dysphagia. Aside from treating co-existing gastroesophageal reflux disease and sources of mechanical obstruction, few options are available for management in this context. We therefore systematically reviewed the literature to identify randomized controlled trials (RCTs) for medical treatments of IEM. Methods: MEDLINE, Embase, Cochrane Library, and Web of Science were searched using controlled vocabulary and keywords to identify RCTs from inception through 9/22/2021. Prospective studies evaluating medical therapy to improve dysphagia in adults with IEM were included. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. Results: Among 1046 studies identified, 6 (0.58%) met inclusion criteria with a total of 65 patients. Most studies evaluated serotonin receptor agonists (buspirone, mosapride, prucalopride, and sumatriptan), primarily assessing changes on esophageal high-resolution manometry parameters, and only 1 study evaluated patient reported outcomes. Overall, medical therapy improved these pooled outcomes in 5 (83%) studies. Although treatment endpoints varied, the risk of bias in study reporting was low for 4 studies and uncertain for 2 studies. Conclusions: There are currently few therapeutic options available for IEM patients with symptomatic non-obstructive dysphagia. Our systematic review identified 6 studies utilizing medical therapy in patients with IEM, and a majority demonstrated an improvement in HRM parameters. Medical therapy may therefore be considered in this context, but additional studies are warranted to assess for similar improvement in patient symptoms.

Effects of serotonergic psychedelics on mitochondria: Transdiagnostic implications for mitochondria-related pathologies.

The use of serotonergic psychedelics has gained increasing attention in research, clinical practice and society. Growing evidence suggests fast-acting, transdiagnostic health benefits of these 5-hydroxytryptamine 2A receptor agonists. Here, we provide a brief overview of their benefits for psychological, cardiovascular, metabolic, neurodegenerative, and immunological pathologies. We then review their effect on mitochondria including mitochondrial biogenesis, functioning and transport. Mitochondrial dysregulation is a transdiagnostic mechanism that contributes to the aforementioned pathologies. Hence, we postulate that psychedelic-induced effects on mitochondria partially underlie their transdiagnostic benefits. Based on this assumption, we propose new treatment indications for psychedelics and that the health benefits induced by psychedelics depend on patient-specific mitochondrial dysregulation.

527. GM-2040 is a Novel Putative Non-Hallucinogenic 5-HT2A Agonist With Attenuated Head Twitch and Retained Antidepressant Activity

527. GM-2040 is a Novel Putative Non-Hallucinogenic 5-HT2A Agonist With Attenuated Head Twitch and Retained Antidepressant Activity

5-HT 1A Agonists for levodopa-induced Dyskinesia in Parkinson’s Disease

Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT1A) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic. Clinical trials testing 5-HT1A agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT1A agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD.

TAAR1 Agonist Ulotaront Improves Glycemic Control and Reduces Body Weight in Rodent Models of Diabetes, Obesity, and Iatrogenic Weight Gain

AbstractIntroductionPreclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is a TAAR1 and 5-HT1A agonist currently in Phase 3 clinical trials for the treatment of schizophrenia. Here we summarize preclinical results assessing the effects of ulotaront on weight and metabolic parameters.MethodsEffects of ulotaront administration were evaluated on oral glucose tolerance (oGTT), gastric emptying, and in rodent models of weight gain (high-fat diet [HFD]-, corticosterone-, and olanzapine-induced).ResultsFollowing 15-day oral administration of ulotaront, rats on HFD showed dose-dependent reduction in body weight, food intake, and liver triglyceride content compared to controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in rats switched to ulotaront (vs. vehicle). Consistent with weight-lowering effects in rats, chronic ulotaront treatment normalized corticosterone-induced weight gain in mice. Assessment of oGTT showed a dose-dependent reduction of glucose excursion in response to acute ulotaront administration in naive and diabetic db/db mice. Ulotaront administration also delayed gastric emptying in mice—a likely mechanism driving reductions in glucose excursions during the oGTT. Whole-brain c-fos imaging of ulotaront-treated mice revealed increased neuronal activity in several brain regions associated with regulation of food intake and metabolic signals.ConclusionsThe data indicate that ulotaront not only lacks metabolic liabilities typically associated with antipsychotics but can reduce body weight and improve glucose tolerance in rodent models. The underlying mechanisms may include TAAR1-mediated peripheral effects on glucose homeostasis and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance. The beneficial metabolic effects of ulotaront may suggest a substantially improved risk-benefit profile compared to established antipsychotics.FundingSunovion Pharmaceuticals Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc.

