Serotonin System Research Articles

Hot and Cold Cognitive Disturbances in Parkinson Patients Treated with DBS-STN: A Combined PET and Neuropsychological Study.

Patients with Parkinson’s disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how the cerebral 5-HT system associates to disturbances in cognition and mood in PD patients with DBS-STN turned on and off. We used psychological tests and questionnaires to evaluate cognitive function and the effects on mood from turning DBS-STN off. We applied a novel PET neuroimaging methodology to evaluate the integrity of the cerebral serotonin system. We measured 5-HT1BR binding in 13 DBS-STN-treated PD patients, at baseline and after turning DBS off. Thirteen age-matched volunteers served as controls. The measures for cognition and mood were correlated to the 5-HT1BR availability in temporal limbic cortex. 5-HT1BR binding was proportional to working memory performance and inverse proportional to affective bias for face recognition. When DBS is turned off, patients feel less vigorous; the higher the limbic and temporal 5-HT1BR binding, the more they are affected by DBS being turned off. Our study suggests that cerebral 5-HTR binding is associated with non-motor symptoms, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

Exploring Association Between Serotonin and Neurogenesis Related Genes in Obsessive-Compulsive Disorder in Chinese Han People: Promising Association Between DMRT2, miR-30a-5p, and Early-Onset Patients.

Obsessive-compulsive disorder (OCD) is a deliberating disorder with complex genetic and environmental etiologies. Hypotheses about OCD mainly include dysregulated neurotransmitters, especially serotonin, and disturbed neurodevelopment. Single nucleotide polymorphism (SNP) association studies regarding OCD are often met with inconsistent results. However, stratification by age of onset may sometimes help to limit the heterogenicity of OCD patients. Therefore, we conducted a stratified SNP association study enrolling 636 patients and 612 healthy controls. Patients were stratified by age of onset as early-onset (EO-OCD) and late-onset (LO-OCD). Blood extracted from the patients was used to genotype 18 loci, including serotonin system genes, Slitrk1, Slitrk5, and DMRT2 and related miRNA genes. Logistic regression was used to compare allele and genotype frequencies of variants. A general linear model was used to evaluate the association between variants and trait anxiety. In our study, rs3824419 in DMRT2 was associated with EO-OCD, G allele was the risk allele. Rs2222722 in miR-30a-5p was associated with EO-OCD, with the C allele being the risk allele. Rs1000952 in HTR3D was found associated with trait anxiety in OCD patients. The significance disappeared after FDR correction. Our results supported neurodevelopment-related genes, DMRT2 and miR-30a-5p, to be related to EO-OCD. However, we cannot prove serotonin genes to be directly associated with EO-OCD. While an association between HTR3D and trait anxiety was discovered, comparisons based on biological or clinical traits may be helpful in future studies. As our detective powers were limited, more large-scale studies will be needed to confirm our conclusion.

Involvement of the TNF-\u03b1/SATB2 axis in the induced apoptosis and inhibited autophagy of osteoblasts by the antipsychotic Risperidone

BackgroundRisperidone, an atypical antipsychotic, impedes serotonin and dopamine receptor systems. Meanwhile, tumor necrosis factor-α (TNF-α) is known to participate in regulating osteoblast functions. Consequently, the current study aimed to investigate whether the influences of Risperidone on osteoblast functions are associated with TNF-α and special AT-rich sequence-binding protein (SATB2).MethodsFirstly, we searched the DGIdb, MEM and GeneCards databases to identify the critical factors involved in the effects of Risperidone on osteoblasts, as well as their interactions. Afterwards, osteoblast cell line MC3T3-E1 was transduced with lentivirus carrying si-TNF-α, si-SATB2 or both and subsequently treated with Risperidone. Various abilities including differentiation, autophagy and apoptosis of osteoblasts were examined after different treatments. Finally, animal experiments were performed with Risperidone alone or together with lentivirus to verify the function of Risperidone in vivo and the mechanism.ResultsIt was found that Risperidone might promote TNF-α expression, thereby inhibiting the expression of SATB2 to affect the autophagy and apoptosis in osteoblasts. Furthermore, as shown by our experimental findings, Risperidone treatment inhibited the differentiation and autophagy, and promoted the apoptosis of osteoblasts, as evidenced by elevated levels of OPG, p62, cleaved PARP1, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9, and reduced levels of LC3 II/I, Beclin1, collagen I, and RANKL. In addition, Risperidone was also found to elevate the expression of TNF-α to down-regulate SATB2, thereby inhibiting the differentiation and autophagy and enhancing the apoptosis of osteoblasts in vitro and in vivo.ConclusionsCollectively, our findings indicated that Risperidone affects the differentiation of osteoblasts by inhibiting autophagy and enhancing apoptosis via TNF-α-mediated down-regulation of SATB2.

