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Serotonergic psychedelics, known for their hallucinogenic effects, have attracted interest due to their ability to enhance neuronal plasticity and potential therapeutic benefits. Although psychedelic-enhanced neuroplasticity is believed to require activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT 2A Rs), serotonin itself is less effective in promoting such plasticity. Also, the psychoplastogenic effects of these molecules correlate with their lipophilicity, leading to suggestions that they act by influencing the intracellular receptors. However, their lipophilicity also implies that a significant quantity of lipids is accumulated in the lipid bilayer, potentially altering the physical properties of the membrane. Here, we probe whether the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) can affect the properties of artificial lipid bilayers and if that can potentially affect processes such as membrane fusion. Solid-state NMR spectroscopy shows that the DOI strongly induces disorder in the lipid acyl chains. Atomic force microscopy shows that it can shrink the ordered domains in a biphasic lipid bilayer and can reduce the force needed to form nanopores in the membrane. Fluorescence correlation spectroscopy shows that DOI can promote vesicle association, and total internal fluorescence microscopy shows that it enhances vesicle fusion to a supported lipid bilayer. While serotonin has also recently been shown to cause similar effects, DOI is more than two orders of magnitude more potent in evoking these. Our results suggest that the receptor-independent effects of serotonergic psychedelics on lipid membranes may contribute to their biological actions, especially those that require significant membrane remodeling, such as neuronal plasticity.

Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing or constriction of the cerebral arteries that supply blood to the brain. The initial manifestation of RCVS often includes a "thunderclap" headache that is sudden, severe, and often disabling. Stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and antipsychotics with serotonergic activity can alter the cerebral arterial tone, trigger vasoconstriction, and place patients at risk of a cerebrovascular accident. Thus, psychiatric medications are commonly discontinued on admission for RCVS, and psychiatry is often consulted for input on acute medication management and longitudinal treatment options. Currently, there is a dearth of literature on managing psychiatric medications in RCVS, resulting in variable practice patterns that place patients at risk of withdrawal, decompensation, and relapse. In this article, we provide a case example and aim to consolidate the limited data surrounding the management of psychiatric illness with comorbid RCVS in our discussion. There is a clear concern about worsening and even potentially lethal consequences due to serotonin or stimulant-induced vasospasm both during an acute episode and in long-term management of RCVS. We discuss the underlying pathophysiologic mechanisms proposed for serotonergic-, noradrenergic-, and dopaminergic-induced cerebral vasospasm and how this correlates with the clinical management of patients on psychiatric medications. These data will then be organized to create a risks versus benefits outline to equip psychiatrists to make decisions about when to stop and when to restart psychiatric medications in the setting of RCVS., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There has been a resurgence of interest in the use of psychedelic therapies for several mental and substance use disorders. Psilocybin, a "classic" serotonergic psychedelic, has emerged as one of the primary compounds of interest in clinical research. While research on psilocybin's potential mental health benefits has grown, data on the safety and efficacy of other serotonergic psychedelics remain limited. A comprehensive scoping review on the use of mescaline, ibogaine, ayahuasca, N,N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD) in the treatment of mental and substance disorders was conducted. Independent reviewers screened titles, abstracts, and full texts and conducted data extraction. Seventy-seven studies met the inclusion criteria. There were 43 studies of LSD, 24 studies of ayahuasca, 5 studies of DMT, 5 studies of ibogaine, and 5 studies of mescaline. Commonly reported benefits included improved mood and anxiety symptoms, improved insight, reduced substance use, improved relationships, and decreased vegetative symptoms. Commonly reported adverse effects were psychological, neurological, physical, and gastrointestinal in nature. Serious adverse events (homicide and suicide) were reported in published studies of LSD. In conclusion, there is only low-level evidence to support the safety and efficacy of non-psilocybin serotonergic psychedelics in individuals with mental and substance use disorders.

Serotonin has been implicated in the neurobiology of attention-deficit/hyperactivity disorder (ADHD) due to its association with impulsivity, attention, and emotional regulation. Many compounds with serotonergic properties have been evaluated in ADHD, but few have been approved by regulatory authorities. Utilizing a search of public databases, we identified interventions studied in ADHD. Prescribing information and peer-reviewed and gray literature helped us to determine which compounds had an underlying mechanism of action associated with changing serotonin levels. Of the 24 compounds that met the search criteria, 16 had either failed clinical studies in an ADHD population or had been discontinued from future development. The available evidence was assessed to identify the developmental history of drugs with serotonergic activity and the outlook for new ADHD drug candidates targeting serotonin. Several treatment candidates floundered due to an inability to balance effectiveness with safety, underscoring the potential importance of potency, and selectivity. Ongoing drug development includes compounds with multimodal mechanisms of action targeting neurotransmission across serotonin, norepinephrine, and dopamine pathways; it appears likely that treatment which balances competing and complementary monoamine effects may provide improved outcomes for patients. It is hoped that continuing research into ADHD treatment will produce new therapeutic options targeting the serotonergic system, which can positively impact a wide range of symptoms, including mood, anxiety, and sleep as well as attention and hyperactivity., (Copyright © 1964–2024 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

There has been renewed interest in the use of 3,4-methylenedioxy-methamphetamine (MDMA) and serotonergic psychedelics in the treatment of multiple psychiatric disorders. Many of these compounds are known to produce prosocial effects, but how these effects relate to therapeutic efficacy and the extent to which prosocial effects are unique to a particular drug class is unknown. In this article, we present a narrative overview and compare evidence for the prosocial effects of MDMA and serotonergic psychedelics to elucidate shared mechanisms that may underlie the therapeutic process. We discuss 4 categories of prosocial effects: altered self-image, responses to social reward, responses to negative social input, and social neuroplasticity. While both categories of drugs alter self-perception, MDMA may do so in a way that is less related to the experience of mystical-type states than serotonergic psychedelics. In the case of social reward, evidence supports the ability of MDMA to enhance responses and suggests that serotonergic psychedelics may also do so, but more research is needed in this area. Both drug classes consistently dampen reactivity to negative social stimuli. Finally, preclinical evidence supports the ability of both drug classes to induce social neuroplasticity, promoting adaptive rewiring of neural circuits, which may be helpful in trauma processing. While both MDMA and serotonergic psychedelics produce prosocial effects, they differ in the mechanisms through which they do this. These differences affect the types of psychosocial interventions that may work best with each compound., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

New psychoactive substances (NPS) are typically synthesized in clandestine laboratories in an attempt to chemically modify already federally regulated drugs in an effort to circumvent the law. Drugs derived from a phenethylamine pharmacophore, such as 4-chloroamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), reliably induce thermogenesis and serotonergic deficits in the striatum and hippocampus of rodents. 4-methylamphetamine (4-MA), a relative newcomer to the NPS scene, was originally investigated in the mid-1900 s as a potential anorexigenic agent. With its phenethylamine pharmacophore, 4-MA was hypothesized to produce similar toxicological alterations as its chemical analogs. In the present study, three doses (1.0, 2.5, and 5.0 mg/kg, ip.) of 4-MA were administered to rats twice daily for two days. Core temperature data were calculated and analyzed as temperature area under the curve (TAUC). On the second day of dosing, a hypothermic response to 4-MA (2.5 and 5.0 mg/kg) was noted between 0.5 and 2.0 h post-treatment. Only the highest dose of 4-MA decreased body weight on the second day of treatment and maintained this reduction in weight for seven days after treatment ceased. None of the doses of 4-MA evaluated significantly altered serotonin levels in the hippocampus or striatum seven days after final treatment. The present findings demonstrate that the 4-methyl substitution to amphetamine generates a pharmacological and toxicological profile that differs from other similar phenethylamine analogs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cocaine blocks dopamine reuptake, thereby producing rewarding effects that are widely studied. However, cocaine also blocks serotonin uptake, which we show drives, in rats, individually variable aversive effects that depend on serotonin 2C receptors (5-HT2CRs) in the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons. 5-HT2CRs produce depolarizing effects in RMTg neurons that are particularly strong in some rats, leading to aversive effects that reduce acquisition of and relapse to cocaine seeking. In contrast, 5-HT2CR signaling is largely lost after cocaine exposure in other rats, leading to reduced aversive effects and increased cocaine seeking. These results suggest a serotonergic biological marker of cocaine-seeking vulnerability that can be targeted to modulate drug seeking., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization., Competing Interests: Declaration of Competing Interest MG reports receiving consulting fees from Psygen Labs Inc. and EntheoTech Bioscience. RLCH reports receiving consulting fees from COMPASS Pathways, Entheon Biomedical, Mydecine, Synthesis Institute, Tryp Therapeutics, and Usona Institute. BB, JS, RNS, and LR report no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

MDMA is a non-selective monoamine releasing stimulant with potent serotonergic effects - a pharmacological effect not typically associated with drugs of misuse or efficacious reinforcers. Nonetheless, MDMA is misused by humans and self-administered by laboratory animals. We have previously shown that repeated exposure to MDMA sensitized both the locomotor activating and reinforcing effects of MDMA in rats. Because repeated MDMA exposure often results in decreased markers of serotonin neurotransmission, it is possible that this might underlie the sensitizing effects of MDMA. This was examined in the current study. Male Sprague-Dawley rats were stereotaxically implanted with guide cannula in the medial striatum. They were then pre-treated with saline (n =  11) or MDMA (10 mg/kg, i.p.; n =  10), once daily for five days. Two-days later, all rats received ascending doses of MDMA (0.0, 5.0, 10.0, mg/kg, i.p.) administered at 2 hr intervals, during which locomotor activity was measured and microdialysis samples were collected. Microdialysates were analyzed using liquid chromatography-mass spectrometry and the concentrations of serotonin and MDMA were quantified. Acute MDMA administration produced dose-dependent increases in locomotor activity, which was significantly enhanced by MDMA pre-treatment. Acute MDMA also produced dose-dependent increases in medial-striatal serotonin and MDMA, but this was not impacted by MDMA pre-treatment. These results suggest that the sensitizing effects of MDMA are not due to changes in MDMA-produced synaptic overflow of serotonin in the medial striatum or the absorption/elimination of systemically administered MDMA. More likely candidates are alterations in serotonin receptor mechanisms and/or dopamine neurotransmission following repeated exposure., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Serotonin is an important neurotransmitter with various receptors and wide-range effects on physiological processes and cognitive functions including sleep, learning, and memory. In this review study, we aimed to discuss the role of serotonergic receptors in modulating sleep-wake cycle, and learning and memory function. Furthermore, we mentioned to sleep deprivation, its effects on memory function, and the potential interaction with serotonin. Although there are thousands of research articles focusing on the relationship between sleep and serotonin; however, the pattern of serotonergic function in sleep deprivation is inconsistent and it seems that serotonin has not a certain role in the effects of sleep deprivation on memory function. Also, we found that the injection type of serotonergic agents (systemic or local), the doses of these drugs (dose-dependent effects), and up- or down-regulation of serotonergic receptors during training with various memory tasks are important issues that can be involved in the effects of serotonergic signaling on sleep-wake cycle, memory function, and sleep deprivation-induced memory impairments. This comprehensive review was conducted in the PubMed, Scopus, and ScienceDirect databases in June and July 2021, by searching keywords sleep, sleep deprivation, memory, and serotonin., (© 2021. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Salvia elegans belongs to a genus plants with biological activities in central nervous system. In this work, the purpose was to evaluate the anxiolytic and antidepressant effects of fractions and compounds isolated from S. elegans and its interaction with serotoninergic drugs by using behavioral tests in mice. Fractions from aerial parts of S. elegans were obtained by column chromatography, SeF1, SeF2, SeF3, and SeF4. Each of them was administered to 25 mg/k in ICR mice subject to forced swimming test (FST), or elevated plus maze test (EPM), or open field test (OFT). The most active fractions were chemically separated until compounds, which were analyzed as anxiolytic or antidepressant and the coadministration of these treatments with 5-HT 1A and 5-HT 2 drugs was measured in the different biological tests. All fractions were anxiolytic and antidepressant, oleanolic acid (OA) was found in SeF2, and from SeF3, a mixture of terpenes was found; a GC-MS analysis confirmed the presence of two main compounds: rosifoliol and agaraspirol (TM, mixture of terpenes). TM (doses-response curve, 0.01, 0.1, 0.5, 1.0, and 2.0 mg/kg) and OA (5 mg/kg) were also evaluated demonstrating an antidepressant and anxiolytic effect, respectively. The combination of TM (0.5 mg/kg) with 8-OH (selective 5-HT 1A receptor agonist) induced an increment of antidepressant activity, while with the antagonist WAY-100635, the effect diminished. But with DOI (5-HT 1 c/5-HT 2  receptor agonist), there was no change, and with KET (5-HT 2 receptor antagonist), the activity was increased. When OA is co-administered with 8-OH or with DOI, the anxiolytic activity of this terpene, diminished; but with the combination with antagonists, the effect of OA shows no change. TM and OA were antidepressant and anxiolytic, respectively, on mice exposed to different tests, and these are able to interact with serotoninergic drugs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D 2 , 5-HT 1A ) and antagonist (5-HT 2A ) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants)., Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083)., Methods: ST studies were three-week randomized, double-blind, flexible dose (2-4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2-4 mg/day) study for patients completing the ST studies., Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (-1.74, 2.03), p  = 0.8797; study 081: -1.62 (-3.56, 0.32), p  = 0.1011. OL study patients ( n  = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients)., Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug-stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self-administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self-administration and the critical role of DA in the maintenance of MDMA self-administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms., (© 2021 International Society for Neurochemistry.)

Medical cannabis and individual cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), are receiving growing attention in both the media and the scientific literature. The Cannabis plant, however, produces over 100 different cannabinoids, and cannabigerol (CBG) serves as the precursor molecule for the most abundant phytocannabinoids. CBG exhibits affinity and activity characteristics between Δ9-THC and CBD at the cannabinoid receptors but appears to be unique in its interactions with α- 2 adrenoceptors and 5-hydroxytryptamine (5-HT 1A ). Studies indicate that CBG may have therapeutic potential in treating neurologic disorders (e.g., Huntington disease, Parkinson disease, and multiple sclerosis) and inflammatory bowel disease, as well as having antibacterial activity. There is growing interest in the commercial use of this unregulated phytocannabinoid. This review focuses on the unique pharmacology of CBG, our current knowledge of its possible therapeutic utility, and its potential toxicological hazards. SIGNIFICANCE STATEMENT: Cannabigerol is currently being marketed as a dietary supplement and, as with cannabidiol (CBD) before, many claims are being made about its benefits. Unlike CBD, however, little research has been performed on this unregulated molecule, and much of what is known warrants further investigation to identify potential areas of therapeutic uses and hazards., Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The Author(s).)

Background: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period., Methods: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed., Results: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research., Conclusions: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions., (Published by Oxford University Press on behalf of CINP 2020.)

Nearly 100 years after the discovery of serotonin, its role remains elusive. Modulation of serotonin transmission is considered in numerous central nervous system (CNS) diseases including depression, anxiety, schizophrenia, obsessive-compulsive disorders, addiction, Parkinson's disease, and Alzheimer's disease. The therapeutic strategies based on serotonin systems have evolved thanks to better identification of the involvement of serotonin in various diseases, the better use of animal models, a better understanding of the molecular environment of serotonin receptors, and ultimately the better understanding of the interaction of serotonin neurotransmission with other biological systems. Some 5-HT receptors are still the object of numerous investigations including 5-HT 1A , 5-HT 2A , and 5-HT 6 receptor subtypes. It is noteworthy that the direction of research is moving towards a simultaneous action at multiple targets either through different 5-HT targets or the consideration of both 5-HT and other targets to achieve better therapeutic responses., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Regulator of G protein Signaling (RGS) proteins inhibit G protein-coupled receptor (GPCR) signaling, including the signals that arise from neurotransmitter release. We have shown that RGS12 loss diminishes locomotor responses of C57BL/6J mice to dopamine transporter (DAT)-targeting psychostimulants. This diminution resulted from a brain region-specific upregulation of DAT expression and function in RGS12-null mice. This effect on DAT prompted us to investigate whether the serotonin transporter (SERT) exhibits similar alterations upon RGS12 loss in C57BL/6J mice., Aims: Does RGS12 loss affect (a) hyperlocomotion to the preferentially SERT-targeting psychostimulant 3,4-methylenedioxymethamphetamine (MDMA), (b) SERT expression and function in relevant brain regions, and/or (c) serotonergically modulated behaviors?, Methods: Open-field and spontaneous home-cage locomotor activities were quantified. 5-HT, 5-HIAA, and SERT levels in brain-region homogenates, as well as SERT expression and function in brain-region tissue preparations, were measured using appropriate biochemical assays. Serotonergically modulated behaviors were assessed using forced swim and tail suspension paradigms, elevated plus and elevated zero maze tests, and social interaction assays., Results: RGS12-null mice displayed no hyperlocomotion to 10 mg/kg MDMA. There were brain region-specific alterations in SERT expression and function associated with RGS12 loss. Drug-naïve RGS12-null mice displayed increases in both anxiety-like and anti-depressive-like behaviors., Conclusion: RGS12 is a critical modulator of serotonergic neurotransmission and serotonergically modulated behavior in mice; lack of hyperlocomotion to low dose MDMA in RGS12-null mice is related to an alteration of steady-state SERT expression and 5-HT uptake.