Review of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist Ulotaront: Part II—Summary of Initial Clinical Efficacy/Safety Results

AbstractIntroductionUlotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we summarize ongoing clinical research characterizing the efficacy and safety of ulotaront as a member of the novel trace amine-associated receptor 1 (TAAR1) agonist class.MethodsSummarized are results from a double-blind, placebo-controlled study to evaluate the efficacy and safety of ulotaront (50 mg or 75 mg) in an acute exacerbation of schizophrenia, and a 6-month, open-label follow-up study. Also summarized are post-hoc analyses evaluating negative symptom efficacy, and key safety and adverse event (AE) outcomes.ResultsIn the short-term study, treatment with ulotaront was associated with significant (p<0.001) endpoint improvement in the PANSS total score (effect size [ES]: 0.45), the CGI-Severity score (ES: 0.52) and the Brief Negative Symptom Scale total score (ES: 0.48). The incidence of any AE was lower on ulotaront versus placebo (45.8% vs. 50.4%), and the number needed to harm (NNH) for individual AEs on ulotaront were all >40. Ulotaront was associated with lower risk for antipsychotic class-related AEs (extrapyramidal symptoms, akathisia, somnolence, nausea/vomiting, increased weight/metabolic labs, prolactinemia). The 6-month study demonstrated further improvement, with a completion rate (67%) that was higher than reported for current dopamine D2 antipsychotics.ConclusionsThe emerging profile of ulotaront is characterized by significant improvement in positive and negative symptoms of schizophrenia. The safety and tolerability profile of ulotaront is markedly different with respect to antipsychotic class-related AEs. The benefit-risk profile of ulotaront, as a member of a novel TAAR1 agonist class, is distinguished from antipsychotics by lack of AEs related to D2 and serotonin 5-HT2A receptor blockade.FundingSunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.

Review of the TAAR1 Agonist Ulotaront: Part I—From Discovery to Clinic

AbstractIntroductionTrace amine-associated receptors (TAARs) are a family of G-protein-coupled receptors (GPCRs) first identified in 2001. TAAR1 has emerged as a promising therapeutic target due to its ability to modulate monoaminergic and glutamatergic neurotransmission. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we provide a brief review of the discovery of ulotaront and preclinical research suggesting efficacy in schizophrenia, leading to the first clinical trial of ulotaront resulting in FDA Breakthrough Therapy Designation.MethodsUlotaront was discovered through a target-agnostic approach optimized to identify drug candidates that demonstrate an antipsychotic-like profile in vivo but lack D2 and 5-HT2A receptor antagonism. Ulotaront was further characterized by in vitro pharmacology, electrophysiology, behavioral, and imaging studies.ResultsUlotaront demonstrated an antipsychotic-like profile in a high-throughput, phenotypic behavior screening platform, as well as efficacy in preclinical models of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition of acoustic startle, and subchronic PCP-induced deficits in social interaction. Although not fully elucidated, ulotaront’s mechanism of action appears to be mediated by agonism at trace amine-associated 1 (TAAR1) and 5-HT1A receptors. This was further corroborated with whole cell patch clamp recordings, demonstrating inhibition of dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) neuronal firing via 5-HT1A and TAAR1 receptors. Furthermore, ulotaront attenuated the ketamine-induced increase in striatal dopamine synthesis capacity, suggesting that it may modulate presynaptic dopamine dysfunction which is hypothesized to contribute to the pathophysiology of schizophrenia.ConclusionsPreclinical studies have identified ulotaront as a TAAR1 agonist with antipsychotic-like activity. Ulotaront’s unique receptor profile led to its designation as a member of the new “-taront” class of TAAR1 agonists, distinct in pharmacology from the D2/5-HT2A class of antipsychotics. A companion poster will summarize the efficacy and safety of ulotaront based on initial clinical trials in schizophrenia.FundingSunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.

New Insight into Selective Serotonin Receptor Agonists in the Central Nervous System, Studied with WAY163909 in Obese and Diabetic Wistar Rats.