Brain Serotonin Deficiency Increases Susceptibility to Stress‐Induced Increases in Binge Drinking in Females, but not Males

Approximately 30 million Americans currently suffer from alcohol use disorders (AUDs), which cost the US economy over $249 billion annually. Men are more likely than women to have an AUD, but rates of AUDs in women are rising rapidly, and women tend to experience more negative health consequences from excessive alcohol consumption than men. The causes of gender disparities in AUDs and alcohol responses remain unknown, but stress has been associated with the development of AUDs, particularly in women, and genetic factors are thought to increase AUD risk. Although the specific genetic factors that confer AUD risk have not been conclusively established, dysfunction of the brain serotonin (5‐HT) system has been hypothesized to play a role. Based on our published work demonstrating that brain 5‐HT deficiency increases susceptibility to stress, we hypothesized that low brain 5‐HT would predispose animals to excessive alcohol consumption following stress. Our unpublished findings demonstrate that chronic restraint stress increases binge‐like alcohol consumption in the drinking in the dark paradigm in 5‐HT‐deficient females but not in WT females or in males of either genotype. In contrast, in the absence of stress, low 5‐HT increased binge‐like drinking in males only. The precise molecular mechanisms underlying this enhanced susceptibility of 5‐HT‐deficient females to stress‐induced binge drinking have not been conclusively established, but RNA sequencing studies followed by gene ontology enrichment analysis reveals that chronic stress leads to dysregulation of several gene sets involved in serotonin signaling and alcoholism in 5‐HT‐deficient females, but not in WT females. These data provide new insight into the mechanisms through which low 5‐HT impacts stress‐sensitive behaviors in a sex‐dependent manner.

Eating a High Fat Diet Enhances Sensitivity of Rats to 5‐HT1A Receptor‐Mediated Behavioral Effects of Serotonergic Drugs

Diet (e.g., type and amount of food consumed) has been shown to impact drug sensitivity, in ways that might be relevant for the therapeutic effects and side effects of medications. For example, previous studies have demonstrated that rats eating a high fat diet are more sensitive to some of the effects of dopaminergic drugs. Considerably less is known about how eating a high fat diet might impact sensitivity to drugs that act on serotonin (5‐HT) systems, many of which might be beneficial for the treatment of obesity, since they can decrease feeding. Drugs with agonist effects at 5‐HT receptors can produce a collection of adverse effects, known as 5‐HT syndrome. Animal models of 5‐HT syndrome include lower lip retraction, flat body posture, penile erections, and forepaw treading. To test the hypothesis that eating a high fat diet enhances sensitivity of rats to 5‐HT syndrome, male (n=16) and female (n=16) rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) laboratory chow were tested once weekly with cumulative doses of 5‐HT receptor agonists, including 8‐OH‐DPAT (0.01‐1.0 mg/kg, s.c.), lorcaserin (1.0‐32.0 mg/kg, i.p.) and WAY 163909 (1.0‐32.0 mg/kg, i.p.). Agonists were also studied in combination with antagonists selective for 5‐HT1A (WAY 100635; 0.178 mg/kg, s.c.), or 5‐HT2C (SB 242084; 1.0 mg/kg; i.p.) receptors. Food consumption and body weight were measured throughout the study. Results were analyzed using either two‐way or three‐way mixed model ANOVAs with diet and dose, diet and day, or diet, sex, and drug as factors, and Bonferroni post hoc comparisons where appropriate. Effects mediated by the 5‐HT2C receptor (e.g, penile erections as well as decreased food consumption), were only observed following injections of lorcaserin and WAY 163909 (but not 8‐OH‐DPAT), and were not different between rats eating standard or high fat chow. Regarding 5‐HT1A receptor‐mediated effects, all three 5‐HT receptor agonists induced forepaw treading in rats; however, flat body posture and lower lip retraction were only induced by 8‐OH‐DPAT. Rats eating high fat chow were more sensitive to forepaw treading, regardless of which drug induced this behavior; however, WAY 163909 induced less forepaw treading as compared to the other two drugs, regardless of diet. Rats eating high fat chow were also more sensitive to 8‐OH‐DPAT‐induced lower lip retraction, but not flat body posture. These results suggest that eating a high fat diet can impact sensitivity of rats to some of the effects of serotonergic drugs. Additionally, these results demonstrate that while both lorcaserin and WAY 163909 decrease feeding, WAY 163909 produces less 5‐HT1A‐mediated forepaw treading than lorcaserin, which might indicate that it will produce fewer side effects in humans as well. Finally, these results suggest that dietary history could influence sensitivity of individuals to the adverse effects of serotonergic drugs, such as 5‐HT syndrome.

Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy.

Serotonin transporter (5-HTT) binding deficits are reported in major depressive disorder (MDD). However, most studies have not considered serotonin system anatomy when parcellating brain regions of interest (ROIs). We now investigate 5-HTT binding in MDD in two novel ways: (1) use of a 5-HTT tract-based analysis examining binding along serotonergic axons; and (2) using the Copenhagen University Hospital Neurobiology Research Unit (NRU) 5-HT Atlas, based on brain-wide binding patterns of multiple serotonin receptor types. [11C]DASB 5-HTT PET scans were obtained in 60 unmedicated participants with MDD in a current depressive episode and 31 healthy volunteers (HVs). Binding potential (BPP) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [11C]DASB tract, the MDD group showed significantly lower BPP compared with HVs (p = 0.02). This BPP diagnosis difference also significantly varied by tract location (p = 0.02), with the strongest MDD binding deficit most proximal to brainstem raphe nuclei. NRU 5-HT Atlas ROIs showed a BPP diagnosis difference that varied by region (p < 0.001). BPP was lower in MDD in 3/10 regions (p-values < 0.05). Neither [11C]DASB tract or NRU 5-HT Atlas BPP correlated with depression severity, suicidal ideation, suicide attempt history, or antidepressant medication exposure. Future studies are needed to determine the causes of this deficit in 5-HTT binding being more pronounced in proximal axon segments and in only a subset of ROIs for the pathogenesis of MDD. Such regional specificity may have implications for targeting antidepressant treatment, and may extend to other serotonin-related disorders.

Serotonin 5-HT7 receptor overexpression in the raphe nuclei area produces antidepressive effect and affects brain serotonin system in male mice.

Heterodimerization between 5-HT7 and 5-HT1A receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio between 5-HT1A /5-HT7 hetero- and 5-HT1A /5-HT1A homodimers in presynaptic neurons toward 5-HT1A /5-HT1A homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5-HT7 receptor number in presynaptic terminals might restore physiological homo-/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno-associated virus (AAV)-based 5-HT7 receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive-like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5-HT7 receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5-HT7 receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5-HT7 receptor overexpression resulted in the reduction of 5-HT1A receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5-HT7 receptor overexpression caused an increase of 5-HIAA/5-HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5-HT7 receptor overexpression in the raphe nuclei area affects brain 5-HT system and causes antidepressive effect both in C57Bl/6J and in "depressive" ASC male mice. Obtained results indicate the involvement of 5-HT7 receptor in the mechanisms underlying depressive behavior.

Is the chemical imbalance an ‘urban legend’? An exploration of the status of the serotonin theory of depression in the scientific literature

The theory that depression is caused by a serotonin abnormality or other chemical imbalance has become widely accepted by the public and is one prominent justification for the use of antidepressants. However, it has been increasingly questioned and there is little evidence it has empirical support. In response, leading psychiatrists suggested it was an ‘urban legend’ that was never taken seriously by the psychiatric profession. To interrogate these claims, we examined the coverage of the serotonin theory of depression in a sample of highly cited and influential academic literature from 1990, when the theory started to be popularized, to 2010 when these responses were articulated. We analysed 30 highly cited reviews of the aetiology of depression in general, 30 highly cited papers on depression and serotonin specifically and a sample of influential textbooks. The majority of the aetiology reviews supported the hypothesis, including some that were entirely devoted to describing research on the serotonin system, and those that reviewed the aetiology of depression more broadly. Research papers on the serotonin system in depression were highly cited and most of them strongly supported the serotonin theory. All textbooks supported the theory, at least in some sections, and devoted substantial coverage to it, although some also acknowledged it remained provisional. The findings suggest that the serotonin theory was endorsed by the professional and academic community. The theory is compared to an exhausted Kuhnian paradigm with professional equivocation about it acting as a means of defending it against encroaching criticism. The analysis suggests that, despite protestations to the contrary, the profession bears some responsibility for the propagation of a theory that has little empirical support and the mass antidepressant prescribing it has inspired.

