Serotonin Antagonist Research Articles

Impact of the Oncology Care Model on use of bone supportive medications, antiemetics, and growth factors.

1517 Background: The Oncology Care Model (OCM) is a voluntary, episode-based alternative payment model for cancer care launched by the Centers for Medicare & Medicaid Services in July 2016. OCM incentivizes participating practices to reduce spending during chemotherapy treatment while maintaining quality of care. We evaluated the impact of OCM on the use of costly supportive care medications. Methods: Using 100% Medicare claims (2013-2019), we evaluated use of outpatient supportive care medications during chemotherapy episodes assigned to OCM practices (n = 186) or propensity-matched comparison practices (n = 534). For bone supportive medications, we evaluated use of bisphosphonates and/or denosumab in beneficiaries with bone metastases from breast, lung, or prostate cancer. For anti-emetic drugs, we evaluated prophylactic use of neurokinin-1 (NK1) antagonists and long-acting (LA) serotonin antagonists. For white blood cell growth factors (GCSFs), we evaluated prophylactic use in beneficiaries starting chemotherapy for breast, lung, or colorectal cancer; we separately evaluated use of biosimilar (vs originator) filgrastim. Analyses employed the difference-in-differences (DID) approach, excepting the filgrastim biosimilar analysis where we assessed the adoption trend. Results: There was no OCM impact on receipt of any bone supportive medication (denosumab or bisphosphonate) among beneficiaries with bone metastases; however, OCM led to a relative decrease in use of denosumab for breast cancer (DID = -5.0 percentage points [90% CI -7.1, -2.8]), prostate cancer (-4.0 percentage points [90% CI -5.9, -2.2]), and lung cancer (-4.1 percentage points [90% CI -7.4, -0.9]). In beneficiaries starting chemotherapy regimens with high or moderate emetic risk, OCM led to reductions in prophylactic use of NK1 antagonists and LA serotonin antagonists (e.g. 6.0 percentage point reduction in use of NK1 antagonists during high emetic risk chemotherapy [90% CI -9.0, -3.1]); there was no impact on antiemetic use during low emetic risk chemotherapy. There was no OCM impact on use of prophylactic WBC growth factors among beneficiaries receiving chemotherapy with high risk for febrile neutropenia (FN). Among beneficiaries receiving chemotherapy with intermediate risk for FN, OCM led to a 7.6 percentage point reduction in prophylactic GCSF use for patients with breast cancer (90% CI -12.6, -2.7); however, there was no OCM impact on prophylactic GCSF use in patients with lung or colorectal cancer. Among beneficiaries receiving filgrastim, OCM led to faster adoption of biosimilar vs. originator filgrastim (differential trend estimate 2.6%, 90% CI 1.0, 4.4). Conclusions: OCM led to reduced use of some high cost supportive care medications, with patterns suggesting more value-conscious care. Alternative payment models have potential to drive value-based changes in medication use during cancer care.

Ondansetron – a Promising Adjunctive Treatment for Persistent Schizophrenia

New treatments are urgently needed for schizophrenia. Serotonin receptor antagonists, used in the ‘second generation’ antipsychotics, are primarily 5 HT2 antagonists with some positive impact on psychotic symptoms, but associated weight gain. Serotonin antagonism with 5HT3 activity may provide antipsychotic effect with less weight gain. Ondansetron is a serotonin 3 receptor antagonist widely used to prevent nausea and vomiting in pregnancy and in patients receiving chemotherapy. There is growing evidence that adjunctive ondansetron treatment improves symptomatology associated with schizophrenia, particularly with respect to the positive, negative and cognitive symptoms. Further studies that are applicable to real world practice are required to assess the efficacy and effectiveness of this treatment, which could be readily and rapidly translated into clinical practice.