We investigated the effect of WAY-163909, a novel 5-hydroxytryptamine selective 2C receptor agonist on body weight, blood glucose levels, and insulin resistance in obese and diabetic Wistar rats. We used twenty male Wistar rats with obesity and obesity-induced diabetes and twenty healthy Wistar rats as a control group. Each of these groups was separated into two subgroups: one with a daily intraperitoneal application of WAY-163909 (1 mg/kg) and one without. During the study, body weight, blood glucose levels, and immunoreactive insulin were tracked. A reduction of 5.5% (p < 0.05) in body weight was registered in the rat group with diabetes and obesity and 2.56% in the control group with a daily application of WAY-163909 (1 mg/kg) at the end of the study. Decreases of 35.4% in blood glucose levels at week four in the diabetic and obese rat group with a daily application of WAY-163909 (1 mg/kg) were registered. A reduction of insulin levels of 4.1% (p < 0.05) in the diabetic and obese rats group using WAY-163909 was also observed. In our study, using WAY-163909 (1 mg/kg) led to a reduction of blood glucose levels, immunoreactive insulin, and body weight.

Next-generation antipsychotics- Trends and perspectives beyond dopaminergic and glutamatergic agents

IntroductionThree generations of antipsychotics, all of which are based on the dopaminergic hypothesis of schizophrenia, are available for clinical use. Still, more than 66% of the patients diagnosed with schizophrenia spectrum disorders (SSD) could not achieve remission. Also, the glutamatergic hypothesis of schizophrenia is supported by translational models of this disease, even if the antipsychotics derived from this conceptual framework are not yet available on the market. However, the need for new pathogenesis models for schizophrenia and new generations of antipsychotics is acute, therefore, an exploration of the antipsychotics in the pipeline could be helpful in understanding the current stage of research in schizophrenia.ObjectivesTo assess the evidence supporting the potential benefits of new antipsychotics in the pipeline.MethodsA literature review was performed through the main electronic databases PubMed, Cochrane, Clarivate/Web Of Science, and EMBASE) and clinical trials repositories (US National Library of Medicine and World Health Organization Clinical Trials Registry Platform) using the search paradigm “antipsychotics” AND “schizophrenia” AND “non-dopaminergic” AND “non-glutamatergic”. All papers published between January 2010 and September 2022 were included.ResultsXanomeline/trospium (xanomeline is a muscarinic M1/M4 receptor agonist at the central nervous system, while trospium limits its peripheral effects) was efficient for schizophrenia in one phase III clinical trial. Pimavanserin (a selective 5HT2A inverse agonist and antagonist) was efficient in improving negative symptoms of schizophrenia in a phase II trial. Roluperidone (a 5HT2A and σ2 receptor antagonist) has been associated with favorable results in phase III clinical trials, mainly on negative symptoms of schizophrenia. SEP-363856 is a TAAR-1 agonist and 5HT1A agonist, currently explored in phase III clinical trials for schizophrenia. MK-8189 is a phosphodiesterase 10A inhibitor, investigated in phase III clinical trials for schizophrenia.ConclusionsBased on the retrieved data in the literature, multiple mechanisms, other than glutamatergic and dopaminergic pathways, are currently being investigated, and many of the antipsychotics based on these mechanisms are in the advanced stage of research. This is important not only for the clinical need to find more efficient and tolerable drugs for patients with schizophrenia but also because they may shed new light on the pathogenesis of this disease.Disclosure of InterestNone Declared

Role of 5-HT2 receptors family in the allergy-induced increased aorta contractile responses to 5-HT.

Asthma poses an increased risk for cardiovascular disorders, suggesting that allergy, which is an underlying process in asthma, causes atypical functioning of organs other than lungs. In a previous study in a guinea pig asthma model, we concluded that allergic sensitization increased aorta contractile responses to 5-HT. To further characterize these responses, here we explored the role of the 5-HT2 receptors family. We found that TCB-2 (5-HT2A agonist) and WAY161503 (5-HT2C agonist) induced aorta contractions resembling those elicited by 5-HT but less intense (~43 % and ~25 %, respectively). In these experiments, aortas from sensitized guinea pigs showed increased contractions to TCB-2, but not to WAY161503. In turn, MDL 100907 (5-HT2A antagonist) and RS-102221 (5-HT2C antagonist) caused a notably and a mild reduction of the 5-HT-induced contractions, respectively, with no differences seen between sensitized and non-sensitized tissues. BW723C86 (5-HT2B agonist) did not induce contractile responses and RS-127445 (5-HT2B antagonist) did not modify the contractile responses to 5-HT. In non-sensitized aortas, the pattern of protein expression of receptors was 5HT2B>5-HT2A=5-HT2C, which did not change in sensitized animals. In conclusion, we found that allergic sensitization increased the aorta contractile responses to 5-HT, partly mediated by enhanced responses of 5-HT2A receptors, which was unrelated to changes in the expression of these receptors.

