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Nowadays, the physiopathological and molecular mechanisms of multiple diseases have been identified, thus helping scientists to provide a clear answer, especially to those ambiguities related to chronic illnesses. This has been accomplished in part through the contribution of a key discipline known as bioinformatics. In this study, the bioinformatics approach was applied on four compounds identified in Centaurea tougourensis, using two axes of research: an in silico study to predict the molecular characteristics, medicinal chemistry attributes as well as the possible cardiotoxicity and adverse liability profile of these compounds. In this context, four compounds were selected and named, respectively, 2,5-monoformal-l-rhamnitol (compound 1), cholest-7-en-3.beta.,5.alpha.-diol-6.alpha.-benzoate (compound 2), 7,8-epoxylanostan-11-ol, 3-acetoxy- (compound 3), and 1H-pyrrole-2,5-dione, 3-ethyl-4-methyl- (compound 4). The second part looked into molecular docking, which objective was to evaluate the possible binding affinity between these compounds and the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor. Results indicated that compounds 1 and 4 were respecting Pfizer and giant Glaxo-SmithKline rules, while compounds 2 and 3 exhibited an optimal medicinal chemistry evolution 18 score. The structural and molecular features of almost all tested compounds could be considered optimal, indicating that these phyto-compounds may possess drug-likeness capacity. However, only compounds 1 and 4 could be considered non-cardiotoxic, but with a level of confidence more pronounced for compound 1 (80%). In addition, these four biocompounds could preferentially interact with G protein-coupled receptor, ion channel, transporters, and nuclear receptors. However, the heat map was less pronounced for compound 2. Data also indicated that these four compounds could possibly interact with serotonin 5-HT2A receptor, but in an antagonistic way. This research proved once again that plants could be crucial precursors of pharmaceutical substances, which could be helpful to enrich the international pharmacopoeia.

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]

Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT 2A R agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. Male and female Sprague-Dawley rats (n = 25–29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2 μg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a ¼ log every 10 minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1 mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q 0 and α. Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT 2A R activation decreased Q 0 in female rats but increased Q 0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT 2A R activation sex-dependently alters opioid reinforcement. • Male and female Sprague-Dawley rats readily acquire fentanyl self-administration. • A modified low price twice within-session threshold procedure characterized fentanyl demand in male and female rats. • The 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) dose-dependently decreased demand intensity in female rats. • DOI dose-dependently increased demand elasticity in male rats but not female rats. • DOI reduced the reinforcing value of fentanyl in male but not female rats. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are severe and difficult-to-treat psychiatric illnesses with high rates of comorbidity. Although both disorders are treated with serotonergic based psychotropic agents, little is known on the influence of the serotonergic neurotransmitter system on the occurrence of comorbid GAD when clinically depressed. To investigate this poorly understood clinical question, we examined the involvement of frontolimbic post-synaptic 5-HT2A receptors in 20 medication-resistant depressed (MRD) patients with half of them diagnosed with comorbid GAD with 123I-5-I-R91150 SPECT. To explore whether 5-HT2A receptor-binding indices (BI) associated with comorbid GAD could be related to distinct psychopathological symptoms, all were assessed with the symptom Checklist-90-Revised (SCL-90-R). MRD patients with comorbid GAD displayed significantly higher 5-HT2A receptor BI in the hippocampal–amygdala complex, compared to MRD patients without GAD. Correlation analyses revealed that the 5-HT2A receptor BI in these areas were significantly related to the SCL-90-R subscale hostility (HOS), especially for those MRD patients with comorbid GAD. Comorbid MRD-GAD may be characterized with increased hippocampal–amygdala 5-HT2A receptor BI which could represent enhanced levels in hostility in such kinds of patients. Adapted psychotherapeutic interventions may be warranted. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. First generation or typical antipsychotics such as haloperidol and second generation or atypical antipsychotics such as clozapine and risperidone remain the current standard for schizophrenia treatment. In some patients with schizophrenia, antipsychotics produce complete remission of positive symptoms, such as hallucinations and delusions. However, antipsychotic drugs are ineffective against cognitive deficits and indeed treated schizophrenia patients have small improvements or even deterioration in several cognitive domains. This underlines the need for novel and more efficient therapeutic targets for schizophrenia treatment. Serotonin and glutamate have been identified as key parts of two neurotransmitter systems involved in fundamental brain processes. Serotonin (or 5-hydroxytryptamine) 5-HT 2A receptor (5-HT 2A R) and metabotropic glutamate 2 receptor (mGluR2) are G protein-coupled receptors (GPCRs) that interact at epigenetic and functional levels. These two receptors can form GPCR heteromeric complexes through which their pharmacology, function and trafficking becomes affected. Here we review past and current research on the 5-HT 2A R-mGluR2 heterocomplex and its potential implication in schizophrenia and antipsychotic drug action. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy". • 5-HT 2A R-mGluR2 heteromeric complex. • 5-HT 2A R-mGluR2 in postmortem schizophrenia brain samples. • Epigenetic crosstalk between 5-HT 2A R and mGluR2. • Bivalent ligands for the 5-HT 2A R-mGluR2 complex. [ABSTRACT FROM AUTHOR]

