Serotonin System Research Articles

Effects of lateral ventricle injection of 5,7-dihydroxytryptamine on neurons in the medial prefrontal cortex of rats: An electrophysiology study

The medial prefrontal cortex (mPFC) is closely associated with various psychopathologies in humans, and its dysfunction is invariably accompanied by abnormalities in the serotonin (5-hydroxytryptamine, 5-HT) system of the brain. In this study, in-vivo extracellular recording techniques were used to investigate changes in the excitability of pyramidal neurons and interneurons in the rat mPFC following injection of 5,7-dihydroxytryptamine (5,7-DHT) into the bilateral lateral ventricles to damage the serotoninergic neurons. The levels of 5-HT in the mPFC and dorsal raphe nucleus of rats were determined by high-performance liquid chromatography. The results showed that the levels of 5-HT were significantly reduced in the mPFC and dorsal raphe nucleus two weeks after injection of 5,7-DHT into the bilateral lateral ventricles, relative to the normal group. The discharge frequency of pyramidal neurons in the mPFC was markedly increased compared to the normal group, with a significant rise in burst discharge, while the average discharge frequency of interneurons was significantly reduced and tended towards irregular activity. The results of the study indicated that the brain’s 5-HT neurotransmitter system not only directly affects the activity of mPFC pyramidal neurons but also modulates the electrical activity of interneurons, thereby regulating the local microcircuitry within the mPFC and participating in its function

Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain

Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in female mice. PerspectiveThis article presents novel mechanisms testosterone’s protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain.

Anxiolytic-like effects of acute serotonin-releasing agents in zebrafish models of anxiety: experimental study and systematic review.

Though commonly used to model affective disorders, zebrafish display notable differences in terms of the structure and function of the brain serotonin system, including responses to pharmacological interventions, as compared to mammals. For example, elevation of brain serotonin following acute administration of serotonin reuptake inhibitors (SRIs) generally has anxiogenic effects, both in the clinical situation and in rodent models of anxiety, but previous research has indicated the opposite in zebrafish. However, several issues remain unresolved. We conducted a systematic review of SRI effects in zebrafish models of anxiety and, on the basis of these results, performed a series of experiments further investigating the influence of serotonin-releasing agents on anxiety-like behaviour in zebrafish, with sex-segregated wild-type animals being administered either escitalopram, or the serotonin releaser fenfluramine, in the light-dark test. In the systematic review, we find that the available literature indicates an anxiolytic-like effect of SRIs in the novel-tank diving test. Regarding the light-dark test, most studies reported no behavioural effects of SRIs, although the few that did generally saw anxiolytic-like responses. In the experimental studies, consistent anxiolytic-like effects were observed with neither sex nor habituation influencing treatment response. We find that the general effect of acute SRI administration in zebrafish indeed appears to be anxiolytic-like, indicating, at least partly, differences in the functioning of the serotonin system as compared to mammals and that caution is advised when using zebrafish to model affective disorders.

Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HT1A autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT1A) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT1A autoreceptors as potential targets to prevent these enduring effects of ELA.

Gray matter volume differences based on sex in first-episode drug-naive patients with major depressive disorder and its molecular analysis.

This study analyzed whether gray matter volume (GMV) differences exist between the sexes in patients with major depressive disorder (MDD) and explored the relationships between these differences and neurotransmitter systems. This study enrolled 190 first-episode drug-naive patients with MDD and 293 healthy controls. All participants underwent T1-weighted high-resolution MRI. The interaction between the diagnosis (healthy controls vs. MDD) and sex (male vs. female) regarding GMV alterations was analyzed. The JuSpace toolbox, which covers a wide range of neurotransmitter systems, was used to identify the relationship between MDD-induced and sex-induced GMV alterations and specific receptor/transporter proteins in the brain. Sex-specific GMV differences were observed in the healthy controls but not in MDD patients. Male healthy controls had a larger GMV in the bilateral parahippocampal, lingual, inferior occipital, fusiform, cerebellar subregions, and left inferior temporal than female healthy controls, but several subregions of the thalamus had a larger GMV in female healthy controls than in male healthy controls. Sex-induced GMV alterations were associated with 5-hydroxytryptamine receptor subtype 1a, cannabinoid receptor, and dopamine receptor (P < 0.01, false discovery rate corrected). GMV differences were not detected in the main effect of diagnosis and the interaction of diagnosis and sex. Sex-specific GMV differences are associated with the spatial distribution of serotonin, dopamine, and cannabinoid neurotransmitter receptor systems. Sex-based physiological differences in the GMV may account for male and female susceptibility to and differences in the clinical symptoms of MDD.