Hypertension is associated with sleep disorders. Spontaneously hypertensive rats are derived from Wistar-Kyoto rats and widely used in research on hypertension. The present study investigated the propensity to sleep and electroencephalographic spectrum changes over 24 hr in spontaneously hypertensive rats, and proposed the involvement of the serotonergic system in these alterations. Time-course analysis showed that spontaneously hypertensive rats exhibit hyperarousal during the light phase but hypersomnia during the dark phase. Spontaneously hypertensive rats also exhibited less slight fluctuation in electroencephalographic delta power density over 24 hr as compared with Wistar-Kyoto rats, suggesting that the accumulation or elimination of sleep pressure was disrupted. Sleep deprivation disrupted the regulation of sleep homeostasis in spontaneously hypertensive rats, reflected by less sleep time and poor sleep quality during the recovery period. The density and activity of serotonergic neurons in the dorsal raphe nucleus were higher in spontaneously hypertensive rats compared with Wistar-Kyoto rats. Interestingly, we observed the absence of fluctuations in 5-hydroxytryptamine and 5-hydroxyindoleacetic acid across the sleep, wake, sleep deprivation and sleep recovery stages in spontaneously hypertensive rats, which were dramatically different from Wistar-Kyoto rats. These results indicate that the disruption of sleep-wake pattern and sleep homeostasis in spontaneously hypertensive rats might be related to abnormalities of the serotonergic system., (© 2019 European Sleep Research Society.)

Purpose: Drug-drug interactions (DDIs) require monitoring in an aging population with increasing polypharmacy exposure. We aimed to estimate the prevalence of exposure to potential DDIs using the French healthcare insurance system database, for six DDIs with various clinical relevance: angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs (ARBs-ACEIs + NSAIDs), antiplatelet agents and NSAIDs (AAP + NSAIDs), serotonergic drugs and tramadol (SD + T), statins and macrolides (S + M), oral anticoagulant and NSAIDs (OAC + NSAIDs), and colchicine and macrolides (C + M)., Methods: We used exhaustive healthcare data from a 1/97th random sample of the population covered by the French health insurance system (EGB) between 2006 and 2016. Exposure to a DDI was defined as overlapping exposure to two interacting drugs. The prevalence of exposure was estimated by year., Results: Prevalence of exposure in 2016 was estimated at 3.7% for ARBs-ACEIs + NSAIDs, 1.5% for AAP + NSAIDs, 0.76% for SD + T, 0.36% for S + M, 0.24% for AOC + NSAIDs, and 0.02% for C + M. In 26% to 58% of episodes of exposure, the two interacting drugs were prescribed by the same physician and dispensed by the same pharmacy the same day. Between 2006 and 2016, the yearly prevalence was increasing for SD + T and for DDIs involving NSAIDs, and it was decreasing for those involving macrolides., Conclusion: Exposures to potential DDIs in France are not uncommon with a high proportion resulting from a co-prescription by the same physician. Monitoring the prevalence of exposure to DDIs is needed to implement prevention measures. Administrative data enable this surveillance in large and representative cohorts.

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , and 5-HT 7 receptors, showed low affinity for off-target receptors (5-HT 2C , H 1 , and α 1 ), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, and DOI-induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Chronic pain is one of the most challenging and debilitating symptoms to manage after traumatic brain injury (TBI), yet the underlying mechanisms remain elusive. The disruption of normal endogenous pain control mechanisms has been linked to several forms of chronic pain and may play a role in pain after TBI. We hypothesized therefore that dysfunctional descending noradrenergic and serotonergic pain control circuits may contribute to the loss of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, weeks to months after TBI. For these studies, the rat lateral fluid percussion model of mild TBI was used along with a DNIC paradigm involving a capsaicin-conditioning stimulus. We observed sustained failure of the DNIC response up to 180-days post injury. We confirmed, that descending α 2 adrenoceptor-mediated noradrenergic signaling was critical for endogenous pain inhibition in uninjured rats. However, augmenting descending noradrenergic signaling using reboxetine, a selective noradrenaline reuptake inhibitor, failed to restore DNIC after TBI. Furthermore, blocking serotonin-mediated descending signaling using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine was also unsuccessful at restoring endogenous pain modulation after TBI. Unexpectedly, increasing descending serotonergic signaling using the selective serotonin reuptake inhibitor escitalopram and the serotonin-norepinephrine reuptake inhibitor duloxetine restored the DNIC response in TBI rats at both 49- and 180- days post injury. Consistent with these observations, spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine eliminated the effects of escitalopram. Intact α 2 adrenoceptor signaling, however, was not required for the serotonin-mediated restoration of DNIC after TBI. These results suggest that TBI causes maladaptation of descending nociceptive signaling mechanisms and changes in the function of both adrenergic and serotonergic circuits. Such changes could predispose those with TBI to chronic pain., Competing Interests: Declaration of Competing Interest No competing financial interests exist., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Since our review of central 5-HT receptors and their function twenty years ago, no new 5-HT receptor has been discovered and there is little evidence that this situation will change in the near future. Nevertheless, over this time significant progress has been made in our understanding of the properties of these receptors and in the clinical translation of this information, and some of these developments are highlighted herein. Such highlights include extensive mapping of 5-HT receptors in both animal and human brain, culminating in readily-accessible brain atlases of 5-HT receptor distribution, as well as emerging data on how 5-HT receptors are distributed within complex neural circuits. Also, a range of important pharmacological and genetic tools have been developed that allow selective 5-HT receptor manipulation, in cells through to whole organism models. Moreover, unexpected complexity in 5-HT receptor function has been identified including agonist-dependent signalling that goes beyond the pharmacology of canonical 5-HT receptor signalling pathways set down in the 1980s and 1990s. This new knowledge of 5-HT signalling has been extended by the discovery of combined signalling of 5-HT and co-released neurotransmitters, especially glutamate. Another important advance has been the progression of a large number of 5-HT ligands through to experimental medicine studies and clinical trials, and some such agents have already become prescribed therapeutic drugs. Much more needs to be discovered and understood by 5-HT neuropharmacologists, not least how the diverse signalling effects of so many 5-HT receptor types interact with complex neural circuits to generate neurophysiological changes which ultimately lead to altered cognitions and behaviour. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT 6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT 6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT 6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT 6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT 6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT 6 receptors with inverse agonists or disrupting the 5-HT 6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Monoaminergic and oxidative dysfunctions have been reported to play a role in depression. The present study investigated the antioxidant potential as well as the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in male Swiss mice. Time and dose-response curves were analyzed with the forced swim (FST) and tail suspension (TST) tests, in which SeBZF1 elicited antidepressant-like effects. Serotonergic mechanisms were investigated in the TST. The pre-administration of WAY100635 (selective 5-HT 1A receptor antagonist, 0.1 mg/kg, subcutaneous route), ketanserin (5-HT 2A/2C receptor antagonist, 1 mg/kg, intraperitoneal route, i.p.), and chlorophenylalaninemethyl ester (p-CPA) (selective tryptophan hydroxylase inhibitor, 100 mg/kg, i.p., for 4 days), but not of ondansetron (selective 5-HT 3 receptor antagonist, 1 mg/kg, i.p.), abolished the antidepressant-like action of SeBZF1 (50 mg/kg, intragastric route, i.g.). Co-administration of sub-effective doses of SeBZF1 (1 mg/kg, i.g.) and fluoxetine (5 mg/kg, i.p., selective serotonin reuptake inhibitor) was effective in producing anti-immobility effects in the TST, revealing a synergistic effect. Besides, p-CPA induced hippocampal oxidative stress, characterized by a reduction of total thiols and lipoperoxidation, which was reversed by SeBZF1 (50 mg/kg). The in vitro screening of the antioxidant action of SeBZF1 in brain tissue reinforced these results. Lastly, SeBZF1 did not cause systemic toxicity at a high dose (300 mg/kg). In summary, the present study demonstrated that SeBZF1 exerted antidepressant-like action in male mice which appears to be mediated by the serotonergic system. Moreover, SeBZF1 elicited in vitro antioxidant action in brain tissue, attenuated the hippocampal oxidative damage induced by 5-HT depletion in mice and showed no toxic signs., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.