The Potential Use of Ebselen in Treatment-Resistant Depression.

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere’s Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium’s anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD.

Additive serotonergic genetic sensitivity and cortisol reactivity to lab-based social evaluative stress: Influence of severity across two samples

Prior work demonstrates that an additive serotonergic multilocus genetic profile score (MGPS) predicts amplified risk for depression following significant life stress, and that it interacts with elevations in the cortisol awakening response to predict depression. The serotonin system and HPA-axis have bidirectional influence, but whether this MGPS predicts acute cortisol reactivity, which might then serve as a mechanism for depression, is unknown. Our prior work suggests that depression risk factors predict blunted cortisol reactivity to explicit negative evaluative lab-based stress. Thus, we hypothesized that a 4-variant serotonergic MGPS (three SNPs from the original 5-variant version plus 5HTTLPR) would predict blunted cortisol reactivity to explicit negative evaluative stress versus a control. In Sample 1, growth curve modeling showed that the MGPS predicted heightened cortisol reactivity (p = 0.0001) in an explicitly negative evaluative Trier Social Stress Test variant (TSST) versus a control condition among non-depressed emerging adults (N = 152; 57% female). In Sample 2, 125 males completed the Socially Evaluative Cold Pressor Test (SECPT), an ambiguously negative evaluative manipulation; findings displayed a similar pattern but did not reach statistical significance (ps.075–.091). A participant-level meta-analysis of the two samples demonstrated a significant effect of negative evaluation severity, such that the MGPS effect size on reactivity increased linearly from control to SECPT to an explicitly negative evaluative TSST. Findings indicate that this MGPS contributes to sensitivity to social threat and that cortisol dysregulation in the context of social stress may be one mechanism by which this MGPS contributes to depression.

Design, Synthesis, and Characterization of a Novel Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor.

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5-HT1A ) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT1A receptor (Ki =1.8 nM). Fluoroprobe 5a was able to label the 5-HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor's role.

A neurobiological perspective on social influence: Serotonin and social adaptation.

Humans are inherently social beings. Being suggestible to each other's expectations enables pro‐social skills that are crucial for social learning and adaptation. Despite their high relevance for psychiatry, the neurobiological mechanisms underlying social adaptation are still not well understood. This review, therefore, provides a conceptual framework covering various distinct mechanisms underlying social adaptation and explores the neuropharmacology — in particular the role of the serotonin (5‐HT) system — in modulating these mechanisms. This article reviews empirical results on social influence processing and reconciles them with recent findings from psychedelic research on social processing to elucidate neurobiological and neuropharmacological underpinnings of social adaptation. Various computational, neurobiological, and neurochemical processes are involved in distinct mechanisms underlying social adaptation such as the multisensory process of social information integration that is crucial for the forming of self‐representation and representations of social norms. This is again associated with self‐ and other‐perception during social interactions as well as value‐based decision‐making that guides our behavior in daily interactions. We highlight the critical role of 5‐HT in these processes and suggest that 5‐HT can facilitate social learning and may represent an important target for treating psychiatric disorders characterized by impairments in social functioning. This framework also has important implications for psychedelic‐assisted therapy as well as for the development of novel treatment approaches and future research directions.

A Computational Model of Hopelessness and Active-Escape Bias in Suicidality.