Activation of ventral pallidum-projecting neurons in the nucleus accumbens via 5-HT2C receptor stimulation regulates motivation for wheel running in male mice

Rodents have a strong motivation for wheel running; however, the neural mechanisms that regulate their motivation remain unknown. We investigated the possible involvement of serotonin (5-HT) systems in regulating motivation for wheel running in male mice. Systemic administration of a 5-HT1A receptor antagonist (WAY100635) increased the number of wheel rotations, whereas administration of a 5-HT2A or 5-HT2C receptor antagonist (volinanserin or SB242084, respectively) decreased it. In the open field test, neither WAY100635 nor volinanserin affected locomotor activity, whereas SB242084 increased locomotor activity. To identify the brain regions on which these antagonists act, we locally injected these into the motivational circuitry, including the nucleus accumbens (NAc), dorsomedial striatum (DM-Str), and medial prefrontal cortex (mPFC). Injection of SB242084 into the NAc, but not the DM-Str or mPFC, reduced the number of wheel rotations without altering locomotor activity. The local administration of WAY100635 or volinanserin to these brain regions did not affect the number of wheel rotations. Immunohistochemical analyses revealed that wheel running increased the number of c-Fos-positive cells in the NAc medial shell (NAc-MS), which was reduced by systemic SB242084 administration. In vitro slice whole-cell recordings showed that bath application of the 5-HT2C receptor agonist lorcaserin increased the frequency of spontaneous excitatory and inhibitory postsynaptic currents in the ventral tegmental area (VTA)-projecting neurons, whereas it only increased the frequency of spontaneous excitatory postsynaptic currents in ventral pallidum (VP)-projecting neurons in the NAc-MS. These findings suggest that the activation of VP-projecting NAc-MS neurons via 5-HT2C receptor stimulation regulates motivation for wheel running.

The serotonin 1A receptor promoter polymorphism, rs6295, is associated with morphofunctional features

Introduction. The tendency to weight gain is influenced by many genetic and environmental factors (nutrition, level of physical activity, social well-being, etc.), as well as complex interactions of these factors. Studying the genetic factors of obesity can help in developing individual strategies for the prevention and treatment of this common disease. One of the most important hereditary factors is the neurotransmitter systems gene polymorphism, (including the serotonin system gene polymorphism). The aim of the investigation is to study the associations of single nucleotide polymorphism of the rs6295 locus of the serotonin receptor gene 1A HTR1A with morphofunctional features and body weight gain. Material and methods. The study used the materials of a comprehensive anthropogenetic examination of 386 men and 418 women aged 17 to 30 years. More than 20 morphofunctional indicators were measured using the traditional anthropometric method. The material for genetic analysis was genomic DNA isolated from buccal epithelium. The reliability of intergroup differences was assessed using the Mann-Whitney criterion, while canonical discriminant analysis was used to study intergroup variability. Results. For the first time, a significant correlation was shown between the polymorphism of the serotonin receptor type 1 gene HTR1A and morphofunctional features: individuals with the G/G genotype with greater body weight have lower (compared to carriers of the C/C and C/G genotypes) values of the indicators of the level of metabolic processes and specific metabolism. Conclusion. The statistically significant obtained results may be used in the development of individual strategies for the prevention and treatment of obesity, and also allow us to supplement the information on the association of serotonin system gene polymorphism with morphofunctional features and contribute to expanding our understanding of the human physique features formation and their relationships with hereditary predisposition.

Role of serotonin neurons in the dorsal raphe nucleus in heroin self-administration and punishment.

One hallmark of substance use disorder is continued drug use despite negative consequences. When drug-taking behavior is punished with aversive stimuli, i.e. footshock, rats can also be categorized into punishment-resistant or compulsive vs. punishment-sensitive or non-compulsive phenotypes. The serotonin (5-hydroxytryptamine, 5-HT) system modulates responses to both reward and punishment. The goal of the current study was to examine punishment phenotypes in heroin self-administration and to determine the role of dorsal raphe nucleus (DRN) 5-HT neurons in both basal and punished heroin self-administration. First, rats were exposed to punished heroin self-administration and neuronal excitability of DRN 5-HT neuronswas compared between punishment-resistant and punishment-sensitive phenotypes using ex vivo electrophysiology. Second, DRN 5-HT neuronal activity was manipulated in vivo during basal and punished heroin self-administration using chemogenetic tools in a Tph2-iCre rat line. While rats separated into punishment-resistant and punishment-sensitive phenotypes for punished heroin self-administration, DRN 5-HT neuronal excitability did not differ between the phenotypes. While chemogenetic inhibition of DRN 5-HT neurons was without effect, chemogenetic activation of DRN 5-HT neurons increased both basal and punished heroin self-administration selectively in punishment-resistant animals. Additionally, the responsiveness to chemogenetic activation of DRN 5-HT neurons in basal self-administration and motivation for heroin in progressive ratio each predicted resistance to punishment. Therefore, our data support the role for the DRN 5-HT system in compulsive heroin self-administration.