Neuroleptic Malignant Syndrome and Serotonin Syndrome

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are iatrogenic life-threatening conditions with similar clinical symptoms. Altered mental status, rigidity, and autonomic instability are common in both serotonin overload and toxic dopamine antagonism. It is paramount that providers understand the key differences between these two pathologies, as pharmacologic treatments can exacerbate the condition if SS is mistaken for NMS or vice versa. Hyperreflexia, clonus, diarrhea, and vomiting suggest the excessive activity of serotonin circuits in SS, whereas prominent rigidity and hyporeflexia suggest the underactivity of dopamine circuits in NMS. Supportive care and discontinuing the offending agent(s) are keys to treating both syndromes, but serotonin antagonists (eg, cyproheptadine) could be helpful in SS, whereas NMS may sometimes benefit from muscle relaxants (eg, dantrolene) and dopamine agonists (eg, bromocriptine). Following recovery, decisions about further use of an inciting agent (or similar agents) require reconsideration of risks, benefits, and alternatives, based on newly realized hazards. It is usually important to wait at least 2 weeks before rechallenge with any drugs resembling the inciting agents. This review contains 1 figure, 8 tables, and 32 references. Key Words: bromocriptine, cyproheptadine, dantrolene, Hunter criteria, neuroleptic malignant syndrome, parkinsonism, serotonin syndrome

Pilot Study to Evaluate Pimavanserin for the Treatment of Motor and Behavioral Symptoms of Tourette Syndrome.

Pimavanserin is a serotonin 2A receptor inverse agonist and antagonist used for the treatment of hallucinations and delusions in Parkinson's disease psychosis. Numerous studies support a modulatory role of serotonin in Tourette syndrome (TS). To determine whether or not pimavanserin affects TS symptoms. In this open-label study of TS adult patients, pimavanserin was titrated to 34 mg/day over 1 week and continued for an additional 7 weeks followed by a 2-week washout. Tic severity, the primary outcome measure, was assessed by the Yale Global Tic Severity Scale Total Tic Severity score (YGTSS-TTS). Secondary outcome measures included changes in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Tourette Syndrome Clinical Global Impression of Change (TS-CGIC), the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII), and the Gilles de la Tourette Syndrome - Quality of Life scale (GTS-QOL). We enrolled 12 patients, but 2 dropped out after week 2 due to non-serious side effects. In the 10 patients, mean (standard deviation (SD)) age 34 (12.9) who completed the study the mean (SD) baseline YGTSS-TTS was 34 (9.3). This decreased by 3.6 (4.9) points at week 8, a 12% reduction in tic severity (P= 0.03). This improvement is small and may not be clinically important. Significant improvement was noted in the TS-CGIC, TS-PGII and GTS-QO. No serious adverse events were reported. The results of this study suggest that pimavanserin is safe and associated with improvement in motor and non-motor TS symptoms. These findings warrant further study by a larger, placebo-controlled, trial.

The efficacy of aprepitant in salvage treatment of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy for patients with gastrointestinal cancer.

To evaluate the efficacy of aprepitant and its effect on the quality of life when added to standard antiemetic therapy as salvage therapy. This is an open-label, noncomparative prospective phase II clinical trial. A total of 224 patients receiving initial moderately emetogenic chemotherapy (MEC) were enrolled. Patients received standard antiemetic treatment (5-hydroxytryptamine (5-HT3) antagonists + dexamethasone) in the first cycle. Patients failing to achieve a complete response (CR) during cycle 1 entered cycle 2 with the addition of aprepitant as salvage treatment. Of the 224 patients eligible for cycle 1, 159 (71.0%, 95% CI 65.0-77.0) had a CR, and 65 patients with a noncomplete response (NCR) proceeded to cycle 2 to receive aprepitant-based salvage therapy. Then, 49 (75.4%, 95% CI 64.6-84.1) of these patients achieved a CR. The Functional Living Index-Emesis (FLIE) questionnaire showed that NCR patients in cycle 1 had an improved quality of life after receiving aprepitant-based salvage therapy in cycle 2 (cycle 1 and 2: 80.3 vs 114.0, P < 0.001). Failing to achieve a CR had a significant impact on the quality of life in both cycle 1 (FLIE score of NCR and CR patients: 80.3 vs 119.7, P < 0.001) and cycle 2 (FLIE score of NCR and CR patients: 88.3 vs 122.4, P < 0.001). The addition of aprepitant as salvage therapy for patients with gastrointestinal cancer is effective and has a positive effect on quality of life.

Early response to trazodone once-a-day in major depressive disorder: review of the clinical data and putative mechanism for faster onset of action.