The serotonin (5-HT) 6 receptor is a Gs-coupled receptor exclusively expressed in the central nervous system. Highest receptor densities are found in brain regions implicated in mnemonic functions where the receptor is primarily but not exclusively located in the primary cilium of neurons. The 5-HT 6 receptor continues to raise particular interest for neuropharmacologists, given the pro-cognitive effects of antagonists in a wide range of cognitive impairment paradigms in rodents and human. The 5-HT 6 receptor also finely controls key neuro-developmental processes including neuron migration and differentiation. However, its influence upon neurodevelopment and cognition is not solely mediated by its coupling to the Gs-adenylyl cyclase pathway, suggesting alternative signal transduction mechanisms. This prompted studies aimed at characterizing the receptor interactome that identified 125 candidate receptor partners, making the 5-HT 6 receptor one of the G protein-coupled receptors with the most extensively characterized interactome. These studies showed that the receptor localization at the plasma membrane and, consequently, its signal transduction, are finely modulated by several receptor partners. They demonstrated that prefrontal 5-HT 6 receptors engage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT 6 -mTOR pathway in temporal epilepsy. Finally, they revealed that the receptor activates Cdk5 signaling in an agonist-independent manner through a mechanism involving receptor phosphorylation by the associated Cdk5 and highlighted its key role in the migration of neurons and neurite growth. These new receptor-operated signaling mechanisms should be considered in the future development of drugs acting on 5-HT 6 receptors. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'., Competing Interests: Declaration of competing interest The authors declare no competing interest with the present article., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT 1A receptor gene expression, but significantly increased 5-HT 2A receptor gene expression. Furthermore, 5-HT 2A receptor antagonist MDL11939, but not 5-HT 1A receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT 2A receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT 2A receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT 2A receptor-mediated serotonergic effects. Our results suggest that 5-HT 2A receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The assessment of clinical efficacy and toxicity is very important in pharmacology and toxicology. The effects of psychostimulants (e.g. amphetamine), psychotomimetics (e.g. Cannabis sativus) and snake antivenoms are sometimes unpredictable even at lower doses, leading to serious intoxication and fatal consequences. Hence, there is need to re-assess some formulas for calculation of therapeutic index, lethal time and safety margin with a view to identifying therapeutic agents with remarkable toxicity potentials., Results: The therapeutic index formula [Formula: see text] was derived from T 1  = LD 50 /ED 50 and ED 50  = [Formula: see text]. Findings have shown that, therapeutic index is a function of death reversal (s), safety factor (10 -4 ) and weight of animal (Wa). However, the new safety margin formula [Formula: see text] derived from LT 50  = [Formula: see text] and MS = [Formula: see text] shows that safety margin is a function of cube root of ratio between LT 50 and LD 50 and ED 100th . Concentration (k) of toxicant at the receptor [Formula: see text] derived from D 1 × T n  = K and LD 1  = [Formula: see text] shows that therapeutic index, lethal time and safety margin is a function of drug or toxicant concentration at the receptor, the drug-receptor interaction and dose of toxicant or drug administered at a particular time.

Chikungunya virus (CHIKV) is an important reemerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness, chikungunya fever, which is characterized by headache, rash, and debilitating (poly)arthralgia that can reside for months to years after infection. Currently, effective antiviral therapies and vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug 5-nonyloxytryptamine (5-NT) was previously identified as a potential host-directed inhibitor for CHIKV infection. In this study, we determined the mechanism of action by which the serotonin receptor agonist 5-NT controls CHIKV infection. Using time-of-addition and entry bypass assays, we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle, at a step prior to RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and genomic RNA (gRNA) release into the cell cytosol. In addition, we show that the serotonin receptor antagonist methiothepin mesylate (MM) also has antiviral properties toward CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of 5-HT receptors may represent a potent way to limit viral spread and disease severity. IMPORTANCE The rapid spread of mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these infections, including those caused by chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus-host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an antiviral compound, elucidated its mechanism of action, and propose serotonergic drugs as potential host-directed antivirals for CHIKV., (Copyright © 2020 American Society for Microbiology.)

Motor and phonic tics associated with Tourette syndrome (TS) can range in severity from barely perceptible to disabling and most patients have a variety of behavioral co-morbidities, particularly, attention deficit disorder and obsessive compulsive disorder. Therefore, therapy must be tailored to the individual needs of the patients. In addition to behavioral therapy, oral medications such as alpha agonists, dopamine depletors, anti-psychotics, and topiramate are used to control the involuntary movements and noises. Botulinum toxin injections are particularly effective in patients with troublesome focal motor and phonic tics, including coprolalia. Deep brain stimulation may be considered for patients with "malignant" TS, that is, refractory to medical therapy. When appropriate therapy is selected and implemented, most patients with TS can achieve their full potential and lead essentially normal life.

Post-traumatic stress disorder (PTSD) is a severe chronic mental illness that develops in individuals exposed to life-threatening trauma and is characterized by hyperarousal, flashbacks and nightmares. The serotonergic (5-HT) and noradrenergic (NE) systems are deeply involved in the pathogenesis of PTSD. We have previously reported a novel anxiolytic compound, ACH-000029, that modulates 5-HT and α1-adrenergic receptors and induces acute anxiolytic-like effects in rodents. Here, we investigated the potential of ACH-000029 to prevent anxiety-like behavior in the single prolonged stress (SPS) PTSD model. Mice were subjected to the SPS procedure, followed by a 7-day treatment with ACH-000029 and, for comparison, with the α1-adrenergic antagonist prazosin. Animals were behaviorally assessed using social interaction, elevated plus maze and open field tests. Interestingly, treatment with ACH-000029 but not with prazosin ameliorated the SPS-induced sociability impairment and anxiety-like behavior. The brain-wide c-fos mapping, used as a surrogate for brain activity, indicated the brain structures that were altered by SPS and putatively involved in the anxiolytic-like effect of ACH-000029. The SPS protocol produced long-lasting impairment of regions involved in stress-anxiety response, such as the amygdala, prefrontal cortex, globus pallidus and superior colliculus. ACH-000029 treatment reversed the SPS-induced c-fos changes in the globus pallidus, lateral septum and entorhinal cortex and exclusively modulated c-fos levels in subregions from the retrosplenial cortex, cerebellum, superior colliculus and ventromedial hypothalamus. These results support the hypothesis that the dual regulation of 5-HT and α1-adrenergic receptors is required to alleviate PTSD symptoms and suggest a possible role of ACH-000029 as a PTSD treatment., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use., Methods: We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively., Results: Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT 2A/2C antagonist ketanserin., Conclusion: These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA's interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2020. Published by Elsevier B.V.)

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl- DL -p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro- DL -phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Stressful experiences are related to the triggering of anxiety and mood disorders. Tryptophan (amino acid precursor of serotonin synthesis) emerges as important treatment of these disorders. Here, we evaluate the effects of pre-treatment with tryptophan (300 mg/L) and fluoxetine (50 μg/L) in response to acute stress in zebrafish. Overall, acute stress decreased the distance traveled, entries and time in top of tank, as well as increased the cortisol levels, demonstrating an anxiogenic behavior. Tryptophan and fluoxetine prevented anxiogenic effects. This study showed the importance of tryptophan and fluoxetine in the regulation of stress and anxiety-like behavior in adult zebrafish. Collectively, our data support tryptophan effects on stress responses in zebrafish and reinforce the growing utility of this aquatic model to screen CNS therapies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Anxiety disorders are serious and common mental diseases, yet there is still a need for the development of more effective anxiolytics with better safety profiles than benzodiazepines and serotonin reuptake inhibitors. The serotonergic and noradrenergic systems have reciprocal interactions and are intricately related to the pathogenesis of anxiety. In this study, the anxiolytic-like effect of the novel compound ACH-000029, 3-(2-(4-(2-methoxyphenyl) piperazine-1-yl) ethyl) quinazoline-4(3H)-one, is reported. This compound acts at selected serotonergic (5-HT1A and 5-HT1D partial agonism and 5-HT2A antagonism) and α-adrenergic (α-1A, 1B and 1D antagonism) receptors, with good selectivity over other G-protein-coupled receptors. ACH-000029 exhibited high blood-brain barrier permeation and acute anxiolytic effects in the marble burying (MB) and light-dark box (LDB) models of anxiety over the dose ranges of 8-32 mg/kg i.p. and 16-30 mg/kg p.o. The anxiolytic activity was comparable to that observed for serotonin reuptake inhibitors (paroxetine and fluoxetine) and benzodiazepines (alprazolam, diazepam and clobazam). The analysis of the whole-brain c-fos expression following oral dosing showed that ACH-000029 regulated regions highly associated with the processing of environmental stimuli and anxiety behavior, such as the amygdala, paraventricular nucleus of the thalamus, retrosplenial dorsal, pallidum, bed nuclei of the stria terminalis, and locus ceruleus. No safety concerns were identified for ACH-000029 in the functional observational battery up to 50 mg/kg i.p. and in the nonprecipitated withdrawal test up to 30 mg/kg p.o. twice daily for 20 days. This work supports the further development of ACH-000029 as a drug candidate for the treatment of anxiety disorders. The analysis of the in vitro pharmacology and brain regions regulated by this compound may also lead to the exploration of other indications within the psychiatry field., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The transporters for dopamine (DAT) and serotonin (SERT) are important targets in the treatment of psychiatric disorders including major depression, anxiety and attention-deficit hyperactivity disorder. Drugs acting at these transporters can act as inhibitors or as releasers. In addition, it has been recently appreciated that some compounds are less efficacious releasers than amphetamine. Thus, they are classified as partial releasers. Compounds can act on both SERT and DAT or display exquisite selectivity for either SERT or DAT, but the structural basis for selectivity is poorly understood. The trifluoromethyl-substitution of methcathinone in the para-position has been shown to dramatically shift the selectivity of methcathinone (MCAT) towards SERT. Here, we examined MCAT, para-trifluoromethyl-methcathinone (pCF 3 MCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF 3 -substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the pCF 3 group, but not of other substituents with larger van der Waal's volume, lipophilicity or polarity, converted the DAT-selective MCAT into a SERT-selective partial releaser. Electrophysiological and superfusion experiments, together with kinetic modelling, showed that pCF 3 MCAT, but not MCAT, trapped a fraction of SERTs in an inactive state by occupying the S2-site. These findings define a new mechanism of action for partial releasers, which is distinct from the other two known binding modes underlying partial release. Our observations highlight the fact that the substrate permeation pathway of monoamine transporters supports multiple binding modes, which can be exploited for drug design. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'., (Copyright © 2019. Published by Elsevier Ltd.)

G-protein-coupled receptors (GPCRs), also known as 7-transmembrane receptors, are the single largest class of drug targets. Consequently, a large amount of preclinical assays having GPCRs as molecular targets has been released to public sources like the Chemical European Molecular Biology Laboratory (ChEMBL) database. These data are also very complex covering changes in drug chemical structure and assay conditions like c 0 = activity parameter ( K i , IC 50 , etc.), c 1 = target protein, c 2 = cell line, c 3 = assay organism, etc., making difficult the analysis of these databases that are placed in the borders of a Big Data challenge. One of the aims of this work is to develop a computational model able to predict new GPCRs targeting drugs taking into consideration multiple conditions of assay. Another objective is to perform new predictive and experimental studies of selective 5-HTA2 receptor agonist, antagonist, or inverse agonist in human comparing the results with those from the literature. In this work, we combined Perturbation Theory (PT) and Machine Learning (ML) to seek a general PTML model for this data set. We analyzed 343 738 unique compounds with 812 072 end points (assay outcomes), with 185 different experimental parameters, 592 protein targets, 51 cell lines, and/or 55 organisms (species). The best PTML linear model found has three input variables only and predicted 56 202/58 653 positive outcomes (sensitivity = 95.8%) and 470 230/550 401 control cases (specificity = 85.4%) in training series. The model also predicted correctly 18 732/19 549 (95.8%) of positive outcomes and 156 739/183 469 (85.4%) of cases in external validation series. To illustrate its practical use, we used the model to predict the outcomes of six different 5-HT2A receptor drugs, namely, TCB-2, DOI, DOB, altanserin, pimavanserin, and nelotanserin, in a very large number of different pharmacological assays. 5-HT2A receptors are altered in schizophrenia and represent drug target for antipsychotic therapeutic activity. The model correctly predicted 93.83% (76 of 86) experimental results for these compounds reported in ChEMBL. Moreover, [ 35 S]GTPγS binding assays were performed experimentally with the same six drugs with the aim of determining their potency and efficacy in the modulation of G-proteins in human brain tissue. The antagonist ketanserin was included as inactive drug with demonstrated affinity for 5-HT2A/C receptors. Our results demonstrate that some of these drugs, previously described as serotonin 5-HT2A receptor agonists, antagonists, or inverse agonists, are not so specific and show different intrinsic activity to that previously reported. Overall, this work opens a new gate for the prediction of GPCRs targeting compounds.

Background: This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed., Methods: The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose)., Results: We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50)., Conclusions: Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

The vitellogenesis-inhibiting hormone (VIH), also known as gonad-inhibiting hormone, is a neuropeptide hormone in crustaceans that belongs to the crustacean hyperglycemic hormone (CHH)-family peptide. There is regulation vitellogenesis by VIH during gonad maturation in crustaceans. A full-length Scylla olivacea VIH (Scyol-VIH) was identified through reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The open reading frame consists of 378 nucleotides, which encodes a 126-amino acid precursor protein, including a 22-residue signal peptide and a 103-amino acid mature peptide in which 6 highly conserved cysteine residues are present. There was expression of the Scyol-VIH gene in immature female Scylla olivacea in the eyestalk, brain and ventral nerve cord. The Scyol-VIH gene expression was localized to the eyestalk X-organ, brain neuronal clusters 6 and 11, and in multiple neuronal clusters of the ventral nerve cord. The relative abundance of Scyol-VIH mRNA transcript in the eyestalk was relatively greater in immature stage females, then decreased as ovarian maturation progressed. Furthermore, eyestalk Scyol-VIH increased after dopamine (5 μg/g BW) injection. The present research provides fundamental information about Scyol-VIH and its potential effect in controlling reproduction., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct., Competing Interests: The authors have declared that no competing interests exist.

Rodents exhibit natural exploratory behaviors, which can be measured by the spontaneous alternation behavior (SAB) test. Perseverance in this test induced by the 5-hydroxytryptamine 1A receptor (5-HT 1A R) agonist, 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), resembles compulsive behaviors observed in humans and manifests as reduced alternation ratio. This study characterized 8-OH-DPAT-induced perseverance in the SAB test in C57BL/6JOlaHsd male mice by coadministration of WAY100635, citalopram and the 5-HT releasing agent, 3,4-methylenedioxymethamphetamine (MDMA), to deepen the understanding of 5-HT-dependent mechanisms. The 5-HT 1A R mechanism of 8-OH-DPAT (1.0 mg/kg, p < 0.01) on perseverance was confirmed by coadministration of the 5-HT 1A R antagonist, WAY100635 (2.0 mg/kg, p < 0.05), which attenuated the effects of 8-OH-DPAT. Such effects could also be reversed by MDMA (1.0 mg/kg, p < 0.05; 10.0 mg/kg, p < 0.001) but not citalopram. These findings confirm the importance of 5-HT in regulating perseverative behavior. Future investigations are required to determine the predictive validity of the 8-OH-DPAT-disrupted SAB test as an inducible mouse model of compulsivity.

Methylenedioxymethamphetamine (MDMA; ecstasy) is used recreationally and has been investigated as an adjunct to psychotherapy. Most acute effects of MDMA can be attributed to activation of the serotonin (5-hydroxytryptamine [5-HT]) system. Genetic variants, such as single-nucleotide polymorphisms (SNPs) and polymorphic regions in 5-HT system genes, may contribute to interindividual differences in the acute effects of MDMA. We characterized the effects of common genetic variants within selected genes that encode the 5-HT system ( TPH1 [tryptophan 5-hydroxylase 1] rs1800532 and rs1799913, TPH2 [tryptophan 5-hydroxylase 2] rs7305115, HTR1A [5-HT 1A receptor] rs6295, HTR1B [5-HT 1B receptor] rs6296, HTR2A [5-HT 2A receptor] rs6313, and SLC6A4 [serotonin transporter] 5-HTTLPR and rs25531) on the physiological and subjective response to 125 mg of MDMA compared with placebo in 124 healthy subjects. Data were pooled from eight randomized, double-blind, placebo-controlled studies that were conducted in the same laboratory. TPH2 rs7305115, HTR2A rs6313, and SLC6A4 5-HTTLPR polymorphisms tended to moderately alter some effects of MDMA. However, after correcting for multiple comparisons, none of the tested genetic polymorphisms significantly influenced the response to MDMA. Variations in genes that encode key targets in the 5-HT system did not significantly influence the effects of MDMA in healthy subjects. Interindividual differences in the 5-HT system may thus play a marginal role when MDMA is used recreationally or therapeutically.

One of the main limitations of pharmacological fMRI is its inability to provide a molecular insight into the main effect of compounds, leaving an open question about the relationship between drug effects and haemodynamic response. The aim of this study is to investigate the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on functional connectivity (FC) using a novel multimodal method (Receptor-Enriched Analysis of functional Connectivity by Targets - REACT). This approach enriches the resting state (rs-)fMRI analysis with the molecular information about the distribution density of serotonin receptors in the brain, given the serotonergic action of MDMA. Twenty healthy subjects participated in this double-blind, placebo-controlled, crossover study. A high-resolution in vivo atlas of four serotonin receptors (5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 ) and its transporter (5-HTT) was used as a template in a two-step multivariate regression analysis to estimate the spatial maps reflecting the whole-brain connectivity behaviour related to each target under placebo and MDMA. Results showed that the networks exhibiting significant changes after MDMA administration are the ones informed by the 5-HTT and 5-HT 1A distribution density maps, which are the main targets of this compound. Changes in the 5-HT 1A -enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT 2A -enriched maps correlated with the spiritual experience subscale of the Altered States of Consciousness Questionnaire. By enriching the rs-fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, we showed that MDMA effects on FC can be understood through the distribution of its main targets. This result supports the ability of this method to characterise the specificity of the functional response of the brain to MDMA binding to serotonergic receptors, paving the way to the definition of a new fingerprint in the characterization of new compounds and potentially to a further understanding to the response to treatment., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term effects is unclear. Sensitization to certain behavioral drug effects is a common rodent model used to assess long-lasting neurobiological adaptations induced by acute drug treatments. Nine independent experiments were undertaken to investigate if and how mice sensitize to the prosocial effects of MDMA. When treated with 7.8 mg/kg MDMA and paired every other day for a week, MDMA-induced social interaction increased precipitously across treatment sessions. This previously unreported phenomenon was investigated and found to be heavily influenced by a social context and 5-HT 2A R activation. Social sensitization did not appear to develop if mice were administered MDMA in isolation, and pretreatment with MDL100907, a selective 5-HT 2A R antagonist, inhibited the development of social sensitization. However, when MDL100907 was administered to mice that had already been sensitized, it did not attenuate social interaction, suggesting that 5-HT 2A R activity may be necessary for the development of social sensitization but not the expression of MDMA-induced social behavior. Additional investigation is warranted to further explore the phenomenon of social sensitization and to determine the underlying neurobiological mechanisms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Key Points: 5-HT increases the excitability of brainstem and spinal motoneurons, including the jaw-closing motoneurons, by depolarizing the membrane potential and decreasing the medium-duration afterhyperpolarization. In this study, we focused on how 5-HT enhances postsynaptic glutamatergic responses in the dendrites of the jaw-closing motoneurons. We demonstrate that 5-HT augments glutamatergic signalling by enhancing the function of the GluN2A-containing NMDA receptor (NMDAR) through the activation of 5-HT 2A receptors (5-HT 2A Rs) and Src kinase. To enhance glutamatergic responses, activation of the 5-HT 2A Rs must occur within ∼60 μm of the location of the glutamate responses. 5-HT inputs to the jaw-closing motoneurons can significantly vary their input-output relationship, which may contribute to wide-range regulation of contractile forces of the jaw-closing muscles., Abstract: Various motor behaviours are modulated by 5-HT. Although the masseter (jaw-closing) motoneurons receive both glutamatergic and serotonergic inputs, it remains unclear how 5-HT affects the glutamatergic inputs to the motoneuronal dendrites. We examined the effects of 5-HT on postsynaptic responses evoked by single- or two-photon uncaging of caged glutamate (glutamate responses) to the dendrites of masseter motoneurons in postnatal day 2-5 rats of either sex. Application of 5-HT induced membrane depolarization and enhanced the glutamate-response amplitude. This enhancement was mimicked by the 5-HT 2A receptor (5-HT 2A R) agonist and was blocked by the 5-HT 2A/2C R antagonist. However, neither the 5-HT 2B R nor the 5-HT 2C R agonists altered glutamate responses. Blockade of the NMDA receptors (NMDARs), but not AMPA receptors, abolished the 5-HT-induced enhancement. Furthermore, the selective antagonist for the GluN2A subunit abolished the 5-HT-induced enhancement. 5-HT increased GluN2A phosphorylation, while the Src kinase inhibitor reduced the 5-HT-induced enhancement and GluN2A phosphorylation. When exposure to the 5-HT 2A R agonist was targeted to the dendrites, the enhancement of glutamate responses was restricted to the loci of the dendrites near the puff loci. Electron microscopic immunohistochemistry revealed that both the NMDARs and the 5-HT 2A Rs were close to each other in the same dendrite. These results suggest that activation of dendritic 5-HT 2A Rs enhances the function of local GluN2A-containing NMDARs through Src kinase. Such enhancement of the glutamate responses by 5-HT may contribute to wide-range regulation of contractile forces of the jaw-closing muscles., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)