Currently, psychiatric practice lacks reliable predictive tools and a sufficiently detailed mechanistic understanding of suicidal thoughts and behaviors (STB) to provide timely and personalized interventions. Developing computational models of STB that integrate across behavioral, cognitive and neural levels of analysis could help better understand STB vulnerabilities and guide personalized interventions. To that end, we present a computational model based on the active inference framework. With this model, we show that several STB risk markers - hopelessness, Pavlovian bias and active-escape bias - are interrelated via the drive to maximize one's model evidence. We propose four ways in which these effects can arise: (1) increased learning from aversive outcomes, (2) reduced belief decay in response to unexpected outcomes, (3) increased stress sensitivity and (4) reduced sense of stressor controllability. These proposals stem from considering the neurocircuits implicated in STB: how the locus coeruleus - norepinephrine (LC-NE) system together with the amygdala (Amy), the dorsal prefrontal cortex (dPFC) and the anterior cingulate cortex (ACC) mediate learning in response to acute stress and volatility as well as how the dorsal raphe nucleus - serotonin (DRN-5-HT) system together with the ventromedial prefrontal cortex (vmPFC) mediate stress reactivity based on perceived stressor controllability. We validate the model by simulating performance in an Avoid/Escape Go/No-Go task replicating recent behavioral findings. This serves as a proof of concept and provides a computational hypothesis space that can be tested empirically and be used to distinguish planful versus impulsive STB subtypes. We discuss the relevance of the proposed model for treatment response prediction, including pharmacotherapy and psychotherapy, as well as sex differences as it relates to stress reactivity and suicide risk.

Features of quantitative EEG in children with hyperkinetic disorder

At the basis of numerous mental disorders lies a synaptic transmission impairment that causes metabolic and ionic changes and affects the current functional state of the brain, the reflection of which we find in electroencephalographic examination.Objective of the study: identification of electroencephalographic features in children under conditions of biochemical heterogeneity of hyperkinetic disorder (HD).Material and methods. 404 children aged 6-8 years with HD were divided into three subgroups according to the state of monoamine activity: the 1-st subgroup with a combination of hypofunction of the dopaminergic and hyperfunction of the noradrenergic systems — 120 children, the 2-nd subgroup with a combination of hyperfunction of the noradrenergic system with relative balance dopamine — 136 children, and the 3-d with a combination of hyperfunction of the dopamine and hypofunction of the noradrenergic systems — 148 children. In the selected groups, the serotonin system plays an inhibitory and modulating role in relation to the catecholamine metabolism systems. The control group consisted of 90 children (54 boys and 36 girls). An electroencephalographic study was carried out, where the following ranges and subranges were differentiated: theta rhythm (4–8 Hz) and beta1 rhythm (14–20 Hz). The power ratios of theta — and — beta1 rhythms (theta/beta1) were calculated.Results. It was the serotonin system that turned out to be the determining factor in the neurophysiological characteristics of HD. Moreover, the division into subgroups, based on the biochemical characteristics of children with HD, did not allow us to obtain significant differences. The only feature that globally distinguishes the subgroups from each other was the increase in the theta/beta1 activity index, corresponding to an increase in the tension and activity of the serotonin system from subgroup 1 to 3. The data obtained allow us to assert that the electroencephalographic index theta / beta1 can serve as a marker of inattention in children with hyperkinetic disorder and reflects the established state of imbalance of all monoamine systems, but better characterizes the behavior of the tryptophan system.Conclusion. The data on the relationship between the power of theta/beta1 rhythms in the EEG may indicate the nature of the activity of the serotonin system in prospective studies, providing a personalized approach to the selection of drug therapy in children with HD.

Effects of prenatal opioid and alcohol exposures on immune and serotonin factors in human placenta

PurposeOpioids and alcohol impact critical serotonin (5-HT) function in the developing placenta and fetus through the actions of immune proinflammatory factors. Yet, possible convergent effects of opioids and alcohol on human placental toll-like receptor 4 (TLR4) activation and subsequent 5-HT homeostasis remain entirely unknown. The purpose of this study was to examine the effect of prenatal exposure to opioids with or without prenatal alcohol exposure (PAE) on the expression of key placental immune and serotonin signaling factors in human placental tissue obtained from a well-characterized prospective cohort. MethodsData were collected from a subset of participants enrolled in the prospective pre-birth Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH-1) cohort. Women were recruited and classified into four study groups: 1) PAE (n = 20); 2) those taking medications for opioid use disorder (MOUD; n = 28), 3) concurrent PAE and MOUD (n = 20); and 4) controls (HC; n = 20) based on prospective, repeated self-report, and biomarker analysis. Placenta samples underwent tissue processing to identify mRNA for TLR4, nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), serotonin transporter (SERT), tryptophan hydroxylase (TPH1), indoleamine 2,3-Dioxygenase 1 (IDO) as well as protein concentrations of TLR4, IL-1β, TNF-α, SERT. To consider the association between study group and mRNA/protein expression of our targets, multivariable regression models were developed with inclusion of a priori selected covariates. ResultsThere was a significant negative association between PAE and SERT mRNA (β = −0.01; p < 0.01) and a positive association with TPH1 mRNA expression (β = 0.78; p < 0.05). In addition, there was a negative association between MOUD and TNF-α protein expression (β = −0.12; p < 0.05). ConclusionsThis study provides the first evidence that PAE may inhibit SERT expression while simultaneously promoting increased TPH1 protein expression in human placenta. This may result in increased 5-HT in fetal circulation known to affect neurodevelopment. Our data suggest that opioids and alcohol may disturb the bidirectional, dynamic interaction between the placental immune and serotonin system. Given the implication for brain development and health across the life-span further investigation of these critical mechanisms in well-defined cohorts is required.