Most antidepressants have a delayed onset of action and must be administered for several weeks to generate therapeutic effects. Trazodone is a serotonin antagonist and reuptake inhibitor approved for the treatment of major depressive disorder. The once-a-day (OAD) formulation of trazodone has an improved tolerability profile compared to its conventional formulations. In this study, we systematically reviewed the evidence available for the antidepressant efficacy and early improvement in depressive symptoms with trazodone OAD treatment. We conducted a PubMed database search for randomized controlled trials published from 2005 to 2020. Two studies, a placebo-controlled and an active-comparator (venlafaxine extended-release or XR) study were found. Both the studies demonstrated that trazodone exhibits antidepressant activity at a starting dose of 150mg/day and results in statistically significant greater reduction in Hamilton Depression Rating Scale (HAM-D17) scores within 1week of starting treatment compared to placebo or venlafaxine XR (P<.05). Trazodone also resulted in significant early improvement in the HAM-D17 sleep disturbance factor compared to placebo or venlafaxine XR at day 7 (P<.05). This clinical effect is supported by in vitro proprietary data for the affinity of trazodone for different target receptors. Activity at these receptors may underlie trazodone's fast antidepressant action. Trazodone, if properly dosed, can be an effective antidepressant with early onset of action and good tolerability. Future studies designed to specifically evaluate onset and timing of improvement of depressive symptoms remain necessary to confirm and extend these results.

Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver.

ABSTRACTThe etiology of non-alcoholic fatty liver disease (NAFLD) consists of various factors, including neural signal pathways. However, the molecular mechanisms of the autonomic neural signals influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut-liver neural axis in NAFLD development and tested the therapeutic effect of modulation of this axis in this study. To test the contribution of the gut-liver neural axis, we examined NAFLD progression with respect to body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota and short-chain fatty acids in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver. Blockade of the neural signal from the liver to the gut in these NAFLD mice models ameliorated the progression of liver weight, hepatic steatosis and fibrosis by modulating serotonin expression in the small intestine. It was related to the severity of the liver pathology, the tight junction protein expression, microbiota diversity and short-chain fatty acids. These effects were reproduced by administrating serotonin antagonist, which ameliorated the NAFLD progression in the NAFLD mice models. Our study demonstrated that the gut-liver neural axis is involved in the etiologies of NAFLD progression and that serotonin expression through this signaling network is the key factor of this axis. Therefore, modulation of the gut-liver neural axis and serotonin antagonist ameliorates fatty and fibrotic changes in non-alcoholic fatty liver, and can be a potential therapeutic target of NAFLD.This article has an associated First Person interview with the first author of the paper.

Sex-Gender Differences in the Effectiveness of Treatment of Irritable Bowel Syndrome: A Systematic Review.

BackgroundIn recent years, research on sex-gender differences in health care has increasingly recognized that men and women differ in the way symptoms occur, in risk factors for certain conditions and in the way they respond to the same treatment. A disease that is known to often present differently in women and men is irritable bowel syndrome (IBS). Given the difference in prevalence, predominant symptoms and possible other pathophysiology, it is conceivable that a difference in treatment effectiveness in men and women is a discovery waiting to be found.PurposeTo determine whether there are differences in treatment effectiveness between men and women with irritable bowel syndrome.Materials and MethodsWe searched on PubMed and EMBASE, selecting randomized controlled trials comparing IBS treatment in men and women over 18 years old. One researcher performed the inclusion process, and two researchers independently performed a quality assessment. A descriptive analysis was conducted.ResultsTwelve studies, randomizing 1847 men and 3562 women, were included in this review. Treatment with serotonin antagonist alosetron, treatment with ibodutant and crofelemer and adding cognitive behavioral therapy to medical treatment found significant differences between men and women in favor of effectiveness towards women in either satisfactory relief of overall IBS symptoms or percentage of pain-free days.ConclusionSex-gender can be a determining factor in the effectiveness of IBS treatment. Due to the limited number of studies per treatment option, no recommendations can be made on the choice of a specific treatment. It is clear, however, that so as not to miss beneficial treatment options for either sex, the inclusion, analysis and description of data on the basis of sex is of the utmost importance.

Serotonin Pathway in Cancer.

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin’s role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin’s role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin’s role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.