Vortioxetine improved negative and cognitive symptoms of schizophrenia in subchronic MK-801 model in rats

Schizophrenia is a devastating psychiatric disorder with complex symptoms and neurobiology. Serotonergic dysregulation is known to contribute to the pathogenesis of schizophrenia although dopaminergic and glutamatergic systems are thought to have central roles in neurobiology. No significant success can be achieved in the treatment of negative and cognitive symptoms while positive symptoms can be significantly reduced with current pharmacotherapy. Vortioxetine is a new multimodal antidepressant with 5-HT1A agonism, 5-HT1B partial agonism, 5-HT3, 5-HT7, and 5-HT1D antagonism, and serotonin reuptake inhibition. A limited number of studies suggest its therapeutic effect on the negative and cognitive symptoms of schizophrenia. Therefore, we investigated the potential beneficial effects of vortioxetine on behavioral and molecular deficits in the MK-801 model of schizophrenia in rats. Female Wistar albino rats (10–12 weeks) were grouped as saline, MK-801 (0.2 mg/kg), MK-801 + vortioxetine (2.5 mg/kg), MK-801 + vortioxetine (5 mg/kg), MK-801 + vortioxetine (10 mg/kg), MK-801 + risperidone (0.3 mg/kg), MK-801 + haloperidol (1 mg/kg) (n = 8 in each group). MK-801 has been daily administered (i.p.) for 14 days. Vortioxetine and antipsychotic treatments were injected for 21 days after a washout period of MK-801 and locomotor activity (LA), social interaction (SI), novel object recognition (NOR), Y-maze and prepulse inhibition (PPI) tests were performed at the 16–20th days of treatments, respectively. ELISA test was conducted to evaluate molecular analyses. MK-801 decreased PPI (%), social behaviors, and discrimination index in NOR and alternation (%) in the Y-maze test. In NOR and Y-maze tests, especially vortioxetine 5 and 10 mg/kg increased discrimination index and alternation (%) compared to MK-801. In addition, vortioxetine administration increased social behaviors. Moreover, MK-801 decreased GAD67 and parvalbumin levels while vortioxetine increased these protein levels compared to MK-801. Herein, we first suggested a potential therapeutic effect of vortioxetine, a new multimodal antidepressant, on negative and cognitive symptoms and neurobiological deficits including GAD67 and parvalbumin low expression in the MK-801 model in rats. It would be beneficial to confirm our results in different rodent models and to shed light on the possible mechanisms underlying these effects.

Rearing behaviour in the mouse behavioural pattern monitor distinguishes the effects of psychedelics from those of lisuride and TBG.

Psychedelics alter consciousness and may have potential for drug development. As psychedelics are likely therapeutically active, it is important to study their effects and mechanisms using preclinical models. Here, we examined the effects of phenylalkylamine and indoleamine psychedelics on locomotor activity and exploratory behaviour using the mouse Behavioural Pattern Monitor (BPM). DOM, mescaline, and psilocin reduced locomotor activity at high doses and influenced rearings, an exploratory behaviour, in a characteristic inverted U-shaped dose-response function. Pretreatment with the selective 5-HT2A antagonist M100907 reversed the drug-induced alterations in locomotor activity, rearings, and jumps after systemic administration of DOM at low doses. However, holepoking at the full range of doses tested was not blocked by M100907. Administration of the hallucinogenic 5-HT2A agonist 25CN-NBOH induced striking similarities in response to that to psychedelics; these alterations were significantly diminished by M100907, whereas the putatively non-hallucinogenic 5-HT2A agonist TBG did not affect locomotor activity, rearings, or jumps at the most effective doses. The nonhallucinogenic 5-HT2A agonist lisuride failed to increase rearing. The results of these experiments provide strong evidence that DOM-elicited increases in rearing are due to mediation by the 5-HT2A receptor. Finally, discriminant analysis was able to distinguish all four psychedelics from lisuride and TBG based on behavioural performance alone. Thus, increased rearing in mice could provide additional evidence of behavioural differences between hallucinogenic and nonhallucinogenic 5-HT2A agonists.