The effects of Vilazodone, YL-0919 and Vortioxetine in hemiparkinsonian rats.

Parkinson's disease is a neurodegenerative disease often characterized by motor deficits and most commonly treated with dopamine replacement therapy. Despite its benefits, chronic use of L-DOPA results in abnormal involuntary movements known as L-DOPA-induced dyskinesia. Growing evidence shows that with burgeoning dopamine cell loss, neuroplasticity in the serotonin system leads to the development of L-DOPA-induced dyskinesia through the unregulated uptake, conversion, and release of L-DOPA-derived dopamine into the striatum. Previous studies have shown that coincident 5-HT1A agonism and serotonin transporter inhibition may have anti-dyskinetic potential. Despite this, few studies have explicitly focused on targeting both 5-HT1A and the serotonin transporter. The present study compares the 5-HT compounds Vilazodone, YL-0919, and Vortioxetine which purportedly work as simultaneous 5-HT1A receptor agonists and SERT blockers. To do so, adult female Sprague Dawley rats were rendered hemiparkinsonian and treated daily for two weeks with L-DOPA to produce stable dyskinesia. The abnormal involuntary movements and forehand adjusting step tests were utilized as measurements for L-DOPA-induced dyskinesia and motor performance in a within-subjects design. Lesion efficacy was determined by analysis of striatal monoamines via high-performance liquid chromatography. Compounds selective for 5-HT1A/SERT target sites including Vilazodone and Vortioxetine significantly reduced L-DOPA-induced dyskinesia without compromising L-DOPA pro-motor efficacy. In contrast, YL-0919 failed to reduce L-DOPA-induced dyskinesia, with no effects on L-DOPA-related improvements. Collectively, this work supports pharmacological targeting of 5-HT1A/SERT to reduce L-DOPA-induced dyskinesia. Additionally, this further provides evidence for Vilazodone and Vortioxetine, FDA-approved compounds, as potential adjunct therapeutics for L-DOPA-induced dyskinesia management in Parkinson's patients.

Direct and indirect mechanisms by which the gut microbiota influence host serotonin systems.

Mounting evidence highlights the pivotal role of enteric microbes as a dynamic interface with the host. Indeed, the gut microbiota, located in the lumen of the gastrointestinal (GI) tract, influence many essential physiological processes that are evident in both healthy and pathological states. A key signaling molecule throughout the body is serotonin (5-hydroxytryptamine; 5-HT), which acts in the GI tract to regulate numerous gut functions including intestinal motility and secretion. The gut microbiota can modulate host 5-HT systems both directly and indirectly. Direct actions of gut microbes, evidenced by studies using germ-free animals or antibiotic administration, alter the expression of key 5-HT-related genes to promote 5-HT biosynthesis. Indirectly, the gut microbiota produce numerous microbial metabolites, whose actions can influence host serotonergic systems in a variety of ways. This review summarizes the current knowledge regarding mechanisms by which gut bacteria act to regulate host 5-HT and 5-HT-mediated gut functions, as well as implications for 5-HT in the microbiota-gut-brain axis.