Sex differences in lever pressing and running wheel tasks of effort-based choice behavior in rats: Suppression of high effort activity by the serotonin transport inhibitor fluoxetine

Selective serotonin transport (SERT) inhibitors such as fluoxetine are the most commonly prescribed treatments for depression. Although efficacious for many symptoms of depression, motivational impairments such as psychomotor retardation, anergia, fatigue and amotivation are relatively resistant to treatment with SERT inhibitors, and these drugs have been reported to exacerbate motivational deficits in some people. In order to study motivational dysfunctions in animal models, procedures have been developed to measure effort-related decision making, which offer animals a choice between high effort actions leading to highly valued reinforcers, or low effort/low reward options. In the present studies, male and female rats were tested on two different tests of effort-based choice: a fixed ratio 5 (FR5)/chow feeding choice procedure and a running wheel (RW)/chow feeding choice task. The baseline pattern of choice differed across tasks for males and females, with males pressing the lever more than females on the operant task, and females running more than males on the RW task. Administration of the SERT inhibitor and antidepressant fluoxetine suppressed the higher effort activity on each task (lever pressing and wheel running) in both males and females. The serotonin receptor mediating the suppressive effects of fluoxetine is uncertain, because serotonin antagonists with different patterns of receptor selectivity failed to reverse the effects of fluoxetine. Nevertheless, these studies uncovered important sex differences, and demonstrated that the suppressive effects of fluoxetine on high effort activities are not limited to tasks involving food reinforced behavior or appetite suppressive effects. It is possible that this line of research will contribute to an understanding of the neurochemical factors regulating selection of voluntary physical activity vs. sedentary behaviors, which could be relevant for understanding the role of physical activity in psychiatric disorders.

The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Cyproheptadine for Serotonin Toxicity: an Updated Systematic Review and Grading of Evidence

Serotonin toxicity (ST) is a serious clinical entity caused by drug-induced serotonin excess in the central nervous system. Animal studies and some human data indicate that activation of specific serotonin receptor subtypes, namely 5-HT1A and 5-HT2A, are involved in ST pathophysiology, suggesting that serotonin antagonists could be used to treat ST. However, to date, high-quality evidence for the clinical utility of the most commonly employed serotonin antagonist, cyproheptadine, is lacking. This systematic review provides a clinical update on the evidence regarding use cyproheptadine for treating ST and compiles cyproheptadine treatment recommendations from recent review articles. Published articles concerning the use of cyproheptadine for treating ST are exclusively case reports and case series (n = 151); most provide very low-quality evidence (i.e., grade D, n = 148) and the remaining few provide low-quality evidence (i.e., grade C, n = 3). Most recent review articles (n = 18) acknowledge this low level of evidence and propose cyproheptadine as an optional treatment, whereas others recommend its use in the clinical setting. Although ST has been recognized as a clinical entity for decades, rigorous trials demonstrating the therapeutic efficacy of cyproheptadine are lacking, warranting large-scale prospective human trials of antiserotonergic agents using a coordinated multicenter approach.

Sarpogrelate and rosuvastatin synergistically ameliorate aortic damage induced by hyperlipidemia in apolipoprotein E-deficient mice.

The current study aimed to investigate whether sarpogrelate and rosuvastatin possess anti-arterial injury, and attempted to elucidate the mechanism of action underlying this activity. Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is extensively used to prevent arterial thrombosis; however, its effects on atherosclerosis remain unknown. In the present study, sarpogrelate combined with rosuvastatin or rosuvastatin alone were administered to male ApoE-/- mice fed a high-fat diet (HFD) for 8 weeks. Metabolic parameters in the blood samples were analyzed using an automatic analyzer. Aortic tissues were stained with hematoxylin and eosin for morphological analysis. The expression levels of oxidized-low density lipoprotein (LDL) specific scavenging receptors, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 68 were detected via immunostaining. mRNA expression levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were determined via reverse transcription-quantitative PCR analysis, while protein expression levels of LOX-1 and phosphor(p)-ERK were determined via western blot analysis. The results demonstrated that sarpogrelate combined with rosuvastatin treatment significantly decreased total cholesterol and LDL cholesterol levels in the serum, and alleviated intimal hyperplasia and lipid deposition, accompanied by decreased inflammatory cell infiltration and lower expression levels of inflammatory cytokines, compared with rosuvastatin monotherapy or HFD treatment. Furthermore, sarpogrelate combined with rosuvastatin treatment significantly decreased the expression levels of LOX-1 and p-ERK. Taken together, these results suggest that the positive effects of sarpogrelate combined with rosuvastatin treatment on aortic injury may be associated with the regulation of the LOX-1/p-ERK signaling pathway. Sarpogrelate and rosuvastatin synergistically decreased aortic damage in ApoE-/- HFD mice, and thus provide a basis for the treatment of aortic injury caused by hyperlipidemia with sarpogrelate.

