-
Best Practice & Research. Clinical... Dec 2020Postoperative nausea and vomiting (PONV) afflict approximately 30% of patients overall and up to 80% of high-risk patients after surgery. Optimal pharmacological... (Review)
Review
Postoperative nausea and vomiting (PONV) afflict approximately 30% of patients overall and up to 80% of high-risk patients after surgery. Optimal pharmacological prophylaxis of PONV is challenging as it necessitates the consideration of PONV risk, drug efficacy, and potential adverse effects. Despite significant advances in our understanding of the pathophysiology and risk factors of PONV, its incidence has remained largely unchanged. Newer antiemetics have been introduced that may have improved safety profiles, longer duration of action, and better efficacy. This review aims to summarize the recent developments pertaining to these new agents and their potential application toward the management of PONV.
Topics: Antiemetics; Aprepitant; Disease Management; Dopamine Antagonists; Drug Therapy, Combination; Humans; Neurokinin-1 Receptor Antagonists; Palonosetron; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists
PubMed: 33288125
DOI: 10.1016/j.bpa.2020.11.004 -
Behavioural Brain Research Sep 2020Anxiety and depression are among the major neuropsychiatric disorders worldwide, and yet the etiologies of these disorders remain unclear to date. Chronic unpredictable...
Effect of 5-HT receptor agonist and antagonist on chronic unpredictable stress (CUS) - Mediated anxiety and depression in adolescent Wistar albino rat: Implicating serotonin and mitochondrial ETC-I function in serotonergic neurotransmission.
Anxiety and depression are among the major neuropsychiatric disorders worldwide, and yet the etiologies of these disorders remain unclear to date. Chronic unpredictable stress (CUS) procedure mimics several behavioral characteristics such as anxiety and depression in rodents. Using this animal model, we have attempted to understand the serotonergic system in the hippocampus and prefrontal cortex, while using the 5-HTR agonist and antagonist in evaluating 5-HT receptor neurotransmission. A decrease in serotonin (5-HT) level, tryptophan hydroxylase-2 activity and, 5-HTR receptor protein down-regulation in the CUS exposed group, explains the involvement of 5-HT and 5-HTR neurotransmission in the genesis of anxiety and depression. Besides, the oxidative stress - attenuated electrolyte imbalance via decrease ATPase pump activity, and compromised oxidative phosphorylation via decrease ETC-I activity are some of the underlying factors affecting neuronal cell survival and serotonergic neurotransmission. To complement our finding, altered behavioral performance scored in the open field test, elevated plus maze test, and the forced swim test, when exposed to CUS is indicative or consistent with anxiety, depression, emotional and locomotor status of the animals. Keeping these findings in mind, treatment with 5-HTR agonist (1-Methylpsilocin at 0.7 mg/kg), and 5-HTR antagonist (RS-102221 hydrochloride at 1 mg/kg) displayed varying results. One prominent finding was the anxiolytic ability of the 5-HTR agonist and the anti-depressive ability of the 5-HTR antagonist on the 7th-day treatment. Though the exact mechanism of action is not clear, their ability to equilibrate brain redox status, restoring Ca level via CaATPase pump activity, and sustaining the mitochondrial bioenergetics can all be accounted for facilitating neurogenesis and the serotonergic system.
Topics: Animals; Anxiety; Depression; Hippocampus; Male; Mitochondria; Prefrontal Cortex; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological; Synaptic Transmission
PubMed: 32579979
DOI: 10.1016/j.bbr.2020.112780 -
The Journal of Pharmacology and... Jul 2021TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine...
TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HTR) ( = 0.23 nM) and 5-HTR ( = 2.58 nM) as well as moderate affinity for DR ( = 11.55 nM) and DR ( = 17.91 nM). In vitro functional assays demonstrated that TPN672 acted as a potent 5-HTR agonist, DR/DR partial agonist, and 5-HTR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidine-induced hyperactivity), significantly better than aripiprazole, and ameliorated negative symptoms and cognitive deficits in the sociability test, dark avoidance response, Morris water maze test, and novel object recognition test. The results of electrophysiological experiments showed that TPN672 might inhibit the excitability of the glutamate system through activating 5-HTR in medial prefrontal cortex, thereby improving cognitive and negative symptoms. Moreover, the safety margin (the ratio of minimum catalepsy-inducing dose to minimum effective dose) of TPN672 was about 10-fold, which was superior to aripiprazole. In conclusion, TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having lower risk of extrapyramidal symptoms and hyperprolactinemia. SIGNIFICANCE STATEMENT: TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having a lower risk of extrapyramidal symptoms and hyperprolactinemia. A phase I clinical trial is now under way to test its tolerance, pharmacokinetics, and pharmacodynamic effects in human volunteers. Accordingly, the present results will have significant impact on the development of new antischizophrenia drugs.
Topics: Animals; Antipsychotic Agents; Avoidance Learning; Female; HEK293 Cells; Humans; Male; Mice; Mice, Inbred ICR; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Serotonin Receptor Agonists; Treatment Outcome
PubMed: 33975897
DOI: 10.1124/jpet.120.000414 -
Molecules (Basel, Switzerland) Jun 2021Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and... (Review)
Review
Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HTR) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HTR modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HTR/G signaling pathway. Through the investigation of recent studies, it is suggested that 5-HTR could be a potential therapeutic target for the treatment of NDDs.