• Head twitch response (HTR) provides a functional readout of psychedelic activity in rodent models. • Differences across sexes in HTR has not been explicitly studied. • The psychedelic DOI elicited more HTR in female as compared to male C57BL/6J mice. • This sex-dependent effect was not observed in 129S6/SvEv mice. • Pharmacokinetic properties of DOI differed among sexes in C57BL/6J mice. Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT 2A receptor (5-HT 2A R). This class of psychoactive substances, which includes lysergic acid diethylamide (LSD), psilocybin, mescaline and the substituted amphetamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), is receiving renewed attention for their potential therapeutic properties as it relates to psychiatric conditions such as depression and substance use disorders. Current studies focused on the potentially clinical effects of psychedelics on human subjects tend to exclude sex as a biological variable. Much of the understanding of psychedelic pharmacology is derived from rodent models, but most of this preclinical research has only focused on male mice. Here we tested the effects of DOI on head-twitch behavior (HTR) – a mouse behavioral proxy of human psychedelic potential – in male and female mice. DOI elicited more HTR in female as compared to male C57BL/6J mice, a sex-specific exacerbated behavior that was not observed in 129S6/SvEv animals. Volinanserin (or M100907) – a 5-HT 2A R antagonist – fully prevente DOI induced HTR in male and female C57BL/6J mice. Accumulation of inositol monophosphate (IP 1) in the frontal cortex upon DOI administration showed no sex-related effect in C57BL/6J mice. However, the pharmacokinetic properties of DOI differed among sexes – brain and plasma concentrations of DOI were lower 30 and 60 min after drug administration in female as compared to male C57BL/6J mice. Together, these results suggest strain-dependent and sex-related differences in the behavioral and pharmacokinetic profiles of the 5-HT 2A R agonist DOI in C57BL/6J mice, and support the importance of studying sex as a biological variable in preclinical psychedelic research. [ABSTRACT FROM AUTHOR]

Compulsivity is a key manifestation of inhibitory control deficit and a cardinal symptom in different neuropsychopathological disorders such as obsessive-compulsive disorder, schizophrenia, addiction, and attention-deficit hyperactivity disorder. Schedule-induced polydipsia (SIP), is an animal model to study compulsivity. In this procedure, rodents develop excessive and persistent drinking behavior under different food-reinforcement schedules, that are not related to homeostatic or regulatory requirements. However, there are important individual differences that support the role of high-drinker HD rats as a compulsive phenotype, characterized in different paradigms by inhibitory response deficit, cognitive inflexibility, and resistant to extinction behavior; with significant differences in response to pharmacological challenges, and relevant neurobiological alterations in comparison with the control group, the non-compulsive low drinker LD group on SIP. The purpose of this review is to collate and update the main findings on the neurobiological bases of compulsivity using the SIP model. Specifically, we reviewed preclinical studies on SIP, that have assessed the effects of serotonergic, dopaminergic, and glutamatergic drugs; leading to the description of the neurobiological markers, such as the key role of the serotonin 5-HT2A receptor and glutamatergic signaling in a phenotype vulnerable to compulsivity as high drinker HD rats selected by SIP. The review of the main findings of HD rats on SIP helps in the characterization of the preclinical compulsive phenotype, disentangles the underlying neurobiological, and points toward genetic hallmarks concerning the vulnerability to compulsivity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT 2A receptor (5-HT 2A R) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT 2A R knockout (5-HT 2A R −/− ) male, but not female mice; an effect that was reversed by Cre-loxP -mediated selective expression of 5-HT 2A R in dorsal root ganglion (DRG) neurons of 5-HT 2A R −/− littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT 2A R −/− animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT 2A R expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant. [Display omitted] • Adjunctive volinanserin augments oxycodone-induced antinociception in male but not female mice. • Adjunctive volinanserin does not affect oxycodone-induced conditioned place preference in male or female mice. • Adjunctive volinanserin reduces oxycodone-induced locomotor sensitization in male and female mice. • 5-HT 2A receptor in dorsal root ganglion neurons is necessary for the adjunctive antinociceptive effect of volinanserin. • Volinanserin may serve as a new approach to augment opioid-induced analgesia. [ABSTRACT FROM AUTHOR]