Re-evaluation of the discriminative stimulus effects of lysergic acid diethylamide with male and female Sprague-Dawley rats.

Recent discoveries from clinical trials with psychedelic-assisted therapy have led to a resurgence of interest in the psychopharmacology of lysergic acid diethylamide (LSD). Preclinical drug discrimination is an invaluable tool to investigate the neurochemical mechanisms underlying subjective drug effects. The current study extends previous drug discrimination research by including both sexes. Adult female (n = 8) and male (n = 8) Sprague-Dawley rats were trained to discriminate 0.08 mg/kg LSD from saline under a fixed ratio 20 schedule of food reinforcement. Substitution tests were conducted with several substances, including other serotonergic hallucinogens, psychostimulants, mixed psychedelic-stimulants and synthetic cathinones. Stimulus antagonist tests were conducted with selected serotonin and dopamine antagonists. LSD-substitution with serotonergic hallucinogens was comparable between sexes. Modest but intriguing differences were observed between male and female rats in the extent of partial substitution by 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine enantiomers and the synthetic cathinones, 3,4-methylenedioxypyrovalerone and 4-methylmethcathinone. Dopamine antagonists failed to block the LSD cue in both sexes and exerted stronger rate suppressant effects in male rats. The 5-hydroxytryptamine antagonist, (R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol (MDL 100 907) blocked LSD discrimination in both sexes, although complete blockade was evident at lower doses in male rats. These results support previous findings regarding the prominent role of serotonergic activities underlying LSDs discriminative stimulus effects in male rats and generalize these findings to female rats. In consideration of the rising popularity in psychedelic-assisted psychotherapy, further research may be warranted to evaluate possible sex differences in the behavioral and subjective effects of LSD.

Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity.

Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

Effects of Haloperidol and Cyproheptadine on the Cytoskeleton of the Sea Urchin Embryos

Early sea urchin embryos are sensitive to agonists and antagonists of transmitter receptors, both metabotropic and channel ones. In this work, we studied mechanisms of the cytostatic action of cyproheptadine and haloperidol–antagonists of serotonin 5HT2 receptors and dopamine D2 receptors, respectively. For this purpose, we employed the model of the blockade of the first cleavage division in sea urchin, which allows quantifying the effects of embryotoxic substances. The action of haloperidol and cyproheptadine is mediated by the effects on cytoskeleton elements. Both antagonists caused an increase in the degree of polymerization of the actin cytoskeleton, both in the cortical layer and in the cytoplasm. In addition, both antagonists affected the tubulin cytoskeleton: haloperidol predominantly disturbed spatial organization of the mitotic spindle, while cyproheptadine caused a complete depolymerization of tubulin and arrest of mitotic processes. The results indicate that cytostatic effects of dopamine and serotonin antagonists on cleavage divisions of sea urchin embryos are mediated by similar and/or crosstalk molecular mechanisms but also have significant differences that require further research.

036 Two-Arm, Prospective, Open-Label, Pilot Study of Flibanserin versus Flibanserin and Sex Therapy in Pre- and Postmenopausal Women with HSDD

Hypoactive Sexual Desire Disorder (HSDD) is the most common sexual dysfunction in women, having both biologic and psychologic components. Flibanserin, a multifunctional serotonin agonist and antagonist, was the first FDA-approved medication indicated for the safe and effective treatment of HSDD in premenopausal women. Flibanserin was studied in postmenopausal women with HSDD with similar safety and efficacy data as in premenopausal women. In our biopsychosocial model of multi-disciplinary sexual healthcare, new patients undergo both psychological and medical assessments routinely, however the benefits of concomitant sex therapy with pharmacological treatment of HSDD have not been adequately studied.

Effects of Microinjections of a Serotonin Receptor (5-HT2A/C) Agonist and Antagonist into the Amygdala in Rats on Anxiety Behavior and Conditioned Reflex Fear

The role of 5-HT2A/C receptors in the amygdala in the acquisition, testing, and extinction of conditioned reflex fear and on anxiety behavior was studied. Microinjections of a receptor antagonist (ketanserin, 0.5 μg/0.5 μl) into the basolateral nucleus of the amygdala decreased signs of conditioned reflex fear in the form of freezing and prevented reacquisition, but had no effect on anxiety behavior in rats. Administration of an agonist (DOI, 1 μg/0.5 μl) led to an increase in movement activity, panic-like behavior, and decreased anxiety, with reductions in the signs of fear in the form of freezing. Both the agonist and the antagonist of 5-HT2A/C receptors were able to accelerate fear extinction in rats with prolonged freezing, which does not extinguish easily. These results provide evidence that 5-HT2A/C receptors in the amygdala play a significant role in the occurrence and persistence of conditioned reflex fear apparent as freezing.

Amisulpride: tackling postoperative nausea and vomiting not a nightmare any more

Vomiting and nausea remains concern in postoperative patients for anaesthesiologists and surgeons. Patients remain at risk for adverse medical consequences as wound dehiscence, dehydration, electrolyte derangement’s and gastric aspiration. This entity delays discharge and is one of the causes of unanticipated admission after ambulatory surgery. Presently dopamine (D2), serotonin (5-HT3), and histamine (H1) antagonists are widely used prophylactic agents, as is the corticosteroid dexamethasone, but the incidence of postoperative nausea and vomiting (PONV) is still appreciable. Safety concerns as QT interval prolongation has led to nearly phasing out of use of D2-antagonist Droperidol, a potent and most favoured formulation. With minimal studies and randomized studies to back up the efficacy of existing modalities viz 5HT-antagonist, promethazine, metoclopramide and dimenhydrinate for management of postoperative nausea and vomiting, need for evaluation, study and incorporation into formulary for management was always persisting. Amisulpride is an anti-psychotic agent, used routinely in &gt;50 countries worldwide is a potent but atypical D2-antagonist with minimal adverse profile mainly QT interval prolongation, extrapyramidal signs and symptoms, which had plagued out other members of same class. In addition to D2 antagonism this drug exhibits potent antagonist action against D3 receptors, implicated in the emetic response. In pre clinical studies and multiple randomized controlled multicenter studies the effectiveness and safety of low dose intra venous Amisulpride was established and approved as Barhemsys @Acacia Pharma by US Food and drug administration in February 2020. This drug will soon add to protocol-based management of PONV.

Cyclohexylamine, an active compound from Toddalia asiatica, contracts epididymal vas deferens via serotonergic receptors.

BackgroundToddalia asiatica of Rutaceae, a Taiwan folk medicine, is used as an analgesic and anti-inflammatory herb. Cyclohexylamine (CHA) is an active compound from T. asiatica. Previous reports indicate CHA contracts rat vas deferens. However, the contractile mechanism of CHA on rat vas deferens was not yet reported. The purpose of this study was to investigate the contractile mechanism of CHA on rat epididymal portion of vas deferens.MethodsMale S.D. rats weighting between 200 g to 250 g were used. The epididymal portion of vas deferens was isolated and was added with various concentrations of serotonin, serotonin antagonists and CHA.ResultsSerotonin elicited dose-dependent (1 × 10−7M~1 × 10−4M) contractions on rat epididymal vas deferens, which were inhibited by pretreatment with ketanserin (1 × 10−8 M ~ 1 × 10−6 M), methysergide (1 × 10−5 M) and propranolol (1 × 10−4 M), respectively. CHA elicited dose-dependent (1 × 10−8M~1 × 10−4M) contractions on rat epididymal vas deferens. The contractions of CHA (1 × 10−4M) on epididymal vas deferens were enhanced by serotonin in a dose-dependent manner. Methysergide (1 × 10−7 ~1 × 10−5 M) did not affect the contractions evoked by CHA. However, the CHA elicited contraction was almost completely inhibited by ketanserin (1 × 10−5 M) and was enhanced by propranolol. The effect of propranolol at the concentration of 1 × 10−4 M on CHA was likely as CHA at high concentration alone.ConclusionsFrom the above results, the contraction evoked by CHA on the isolated rat epididymal vas deferens might be mediated by serotonergic receptors through 5-HT2A subtype.