Topics: Animals; Humans; Molecular Targeted Therapy; Neurodevelopmental Disorders; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction
PubMed: 34199418
DOI: 10.3390/molecules26113348 -
Pharmacological Reports : PR Jun 2020LY393558 is a combined antagonist of serotonin (5-HT) 5-HT receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and...
Reduction of the serotonin 5-HT and 5-HT receptor-mediated contraction of human pulmonary artery by the combined 5-HT receptor antagonist and serotonin transporter inhibitor LY393558.
BACKGROUND
LY393558 is a combined antagonist of serotonin (5-HT) 5-HT receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and remodelling of rat and/or mouse pulmonary arteries. The aim of our study was to examine the effect of LY393558 on the 5-HT-stimulated vasoconstriction of human pulmonary arteries (hPAs) and to determine the underlying mechanism(s).
METHODS
Vascular effects of 5-HT receptor agonists, antagonists and a SERT inhibitor were examined in organ bath studies on intralobar hPAs obtained from patients during resection of lung carcinoma.
RESULTS
Serotonin and agonists of the 5-HT receptor (5-carboxamidotryptamine, 5-CT) and 5-HT receptor (α-methyl-5-HT) contracted endothelium-intact hPAs in a concentration-dependent fashion. The 5-HT antagonists SB224289 and GR55562 reduced responses induced by 5-HT and 5-CT and the 5-HT antagonist ketanserin inhibited the effects of 5-HT and α-methyl-5-HT. Administration of the SERT inhibitor citalopram (at a concentration that failed to modify the 5-HT-induced vasoconstriction) in combination with SB224289 or GR55562 was more effective in inhibiting the response to 5-HT than the 5-HT antagonists alone. LY393558 showed the greatest antagonistic effect against the vasoconstriction elicited by 5-HT, 5-CT and α-methyl-5-HT.
CONCLUSIONS
LY393558 reduces the 5-HT-induced contraction antagonizing 5-HT and 5-HT receptors probably due to synergic interaction between SERT inhibition and 5-HT receptor antagonism. Thus, it might represent a valuable future option in the pulmonary arterial hypertension therapy.
Topics: Aged; Benzamides; Citalopram; Cyclic S-Oxides; Female; Humans; Male; Middle Aged; Piperidones; Pulmonary Artery; Pyridines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Selective Serotonin Reuptake Inhibitors; Spiro Compounds; Thiadiazines; Vasoconstriction
PubMed: 32333296
DOI: 10.1007/s43440-020-00105-2 -
Expert Opinion on Emerging Drugs Jun 2020While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits.... (Review)
Review
INTRODUCTION
While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits. Given that these aspects of the disease contribute to poor functional outcomes independently of positive symptoms, treatments would have profound implications for quality of life. The 5-HT- receptor has been considered a potential target for interventions aimed at negative and cognitive symptoms and multiple antagonists and inverse agonists of this receptor have been tested.
AREAS COVERED
Ritanserin and volinanserin, are historically important compounds in this area, while pimavanserin, roluperidone, and lumateperone are either newly approved, in late stages of development, or currently being tested for efficacy in schizophrenia-related features. The focus will be on their efficacy in the treatment of negative symptoms, with a limited secondary discussion of cognition.
EXPERT OPINION
In addition to their efficacy in treating negative symptoms and cognition, these compounds may also have a role in modulating antipsychotic-induced dopamine super-sensitivity and preventing relapse. They may also show efficacy in treating patients with milder symptoms such as patients with schizotypal personality disorder and attenuated psychosis syndrome. Their utility may also expand outside the spectrum of schizophrenia to encompass Parkinson's Disease psychosis, major depression, bipolar depression, and dementia-associated apathy.
Topics: Animals; Antipsychotic Agents; Cognition Disorders; Drug Design; Drug Development; Humans; Quality of Life; Schizophrenia; Serotonin Antagonists
PubMed: 32449404
DOI: 10.1080/14728214.2020.1773792 -
Neuropsychopharmacology Reports Mar 20215-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of...
AIMS
5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of 5-MeO-DIPT involve the serotonin transporter (SERT) and serotonin 5-hydroxytryptamine-1A (5-HT ) receptor in the striatum and prefrontal cortex (PFC).
METHODS
We investigated the effects of 5-MeO-DIPT on extracellular 5-HT (5-HT ) and dopamine (DA ) levels in the striatum and PFC in wildtype and SERT knockout (KO) mice using in vivo microdialysis, and for comparison the effects of the 5-HT receptor antagonist WAY100635 and the 5-HT receptor agonist 8-OH-DPAT on 5-HT .
RESULTS
5-MeO-DIPT decreased 5-HT levels in the striatum, but not PFC. In SERT-KO mice, 5-MeO-DIPT did not affect 5-HT levels in the striatum or PFC. In the presence of WAY100635, 5-MeO-DIPT substantially increased 5-HT levels, suggesting that 5-MeO-DIPT acts on SERT and these effects are masked by its 5-HT actions in the absence of WAY100635. 8-OH-DPAT decreased 5-HT levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8-OH-DPAT-induced decrease in 5-HT levels. In SERT-KO mice, 8-OH-DPAT did not decrease 5-HT levels in the striatum and PFC. 5-MeO-DIPT dose-dependently increased DA levels in the PFC, but not striatum, in wildtype and SERT-KO mice. The increase in DA levels that was induced by 5-MeO-DIPT was not antagonized by WAY100635.
CONCLUSION
5-MeO-DIPT influences both 5-HT and DA levels in the striatum and PFC. 5-MeO-DIPT dually acts on SERT and 5-HT receptors so that elevations in 5-HT levels produced by reuptake inhibition are limited by actions of the drug on 5-HT receptors.
Topics: 5-Methoxytryptamine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Corpus Striatum; Female; Male; Mice; Mice, Knockout; Microdialysis; Piperazines; Prefrontal Cortex; Pyridines; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins
PubMed: 33547882
DOI: 10.1002/npr2.12161 -
Child and Adolescent Psychiatric... Oct 2019Psychotropic medications are commonly used in the treatment of eating disorders in children and adolescents. This article reviews the evidence base on psychotropic... (Review)
Review
Psychotropic medications are commonly used in the treatment of eating disorders in children and adolescents. This article reviews the evidence base on psychotropic medications, including all randomized trials, uncontrolled trials, and case reports for the treatment of anorexia nervosa, bulimia nervosa, other specified feeding and eating disorders, binge-eating disorder, and avoidant/restrictive food intake disorder. Despite advances in the number of medication-based studies completed in young patients with eating disorders over the last 2 decades, significantly more work needs to be done in terms of identifying what role, if any, psychotropic medications can have on treatment outcomes.
Topics: Adolescent; Anorexia Nervosa; Avoidant Restrictive Food Intake Disorder; Binge-Eating Disorder; Bulimia Nervosa; Child; Feeding and Eating Disorders; Humans; Olanzapine; Psychotropic Drugs; Risperidone; Serotonin Antagonists; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 31443877
DOI: 10.1016/j.chc.2019.05.005 -
Current Pharmaceutical Design 2021Lurasidone is a novel azapirone derivative and atypical antipsychotic agent with a high binding affinity for dopaminergic (D), serotoninergic (5-HT), and 5-HT receptors...
Lurasidone is a novel azapirone derivative and atypical antipsychotic agent with a high binding affinity for dopaminergic (D), serotoninergic (5-HT), and 5-HT receptors (antagonist), a moderate affinity for 5- HT receptors (partial agonist), and no appreciable affinity for histaminergic (H) and muscarinic (M) receptors. It was recently included by the European Medication Agency among the in-label pharmacological treatments for children and adolescents affected by early onset schizophrenia. As a dopamine and serotonin antagonist, lurasidone acted on a variety of receptors and showed its efficacy both as an antipsychotic and an activating compound. Administered with food or within 30 minutes from a meal, it presents sufficient bioavailability and does not interact with most of the other drugs during metabolism. With little effects on hormones and weight gain, potential procognitive profile due to its 5-HT antagonism, and reduced extrapyramidal side effects, lurasidone could be a good choice in terms of both effectiveness and tolerability, particularly for patients headed towards a long-term treatment. This article aims to summarize the available scientific evidence from the literature on the use of lurasidone in children and adolescents and to provide recommendations for clinical management and future research.
Topics: Adolescent; Antipsychotic Agents; Child; Dopamine; Humans; Lurasidone Hydrochloride; Schizophrenia; Serotonin Antagonists
PubMed: 34348620
DOI: 10.2174/1381612827666210804110853 -
International Journal of Molecular... Nov 20215-hydroxytryptamine type 3 (5-HT) receptors are ligand gated ion channels, which clearly distinguish their mode of action from the other G-protein coupled 5-HT or... (Review)
Review
5-hydroxytryptamine type 3 (5-HT) receptors are ligand gated ion channels, which clearly distinguish their mode of action from the other G-protein coupled 5-HT or serotonin receptors. 5-HT receptors are well established targets for emesis and gastrointestinal mobility and are used as adjunct targets in treating schizophrenia. However, the distribution of these receptors is wider than the nervous system and there is potential that these additional sites can be targeted to modulate inflammatory and/or metabolic conditions. Recent progress in structural biology and pharmacology of 5-HT receptors have provided profound insights into mechanisms of their action. These advances, combined with insights into clinical relevance of mutations in genes encoding 5-HT subunits and increasing understanding of their implications in patient's predisposition to diseases and response to the treatment, open new avenues for personalized precision medicine. In this review, we recap on the current status of 5-HT receptor-based therapies using a biochemical and physiological perspective. We assess the potential for targeting 5-HT receptors in conditions involving metabolic or inflammatory disorders based on recent findings, underscoring the challenges and limitations of this approach.
Topics: Animals; Humans; Immunity; Inflammation; Metabolic Diseases; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists
PubMed: 34769340
DOI: 10.3390/ijms222111910