Schizophrenia is a devastating mental disorder resulting in marked morbidity and mortality despite the optimal use of all currently available interventions. For this reason, the release of lumateperone (Captyla R ), also known as ITI-007, an orally administered, atypical antipsychotic provided a welcome novel tool for clinicians to utilize precision medicine to tailor an optimal treatment plan to the specific needs of each person with schizophrenia. To generate a foundation for clinicians to assess the risks and benefits of lumateperone in relation to other interventions for schizophrenia, we conducted a search of items for 'ITI-007' and 'lumateperone' on PubMed, ScienceDirect, Web of Science, Google Scholar, and www.clinicaltrials.gov. We present a critical evaluation of the limited information about lumateperone for schizophrenia, its use approved by the US Food and Drug Administration. Lumateperone merits consideration for patients with treatment-resistant schizophrenia and for patients with schizophrenia who are vulnerable to developing metabolic dysfunction and movement disorders. On the other hand, lumateperone should not be used for (a) women who are pregnant or breastfeeding, children, adolescents, and elderly patients with dementia-related psychosis, (b) patients who are at risk for cerebrovascular diseases, (c) patients who use inducers and moderate or strong inhibitors of the cytochrome P450-3A4 (CYP3A4) isozyme, and (d) patients who use alcohol and other sedating agents. Clinical trials from multiple centers without financial conflicts of interest to market lumateperone are needed to directly compare and contrast lumateperone and other antipsychotic agents to generate trustworthy evidence to be assessed objectively by clinicians treating patients with schizophrenia. Future investigations will provide the foundations to identify the evidence for comprehensive evaluations of the role of lumateperone in the treatment of people with schizophrenia and other conditions., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

The serotonin 5-HT 2A receptor (5-HT 2A R) is a member of the GPCR family that is important for various neurological functions and whose dysregulation causes many mental health disorders. Structural investigations of 5-HT 2A R require the production of functionally active receptors expressed from eukaryotic cell cultures. In this protocol, we describe a step-by-step method to express and purify serotonin 5-HT 2A R using a baculoviral expression vector system in Sf9 cell cultures, derived from our work with the rat (matching Uniprot ID P14842) and human (matching Uniprot ID P28223) 5-HT 2A Rs. A unique feature of this method is the utilization of cell culture additives to infect cells at low multiplicity of infection, thereby using several fold less quantity of viral titer compared to prior methods without the additive. This protocol can be tweaked to selectively over-express glycosylated or non-glycosylated forms of the receptor by varying the post-infection harvest times., Competing Interests: Competing interestsThe authors declare no conflict of interest., (Copyright © 2020 The Authors; exclusive licensee Bio-protocol LLC.)

Introduction : Schizophrenia, a devastating disorder with onset in adolescence or young adulthood, afflicts 1% of the population leading to severe social, educational, and occupational impairments. Lumateperone is a first-in-class investigational drug under development for the treatment of multiple neuropsychiatric and neurodegenerative disorders including schizophrenia. Its unique receptor affinity profile together with synergistic modulation of serotonergic, glutamatergic, and dopaminergic pathways imparts efficacy over a broad-spectrum of symptoms associated with schizophrenia. Areas covered : This narrative drug evaluation includes a review of lumateperone tosylate (lumateperone, ITI-007, ITI-722, Intra-Cellular Therapies, Inc.) for patients with schizophrenia. This review describes the receptor affinity profile, pharmacodynamics, pharmacokinetics, distribution, metabolism, and clinical trials that address how lumateperone could potentially emerge as an important therapeutic option for schizophrenia patients. Expert opinion : The unique pharmacological properties of lumateperone may provide the key to dramatically ameliorate the symptoms of schizophrenia as indicated by some clinical trials. Future clinical trials may be enhanced by the administration of more comprehensive long-term behavioral measures and utilization of molecular imaging to confirm the target engagement of the many possible sites of action. The results of ongoing and future studies will provide the evidence to determine if lumateperone will revolutionize the therapy of schizophrenia.

Pharmacophore models for 5-HT 2A receptor antagonists consist of two aromatic/hydrophobic regions at a given distance from a basic amine. We have previously shown that both aromatic/hydrophobic moieties are unnecessary for binding or antagonist action. Here, we deconstructed the 5-HT 2A receptor antagonist/serotonin-dopamine antipsychotic agent risperidone into smaller structural segments that were tested for 5-HT 2A receptor affinity and function. We show, again, that the entire risperidone structure is unnecessary for retention of affinity or antagonist action. Replacement of the 6-fluoro-3-(4-piperidinyl)-1,2-benz[ d]isoxazole moiety by isosteric tryptamines resulted in retention of affinity and antagonist action. Additionally, 3-(4-piperidinyl)-1,2-benz[ d]isoxazole (10), which represents less than half the structural features of risperidone, retains both affinity and antagonist actions. 5-HT 2A receptor homology modeling/docking studies suggest that 10 binds in a manner similar to risperidone and that there is a large cavity to accept various N 4 -substituted analogues of 10 such as risperidone and related agents. Alterations of this "extended" moiety improve receptor binding and functional potency. We propose a new risperidone-based pharmacophore for 5-HT 2A receptor antagonist action.

The 5-HT 2A receptor (5-HT 2A R) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HT 2A R:5-HT 2A R homodimer in these disorders are necessary. We chemically modified the selective 5-HT 2A R antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HT 2A R:5-HT 2A R homodimer function. We tested these molecules for 5-HT 2A R antagonist activity in a cell line stably expressing the functional 5-HT 2A R and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK 1/2 ), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK 1/2 in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The K i values for the binding of bivalent ligands to 5-HT 2A R were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HT 2A R over 5-HT 2B R or 5-HT 2C R binding was retained. In addition, the 11-atom-linked bivalent 5-HT 2A R antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT 2A R antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT 2A R structure and function.

Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression.