Serotonergic Effects Research Articles

Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.

In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT1D/1A and 5-HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved. Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg-1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control. Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D), whereas the selective 5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT1A/1B/1F, 5-HT2B/2C, 5-HT4, 5-HT5A or 5-HT7) modified these vasoconstrictions. Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenous noradrenaline. In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT1D receptor activation, whereas pre and/or postjunctional 5-HT3 and prejunctional 5-HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.

An Overview of Opioid Prescription Patterns among Non-Opioid Users Following Emergency Department Admission.

The evolving landscape of opioid prescription practices necessitates a comprehensive understanding of emerging patterns, particularly among new opioid users discharged from emergency departments. This study delves into the intricate realm of opioid utilization by elucidating the prevalence of their prescriptions. A retrospective analysis of electronic health records was conducted, including a cohort of 71 patients who received opioid prescriptions upon discharge from emergency departments from 1 January 2022 to 30 June 2022. Demographic characteristics and prescription details were systematically examined. This study illuminates tramadol's prominence, with 84% of prescriptions and a Defined Daily Dose (DDD) morphine equivalent of 60 mg, as the primary choice as a new opioid, a finding that draws attention due to the closely aligned dosages with morphine equivalents. This discovery prompts a critical reassessment of tramadol's therapeutic role, considering its multifaceted nature encompassing serotonergic effects and heightened fall risks. This study advocates for a nuanced and vigilant approach to tramadol prescription, cognizant of its potential risks and therapeutic implications, and highlights the imperative of optimizing data quality and traceability within electronic health records to enhance patient care and facilitate future research endeavors.

Sertraline-Induced Stuttering in an Adolescent with Autism Spectrum Disorder

There is also evidence that stuttering is caused by an adverse reaction to various medications. Antiepileptic drugs, antidepressants, antipsychotics, and methylphenidate have all been linked to drug-induced stuttering. The patient was 13 years old (male) and was diagnosed with autism spectrum disorder, attention deficit hyperactivity disorder, and mild mental retardation. The patient had language development and was able to form sentences of 4-5 words. Atomoxetine 50 mg/day and aripiprazole 15 mg/day treatment was used. Sertraline 50 mg/day treatment was initiated because of repeated questioning, order-symmetry compulsions and repetitive behaviors. Approximately one month after the initiation of sertraline treatment, the patient came for a follow-up visit and it was found that the compulsions of the patient had decreased, but one week after sertraline treatment, it was learned that the patient started to have word blocks, prolongation of words and repetitions during speech. No pathology was found in the examination, hemogram and biochemistry tests, brain MRI and EEG tests. After sertraline treatment was discontinued, the stuttering of the patient gradually decreased and improved within 2 weeks. Both serotonergic and dopaminergic effects of sertraline as well as autism spectrum disorder (white matter anomalies) are thought to contribute to sertraline-induced stuttering.

Insight into differing decision-making strategies that underlie cognitively effort-based decision making using computational modeling in rats.

The rat cognitive effort task (rCET), a rodent model of cognitive rather than physical effort, requires animals to choose between an easy or hard visuospatial discrimination, with a correct hard choice more highly rewarded. Like in humans, there is stable individual variation in choice behavior. In previous reports, animals were divided into two groups-workers and slackers-based on their mean preference for the harder option. Although these groups differed in their response to pharmacological challenges, the rationale for using this criterion for grouping was not robust. We collated experimental data from multiple cohorts of male and female rats performing the rCET and used a model-based framework combining drift diffusion modeling with cluster analysis to identify the decision-making processes underlying variation in choice behavior. We verified that workers and slackers are statistically different groups but also found distinct intra-group profiles. These subgroups exhibited dissociable performance during the attentional phase, linked to distinct decision-making profiles during choice. Reanalysis of previous pharmacology data using this model-based framework showed that serotonergic drug effects were explained by changes in decision boundaries and non-decision times, while scopolamine's effects were driven by changes in decision starting points and rates of evidence accumulation. Modeling revealed the decision-making processes that are associated with cognitive effort costs, and how these differ across individuals. Reanalysis of drug data provided insight into the mechanisms through which different neurotransmitter systems impact cognitively effortful attention and decision-making processes, with relevance to multiple psychiatric disorders.

Role of serotonin, estrogen, and TNF-α in the paroxetine-impaired steroidogenesis and testicular macrophages polarization.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes are still unclear. Paroxetine serotonergic effects in testes were evaluated, focusing on steroidogenesis and the correlation between macrophages population and possible TNF-α-derived oxidative stress. We also verified whether the changes are reversible following treatment interruption. Adult rats received paroxetine (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and malondialdehyde concentrations were measured. To confirm serotonergic and estrogenic effects, Htr1b and Esr1 expressions were analyzed. The daily sperm production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL+ germ cells, M1 (CD68+ ), and M2 (Perls+ ) macrophages were quantified. 17β-HSD7, CYP19A1, NDRG2, oxytocin, TNF-α, and iNOS were evaluated by immunoreactions. Oxytocin and NDRG2 protein levels as well as Tnfa mRNA expression were also analyzed. The Htr1b downregulation in testes confirmed the paroxetine serotonergic effect. The testicular sections showed abnormal ST frequency, ST atrophy and reduction of DSP, LCnu, SC number and Perls+ macrophages. TUNEL+ germ cells and LC were associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 17β-HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF-α and iNOS. Esr1 and Tnfa overexpression and increased number of CD68+ macrophages were also observed together with high nitrite and malondialdehyde levels. Most parameters were not recovered in PG65. Paroxetine serotonergic effect impairs LC steroidogenesis, via aromatization, increasing estrogen/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, and impairing sperm production. Serotonin-estrogen pathways may be responsible for M2/M1 polarization, Tnfa upregulation, and induction of oxidative stress. The unrecovered testicular changes after treatment discontinuation are due to persistent paroxetine serotonin/estrogen effects.

The association between brain serotonin transporter binding and impulsivity and aggression in healthy individuals

The serotonin system plays a critical role in the modulation of impulsive aggression. Although serotonin transporters (SERT) are key in modulating synaptic serotonin levels, few studies have investigated the role of SERT levels in human impulsive aggression. The aim of this study was to investigate whether brain SERT levels are associated with trait impulsive aggression. We included 148 healthy individuals (mean age 29.3 ± 13.0, range 18–80 years, 91 females) who had undergone positron emission positron (PET) examinations with the SERT tracer [11C]DASB and filled in self-report questionnaires of trait aggression, trait impulsivity and state aggression. We evaluated the association between cerebral SERT binding (BPND) and trait impulsive aggression in a latent variable model, with one latent variable (LVSERT) modelled from SERT BPND in frontostriatal and frontolimbic networks implicated in impulsive aggression, and another latent variable (LVIA) modelled from various trait measures of impulsivity and aggression. The LVSERT was not significantly associated with the LVIA (p = 0.8). Post-hoc univariate analyses did not reveal any significant associations between regional SERT levels and trait aggression, trait impulsivity or state aggression, but we found that state aggression at the day of PET scan was significantly lower in LA/LA homozygotes vs S-carriers of the 5-HTTLPR gene (p = 0.008). We conclude that brain SERT binding was not related to variations in trait impulsive aggression or state aggression. Our findings do not support that SERT is involved in mediating the serotonergic effects on aggression and impulsivity, at least not in individuals with non-pathological levels of impulsive aggression.

Receptor-specific contributions of caveolae, PKC, and Src tyrosine kinase to serotonergic and adrenergic regulation of Kv channels and vasoconstriction

AimsCaveolae are invaginated, Ω-shaped membrane structures. They are now recognized as portals for signal transduction of multiple chemical and mechanical stimuli. Notably, the contribution of caveolae has been reported to be receptor-specific. However, details of how they differentially contribute to receptor signaling remain unclear. Main methodsUsing isometric tension measurements, patch-clamping, and western blotting, we examined the contribution of caveolae and their related signaling pathways to serotonergic (5-HT2A receptor-mediated) and adrenergic (α1-adrenoceptor-mediated) signaling in rat mesenteric arteries. Key findingsDisruption of caveolae by methyl-β-cyclodextrin effectively blocked vasoconstriction mediated by the 5-HT2A receptor (5-HT2AR), but not by the α1-adrenoceptor. Caveolar disruption selectively impaired 5-HT2AR-mediated voltage-dependent K+ channel (Kv) inhibition, but not α1-adrenoceptor-mediated Kv inhibition. In contrast, both serotonergic and α1-adrenergic effects on vasoconstriction, as well as Kv currents, were similarly blocked by the Src tyrosine kinase inhibitor PP2. However, inhibition of protein kinase C (PKC) by either GO6976 or chelerythrine selectively attenuated the effects mediated by the α1-adrenoceptor, but not by 5-HT2AR. Disruption of caveolae decreased 5-HT2AR-mediated Src phosphorylation, but not α1-adrenoceptor-mediated Src phosphorylation. Finally, the PKC inhibitor GO6976 blocked Src phosphorylation by the α1-adrenoceptor, but not by 5-HT2AR. Significance5-HT2AR-mediated Kv inhibition and vasoconstriction are dependent on caveolar integrity and Src tyrosine kinase, but not on PKC. In contrast, α1-adrenoceptor-mediated Kv inhibition and vasoconstriction are not dependent on caveolar integrity, but rather on PKC and Src tyrosine kinase. Caveolae-independent PKC is upstream of Src activation for α1-adrenoceptor-mediated Kv inhibition and vasoconstriction.

Comparative Effect between Antidepressants and D-phenylalanine, a Phenethylamine Precursor, in an Animal Model of Depression

A relevant role has been attributed to phenethylamine in depressive disorders. It has been measured in human urine and rat brain in pathological conditions and after drug administration. Furthermore, a clinical correlation has been proposed between urinary elimination and depressive symptoms. Furthermore, its metabolic predecessor, D-phenylalanine, has been used as an antidepressant drug in the treatment of depressive disorders. The use of this amino acid has been realized alone, or in combination with classical antidepressants. In the present study, we tried to characterize its behavioural profile comparing it with imipramine and fluoxetine. Antidepressant drugs have been studied using diverse animal models. We used here the Porsolt test, or Forced Swimming Test (FST), measuring times of climbing, swimming and resting. When a comparison was performed between groups in climbing behaviour, significant differences were observed between imipramine treated group and saline controls (p < 0.05), and imipramine versus fluoxetine and D-phenylalanine (p < 0.01). When swimming was evaluated, clear differences between D-phenylalanine and the other groups were observed (p < 0.001). Additionally, a significant difference was also observed between imipramine and fluoxetine (p < 0.01). When resting was evaluated, high differences between D-phenylalanine versus all other groups were shown (p < 0.001). Observed behavioural profile was according to serotonergic antidepressant drugs effects. It is supported by the fact that swimming behaviours were increased, and a correlative decrease in resting was also present. We conclude that D-phenylalanine showed higher antidepressant potency than other classical antidepressants, at least at the doses used.

Pharmacological Risk Assessment Among Older Patients with Polypharmacy Using the Clinical Decision Support System Janusmed Risk Profile: A Cross-Sectional Register Study.

Polypharmacy in older people is steadily increasing and a combination of many medicines may result in adverse effects, especially if the medicines interact pharmacodynamically. Examples are additive or synergistic effects increasing the risk of falls, haemorrhage, serotonin syndrome and torsade de pointes. The clinical decision support system Janusmed Risk Profile has been developed to find such risks based on a patients' medication list. The main aim of this retrospective register-based study was to study what pharmacodynamic risks older patients (aged 65 years or older) on polypharmacy (defined as using five or more medicines) are exposed to. Second, we studied if the introduction of the Janusmed Risk Profile in the main electronic health record system in Region Stockholm influenced the proportion of patients prescribed combinations that increase the risk for the nine adverse-effect categories defined (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonin syndrome). Data on all prescription medicines to individuals aged 65 years or older, and with at least five concomitant medicines were retrieved and analysed for the risk categories in the Janusmed Risk Profile. The proportions of patients with a high/moderate risk during a 4-month period before (period 1) and after (period 2) the introduction were compared. A total of 127,719 patients in period 1 (November 2016-February 2017), and 131,458 patients in period 2 (November 2017-February 2018) were included in the study. The proportion of patients with a high or moderate risk for each of the nine properties (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonergic effects) were 10.9, 34.7, 32.8, 33.6, 17.2, 0.7, 15.4, 0.5 and 2.4%, respectively, in period 1 and 10.4, 35.5, 32.8, 33.3, 10.8, 0.71, 14.9, 0.5 and 2.3% in period 2. The changes for sedation and QT prolongation were statistically significant, with the most pronounced decrease for QT prolongation from 17.2 to 10.8% (p < 0.001). When analysing patients at a high risk, the decrease was significant for haemorrhage, orthostatism, QT prolongation and sedation. Older people are exposed to combinations of medications that increase the risk for potentially severe adverse effects. Prescribers seem to respond especially to warnings for QT prolongation, presented in the Janusmed Risk Profile implemented in the electronic health record system.

Characterization of Viloxazine Effects on Cortical Serotonin Neurotransmission at Doses Relevant for ADHD Treatment

AbstractIntroductionMost ADHD treatments are thought to be effective due to augmentation of dopamine (DA) and norepinephrine (NE). Our prior preclinical studies found that the ADHD treatment, viloxazine, may augment serotonin (5-HT) in addition to NE and DA; however, it was unclear if these effects occurred at clinically relevant concentrations. To further understand these potential 5-HT effects, we conducted a series of experiments with two objectives: 1) Can we confirm and better elucidate the previously observed serotonergic effects of viloxazine and determine if they occur at clinically relevant concentrations? 2) Are these effects observed in species with close physiology to humans?MethodsObjective 1: The affinity of viloxazine for human isoforms of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors was assessed via cell-based binding assays. Viloxazine agonism of 5-HT2C and antagonism at 5-HT7 was elucidated with IP1, Ca2+, β-arrestin, internalization, and cAMP assays in cells expressing human receptor isoforms. A microdialysis study was conducted in rats to determine the relationship between viloxazine concentrations in the interstitial fluid (ISF) and changes in NE, DA, 5-HT, and their metabolite concentrations in the prefrontal cortex (PFC). Objective 2: A PET imaging study using a 5-HT2A/2C radioligand agonist, [11C]CIMBI-36, is being conducted in non-human primates (NHPs) to evaluate if viloxazine binds these receptors and/or increases 5-HT release.Animal research was approved by animal care and use committees. Animals were cared for according to international standards.ResultsObjective 1: Cell-based assays to measure viloxazine affinity for NET, 5-HT2B, 5-HT2C, and 5-HT7 found Ki values of 0.14, 0.65, 0.84, 1.90 μM respectively. These values were lower than therapeutically relevant rat ISF concentrations (3.5 ± 1.6 μM) approximating pediatric ADHD patients unbound plasma concentrations (2.1-3.3 μM), indicating receptor recruitment. Binding affinity and functional activity assays found viloxazine had negligible activity for 5-HT2A and SERT at therapeutic concentrations. Viloxazine 5-HT2C agonism activated Gq-protein signaling (EC50=1.6 μM, Ca2+ assay), but not β-arrestin or internalization pathways (EC50 values &gt;150 μM). Viloxazine 5-HT7 antagonism decreased Gs-protein signaling (IC50 =6.7 μM). The microdialysis study found that at therapeutically relevant ISF concentrations, 5-HT levels were significantly increased over baseline; no changes were seen in the 5-HIAA metabolite, indicating 5-HT increase is not due to 5-HT reuptake inhibition. Objective 2: PET imaging studies are ongoing.ConclusionsTo date, our experiments to further elucidate the potential 5-HT effects of viloxazine have shown that the previously observed effects of viloxazine on 5-HT receptors and its augmentation of 5-HT in rat PFC occur at clinically relevant concentrations. Further exploration is needed to ascertain if these effects occur in NHPs and are relevant to ADHD.FundingSupernus Pharmaceuticals, Inc.

Is the most really the best: a review for the most selective SSRI concept three decades later

IntroductionPharmaceutical slogans presuming a particular antidepressant molecule being the best solely based on a core concept could be proved “not accurate” especially following patients’ actual exposure to the antidepressant for longer than the usual six or twelve weeks’ trialsObjectivesReviewing the current situations of SSRI induced anhedonia recognition and its management. Distinguishing anhedonia as a core symptoms of depression from SSRI induced anhedonia and the combination of both.MethodsReview of literatures including theses related to the same topicResultsResearch suggests that, SSRIs might be more effective at treating some symptoms than others. More specifically, it has been suggested that, SSRIs might be more effective at improving symptoms such as low mood and anxiety but not anhedonia (Argyropoulos et al. psych.pharmaology, 2013; 27(10), 869-877). It has been proposed that, catecholaminergic antidepressants might be more effective treatments for anhedonia and emotional blunting in MDD than SSRIs (McCabe et al. Biological psychiatry, 2010; 67(5), 439–445. The primary effect of SSRIs is reduced processing of negative stimuli rather than increased positive stimuli. Emotional blunting is related to SSRI dose and possibly serotonergic effects on the frontal lobes and/or serotonergic modulation of midbrain dopaminergic systems projecting to the prefrontal cortex (PFC). By enhancing serotonergic transmission, SSRIs can activate the inhibitory Gamma Aminobutyric Acid (GABA) interneurons, thereby dampening the noradrenergic and dopaminergic input ( Blier. Int J Neuropsychopharmacol., 2014; 17:997–1008).Management of SSRI induced anhedonia includes lowering the current SSRI dose. Adding non SSRI antidepressant to the current SSRI dose or to a lowered SSRI dose. Gradual discontinuation of the SSRI and switching to another antidepressant with a different profile (SNRI) that might improve the patient’s emotional response (Koenigs. Behav Brain Res., 2009;201:239–43).Bupropion is an antidepressant with less possibility to give rise to emotional blunting. (Tomoko et al. Neuroscience Letters., 2021; 749, 135716. agomelatine(Thome et al. Journal of neural transmission., 2015; 122(1), 3-7.Vortioxetine and others (Bing et al. frontiers in psychiatry., Jan, 2019; 10-17. are of inrerest in this regard.Image 2:ConclusionsThe most selective SSRI concept assumes that most selective means less affinity to other receptors or secondary binding sites which might suggest less side effects and perhaps being the most efficacious. Not only serotonin but multiple neurotransmitters are in action at the downstream part of a cascade of events underpinning the etiology of MDD. MDD has heterogeneous etiology and this explains why patients respond differently. SSRI induced anhedonia could be tackled and we need to explore how many patients would benefit from that now and have not yet.Disclosure of InterestNone Declared

Venlafaxine increases aromatization, reduces apical V-ATPase in clear cells and induces increased number of mast cells and smooth muscle cells death in rat cauda epididymis

Depressive disorders (DD) have affected millions of people worldwide. Venlafaxine, antidepressant of the class of serotonin and norepinephrine reuptake inhibitors, has been prescribed for the treatment of DD. In rat testes, venlafaxine induces testosterone (T) aromatization and increases estrogen levels. Aromatase is a key enzyme for the formation of estrogen in the epididymis, an essential organ for male fertility. We investigated the impact of serotonergic/noradrenergic venlafaxine effect on the epididymal cauda region, focusing on aromatase, V-ATPase and EGF epithelial immunoexpression, smooth muscle (SM) integrity and mast cells number (MCN). Male rats were distributed into control (CG; n = 10) and venlafaxine (VFG, n = 10) groups. VFG received 30 mg/kg b.w. of venlafaxine for 35 days. The epididymal cauda was processed for light and transmission electron microscopy (TEM). The expression of connexin 43 (Cx43) and estrogen alpha (Esr1), adrenergic (Adra1a) and serotonergic (Htr1b) receptors were analyzed. Clear cells (CCs) area, SM thickness, viable spermatozoa (VS) and MCN were evaluated. Apoptosis was confirmed by TUNEL and TEM. The following immunoreactions were performed: T, aromatase, T/aromatase co-localization, V-ATPase, EGF, Cx43 and PCNA. The increased Adra1a and reduced Htr1b expressions confirmed the noradrenergic and serotonergic venlafaxine effects, respectively, corroborating the increased MCN, apoptosis and atrophy of SM. In VFG, the epithelial EGF increased, explaining Cx43 overexpression and basal cells mitotic activity. T aromatization and Esr1 downregulation indicate high estrogen levels, explaining CCs hypertrophy and changes in the V-ATPase localization, corroborating VS reduction. Thus, in addition to serotonergic/noradrenergic effects, T/estrogen imbalance, induced by venlafaxine, impairs epididymal structure and function.

The role of extracellular serotonin and MDMA in the sensitizing effects of MDMA

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.

Evidence for anti-inflammatory effects and modulation of neurotransmitter metabolism by Salvia officinalis L.

BackgroundCognitive health is of great interest to society, with neuroinflammation and systemic inflammation age-related risk factors that are linked to declines in cognitive performance. Several botanical ingredients have been suggested to have benefits in this area including Salvia officinalis (sage), which has shown anti-inflammatory effects and exhibited promising cognitive improvements in multiple human studies. The current study demonstrates anti-inflammatory effects for S. officinalis across a broad set of in vitro models in human cells, and adds further evidence to support modulation of acetylcholine and monoamine neurostransmitter levels as mechanisms that contribute towards the benefits of the herb on cognitive health.MethodsThe effect of S. officinalis extract on release of multiple cytokines and chemokines was measured in human primary intestinal epithelial cells treated with or without LPS stimulation, and Blood Brain Barrier (BBB) cells in presence or absence of recombinant IL-17A and/or Human IL-17RA/IL-17R Antibody. Antioxidant effects were also assessed in BBB cells incubated with the extract and H2O2. The anti-inflammatory effects of S. officinalis extract were further assessed based on clinically-relevant biomarker readouts across 12 human primary cell-based disease models of the BioMAP Diversity PLUS panel.ResultsS. officinalis showed significant attenuation of the release of most cytokines/chemokines into apical media in LPS-stimulated intestinal cells, but small increases in the release of markers including IL-6, IL-8 in basolateral media; where TNF-α was the only marker to be significantly reduced. S. officinalis attenuated the release of CRP and VCAM-1 from BBB cells under IL-17A induced conditions, and also decreased H2O2 induced ROS overproduction in these cells. Phenotypic profiling with the BioMAP Diversity PLUS Panel identified additional anti-inflammatory mediators, and based on a similarity search analysis suggested potential mechanistic similarity to caffeic acid and drugs known to inhibit COMT and MAO activity to modulate monoamine metabolism. Subsequent in vitro assessment showed that S. officinalis was able to inhibit the activity of these same enzymes.ConclusionsS. officinalis extract showed anti-inflammatory effects across multiple human cell lines, which could potentially reduce peripheral inflammation and support cognitive health. S. officinalis extract also showed the ability to inhibit enzymes related to the metabolism of monoamine neurotransmitters, suggesting possible dopaminergic and serotonergic effects acting alongside proposed cholinergic effects to mediate acute cognitive performance benefits previously demonstrated for the extract.

Selective serotonin reuptake inhibitors and lung function in the multi-ethnic study of atherosclerosis lung study

ObjectiveDepression in patients with Chronic Obstructive Pulmonary Disease (COPD) has been shown to be chronic and potentially increase the burden of symptoms. Selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory and serotonergic effects that may improve lung function. We hypothesized that participants taking SSRIs have better lung function than those not taking SSRIs. The dataset was the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Use of SSRIs was assessed by medication inventory; spirometry was conducted following standard guidelines; dyspnea ratings were self-reported. ResultsContrary to our hypothesis, FEV1 was lower, and odds of dyspnea were higher among participants taking SSRIs as compared with those not taking an antidepressant; these differences persisted even with control for potential confounders including depressive symptoms. We found no evidence of a beneficial association between SSRI use and lung function or dyspnea in a large US-based cohort.

Decrease in Salivary Serotonin in Response to Probiotic Supplementation With Saccharomyces boulardii in Healthy Volunteers Under Psychological Stress: Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial

BackgroundBacterial probiotics are thought to exert a serotonergic effect relevant to their potential antidepressant and pro-cognitive action, but yeast probiotics have not been tested. The aim of the present study was to determine whether 30-day supplementation with Saccharomyces boulardii affects the level of salivary serotonin under psychological stress and identify the factors associated with it.MethodsHealthy medical students were randomized to ingest Saccharomyces boulardii CNCM I-1079 or placebo before a stressful event. Salivary serotonin concentration was assessed before and at the end of supplementation. Moreover, obtained results were compared to psychological, biochemical, physiological and sociodemographic study participants data.ResultsData of thirty-two participants (22.8 ± 1.7 years of age, 16 males) was available for the main analysis. Supplementation with Saccharomyces boulardii decreased salivary serotonin concentration under psychological stress by 3.13 (95% CI 0.20 to 6.07) ng/mL, p = 0.037, as compared to placebo. Salivary serotonin was positively correlated with salivary metanephrine (β = 0.27, 95% CI 0.02 to 0.52, p = 0.031) and pulse rate (β = 0.28, 95% CI 0.05 to 0.50, p = 0.018), but insignificantly with anxiety, depression, eating attitudes and information retrieval.Conclusions Saccharomyces boulardii CNCM I-1079 may be distinct from bacterial probiotics in its salivary serotonergic effect, which appears positively linked to symapathoadrenal markers. The study requires cautious interpretation, and further investigation.

«Золотой выстрел» в лечении и диагностике шизофрении: психиатры или нейробиологи?

The available published data indicate that antagonism towards D2 receptors of dopamine is a «necessary condition» in the process of effective treatment of schizophrenia, but at the same time, this antagonism is insufficient to achieve a state of complete remission. These data serve as a powerful stimulus for the process of searching new treatments and synthesizing new drugs. The current status of the theory of neural networks demonstrates to the professional community that in order to effectively change the functioning of basic biological systems, a number of subtle changes in the central nervous system are required, which are possible with the use of certain substances. The influence of modulation of glutamate on these processes is currently a very «popular» direction both in neurobiology and in clinical psychiatry. At the same time, the role of the latter in the pathogenesis of a number of mental disorders remains unproven. In parallel with this direction, the mechanisms of serotonergic and cholinergic effects on the main components of the pathogenesis of mental disorders are being studied and used in the development of new antipsychotic drugs. Most antipsychotic drugs which belong to «new wave» exhibit an affinity for different types of receptors, which mediate the effect on several therapeutic targets. In practice, a large number of patients take certain drugs not only as monotherapy, but often combine them with other drugs. At the same time, the effectiveness of such therapeutical regimens is low. Therefore, in most modern protocols, monotherapy is still recommended. In recent years, there has been a growing body of research on pharmacotherapy augmentation strategies. The results of these studies demonstrate that augmentation preparations belonging to different pharmacological classes can be generally effective, not only in certain diseases, but also in certain types of patients. In attempts to create a model of «rational polypharmacy», it is very important to accurately define and target the therapy to «problematic symptoms», and it is also necessary to develop an optimal withdrawal strategy from the active therapy regimen. To date, the only existing «lifeline» is Clozapine, which, despite its many disadvantages, remains an effective therapeutic agent for resistant forms of schizophrenic spectrum disorders. New methods of drug synthesis, including «individual drug affinity» analysis and strategies based on the study of gene polymorphism, look promising in the context of antipsychotic drug development. It is unlikely that there will be a «golden shot» for the schizophrenic spectrum disorders in the coming decades, both in terms of diagnostics and treatment. There is a hope that some of the strategies currently being developed (polypharmacy, augmentation), along with new antipsychotic drugs entering the pharmaceutical market, will ultimately become the «shot» that the professional community, patients and their families are looking forward to.

Blockade of 5-HT2 receptors suppresses rate of torque development and motor unit discharge rate during rapid contractions.

Serotonin (5-HT) is a neuromodulator that is critical for regulating the excitability of spinal motoneurons and the generation of muscle torque. However, the role of 5-HT in modulating human motor unit activity during rapid contractions has yet to be assessed. Nine healthy participants (23.7 ± 2.2 yr) ingested 8 mg of the competitive 5-HT2 antagonist cyproheptadine in a double-blinded, placebo-controlled, repeated-measures experiment. Rapid dorsiflexion contractions were performed at 30%, 50%, and 70% of maximal voluntary contraction (MVC), where motor unit activity was assessed by high-density surface electromyographic decomposition. A second protocol was performed where a sustained, fatigue-inducing dorsiflexion contraction was completed before undertaking the same 30%, 50%, and 70% MVC rapid contractions and motor unit analysis. Motor unit discharge rate (P < 0.001) and rate of torque development (RTD; P = 0.019) for the unfatigued muscle were both significantly lower for the cyproheptadine condition. Following the fatigue inducing contraction, cyproheptadine reduced motor unit discharge rate (P < 0.001) and RTD (P = 0.024), whereas the effects of cyproheptadine on motor unit discharge rate and RTD increased with increasing contraction intensity. Overall, these results support the viewpoint that serotonergic effects in the central nervous system occur fast enough to regulate motor unit discharge rate during rapid powerful contractions.NEW & NOTEWORTHY We have shown that serotonin activity in the central nervous system plays a role in regulating human motor unit discharge rate during rapid contractions. Our findings support the viewpoint that serotonergic effects in the central nervous system are fast and are most prominent during contractions that are characterized by high motor unit discharge rates and large amounts of torque development.

Особенности применения ламотриджина в современном лечении эпилепсии

Более 70 млн человек во всем мире страдают от эпилепсии — обременительного неврологического заболевания, которое может влиять на продолжительность жизни и приводить к инвалидности. Ламотриджин — это современный противоэпилептический препарат второго поколения. По сравнению с препаратами первого поколения (фенобарбитал, фенитоин, примидон, карбамазепин, вальпроат) он отличается меньшим количеством побочных эффектов и лучшей переносимостью. Основной механизм действия ламотриджина связан с блокированием натриевых каналов. К тому же известно его влияние на кальциевые каналы, ГАМКергические, серотонинергические эффекты. Комплексный механизм действия обусловливает широкий спектр показаний при эпилепсии, то есть возможно купирование как генерализованных, так и фокальных приступов. Ламотриджин отличается линейной фармакокинетикой. Он быстро и хорошо всасывается при приеме внутрь: общая биодоступность при пероральном приеме составляет 98 %, максимальная концентрация в плазме крови достигается через 1–3 ч после приема. На сегодня ламотриджин имеет убедительно доказанную эффективность как противоэпилептический препарат (как в монотерапии, так и в составе комбинированной терапии) при первично-генерализованных тонико-клонических, простых и сложных парциальных, вторично-генерализованных припадках, абсансах и атипичных абсансах, миоклонических приступах, а также при синдроме Леннокса — Гасто у пациентов в возрасте 2 лет и старше. Не менее важно и то, что ламотриджин также эффективен при ассоциированных с эпилепсией психических нарушениях: эпилептической депрессии, эпилептической дисфории, эпилептических психозах, психомоторных и соматовегетативных эквивалентах приступов. Итак, ламотриджин является одним из новейших противоэпилептических препаратов, который эффективно применяется при лечении эпилепсии у детей и взрослых.

Patient with pain and depression – practical therapeutic implications

Depression and pain are often coexisting phenomena, and the relationship between both phenomena is two-way – the occurrence of depression increases the risk of pain, and both acute and chronic pain increase the risk of depression. Pain may be part of the clinical picture of depression, be a result of comorbid psychiatric disorders, be associated with comorbidities, be a chronic pain syndrome, or be a complication of pharmacotherapy. The comorbidity of pain and depression is associated with a worse prognosis, lower therapeutic response, lower quality of life, impaired functioning, and a greater risk of relapse and suicide. There are indications that the same structures and neurotransmitters are involved in the pathophysiology of pain and depression, which may explain the coanalgesic effect of some antidepressants. The drugs with the best proven effectiveness are serotonin and noradrenaline reuptake inhibitors (especially duloxetine) and amitriptyline. Other drugs that may be of use in the treatment of pain are mirtazapine, mianserin, trazodone, agolemelatine, bupropion, and moclobemide. Selective serotonin reuptake inhibitors are used primarily in the treatment of depression symptomatic pain, but there is little evidence that they are effective in other types of pain. The use of certain psychotropic drugs, incl. SSRIs, clomipramine, benzodiazepines, Z drugs, and anticholinergics may be associated with increased pain. Caution is required when using polypharmacy in the form of a combination of an antidepressant and an analgesic because of the risk of worsening side effects or loss of treatment effectiveness. In the case of opioid drugs, in particular tramadol, the combination with drugs with a serotonergic effect may be associated with the risk of serotonin syndrome.