INTER-RELATIONSHIP BETWEEN THE BRAIN-INTESTINE AXIS AND THE SEROTONERGIC MECHANISM IN OBESITY

The enteric nervous system (ENS), communicates with the central nervous system (CNS) in a dynamic and complex fashion, through different pathways forming a bidimensional axis. This balance depends on several factors, between these systems and serotonin synthesis (5 HT). The gut synthesizes about 90% of the serotonin in our body and participates in various functions such as physiological control of the energy balance and maintenance of intestinal homeostasis. However, does serotonin that is synthesized in the gut have any impact on the brain and gut? Knowledge of the relationship between the gut-brain axis and participation of the serotonin system in the control of food intake and satiety in obesity is of great interest and importance, a fascinating and growing field. Objective: To describe and analyze interactions between the Central Nervous System (CNS) and the Enteric Nervous System (ENS), related to the serotonergic mechanism in obesity. Method: A bibliographic review included data from 134 scientific articles published between 2014 and 2021 in the PubMed, SciELO, LILACS, PsycINFO and ISI Web of Knowledge databases. Results and Conclusions: Interactions between the CNS and the ENS show gastrointestinal sensory motor functions. The gut produces around 90% of serotonin in our body. However, serotonin exerts approximately 80% of its action within the gut and most of the body’s 5-HT is secreted into the bloodstream, where it is largely and rapidly eliminated by the liver and lungs. CNS serotonergic neurons are independent from ENS serotonergic neurons and enteroendocrine cells. In addition, the blood-brain barrier is impermeable to serotonin. Therefore, serotonin synthesis in the brain is one of the major mechanisms that control hunger and satiety as well as carbohydrate ingestion, some of the contributing factors in the development of obesity. Integrative medicine represents a change in paradigm from a medical view of hermetically closed compartments to an interdisciplinary view between the brain-gut axis and the serotonin mechanism in obesity.

Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion.

2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1α heterozygosity on cerebral metabolism, in mice, using 14C‐2‐deoxyglucose imaging. We also assess performance in an olfactory‐based discrimination and reversal learning (OB‐DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1α genotype. Our data show that Nrxn1α heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1α +/− mice. Behaviorally, Nrxn1α +/− mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1α +/− mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1α +/− mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1α heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1α +/− mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion.Lay SummaryDeletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1α expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism.

Effect and Mechanism of Catalpol on Behavior in Rats with Post-stroke Depression

<sec><title>Objective</title> To explore the effect of catalpol on the behavior of post-stroke depression rats, and to explore its mechanism from the aspects of behavior, the expression of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in peripheral serum and brain tissue. </sec><sec><title>Methods</title> A total of twenty-four SD rats were randomly divided into model group, catalpol intervention group and sham operation group, with 8 rats in each group. The rats model of post-stroke depression were established by middle cerebral artery occlusion (MCAO) combined with the chronic unpredictable mild stress (CUMS) to induce depression-like behavior. The modeling time was 7 days. After the end of modeling, the open field test was used on the 1st, 4th, and 7th day. The behavior of the rats was evaluated by elevated plus maze measurement. TTC staining was used to detect cerebral infarction volume. The serum and hippocampus levels of 5-HT, NE, and BDNF were measured by enzyme-linked immunosorbent assay. </sec><sec><title>Results</title> Compared with the model group, the number of crossing grid, the number of standing and the total distance moved were significantly increased on the 4th and 7th day after intervention in the open field test, and the differences were significant (<italic>P</italic><0.05). In the elevated plus maze measurement, the OE% and OT% were significantly increased in the catalpol intervention group on the 4th and 7th day after intervention, and the differences were significant (<italic>P</italic><0.05), indicating that the catalpol could significantly increase the spontaneous activity of rats and relieve depression-like behavior. TTC staining showed that the volume of cerebral infarction in the catalpol intervention group was significantly reduced compared with model group (<italic>P</italic><0.05). In the ELISA experiment, compared with the model group, 5-HT and BDNF in the catalpol intervention group were significantly increased on the 4th and 7th day after intervention, and the difference was significant (<italic>P</italic><0.05); there was no significant difference in NE content in the catalpol intervention group on the 4th and 7th day after intervention (<italic>P</italic>>0.05); compared with the model group, the hippocampal 5-HT and BDNF in the catalpol intervention group increased significantly (<italic>P</italic><0.05); there was no significant difference in the content of NE in hippocampus between the catalpol intervention group and the model group (<italic>P</italic>>0.05), indicating that catalpol could increase 5-HT and BDNF levels in rats with post-stroke depression, but did not significantly improve NE. </sec><sec><title>Conclusion</title> Catalpol can improve post-stroke depression, promote the recovery of neurological function, regulate the function of central serotonin system and promote the secretion of BDNF. </sec>