Sex-specific and Developmental Effects of Early Life Adversity on Stress Reactivity are Rescued by Postnatal Knockdown of 5-HT 1A Autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT 1A ) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT 1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT 1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT 1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT 1A autoreceptors as potential targets to prevent these enduring effects of ELA.

Endocannabinoid signaling in stress, nausea, and vomiting.

Classical antiemetics that target the serotonin system may not be effective in treating certain nausea and vomiting conditions like cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome (CHS). As a result, there is a need for better therapies to manage the symptoms of these disorders, including nausea, vomiting, and anxiety. Cannabis is often used for its purported antiemetic and anxiolytic effects, given regulation of these processes by the endocannabinoid system (ECS). However, there is considerable evidence that cannabinoids can also produce nausea and vomiting and increase anxiety in certain instances, especially at higher doses. This paradoxical effect of cannabinoids on nausea, vomiting, and anxiety may be due to the dysregulation of the ECS, altering how it maintains these processes and contributing to the pathophysiology of CVS or CHS. The purpose of this review is to highlight the involvement of the ECS in the regulation of stress, nausea, and vomiting. We discuss how prolonged cannabis use, such as in the case of CHS or heightened stress, can dysregulate the ECS and affect its modulation of these functions. The review also examines the evidence for the roles of ECS and stress systems' dysfunction in CVS and CHS to better understand the underlying mechanisms of these conditions.

Association between serotonin transporter gene polymorphism and obsessive–compulsive disorder in the Egyptian population

BackgroundObsessive–compulsive disorder (OCD) is a debilitating disorder that has multifactorial etiology including genetic, neurobiological, cognitive, and environmental influences. Genetic studies have focused on the genes of the serotonin system. This study aimed to look for the possible relation between the polymorphism in the promotor region of the serotonin transporter gene and obsessive–compulsive disorder in the Egyptian population.ResultsThis study included 94 OCD patients and 116 healthy control individuals. Blood samples were collected from all participants for DNA extraction and genotyping. The assessment of patients was done by application of the structured clinical interview according to DSM-V, the dimensional Yale-Brown Obsessive–Compulsive Scale. There was an association between serotonin transporter gene polymorphism and OCD development. The carriage of the short allele was a risk factor for having OCD.ConclusionObsessive–compulsive disorder is associated with serotonin transporter gene polymorphism. This will contribute to considering the genetic information of patients for the prediction of best drug response and tolerability by personalizing the choice of treatment.

Successful treatment with traditional Japanese medicine (kampo medicine) Yokukansan as a migraine prophylactic drug: A case report.

The use of anti-CGRP antibody drugs as migraine preventive drugs is increasing worldwide, but there are still a certain number of cases where antibody drugs are ineffective or cannot be used due to high prices. Conventional prophylactic drugs or traditional Japanese medicine (kampo medicine) are still often used in such cases. However, to date, only limited evidence supports the efficacy of kampo medicine for headaches because these treatments have been used primarily empirically and traditionally. However, in recent years studies have begun to be published that describe the efficacy of kampo medicine for various types of headache. Here, we report the case of a patient who achieved a marked reduction in migraine frequency and severity by prophylactic therapy with the kampo drug yokukansan (TSUMURA Yokukansan Extract Granules). The patient was a 50-year-old woman. She began to experience headaches around high school age and was diagnosed with migraine without aura at 42 years of age. She started prophylactic therapy with amitriptyline and topiramate and this treatment reduced the frequency of migraines for several years. However, the frequency began to increase again around 47 years, which is when she presented at our hospital. We achieved a temporary reduction in migraine frequency by adjusting the dose of drugs in her prophylactic therapy regimen, but the frequency increased again around age 49. We then tried monotherapy with the kampo medicine yokukansan, and this markedly reduced migraine frequency and severity over the following year. This therapy has remained effective to date. We speculate that, in this case, migraine without aura was improved by prophylactic therapy with yokukansan due to its action on the glutamatergic system or serotonin system through suppression of orexin-A secretion or its anti-inflammatory effects as reported in previous animal studies. Yokukansan could be a usable kampo medicine for migraine prophylaxis in countries all over the world and should be investigated in a large clinical trial as soon as possible.

Serotonergic Regulation of Synaptic Dopamine Levels Mitigates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

The serotonin (5-HT) system can manipulate the processing of exogenous L-DOPA in the DA-denervated striatum, resulting in the modulation of L-DOPA-induced dyskinesia (LID). To characterize the effects of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) or the serotonin transporter (SERT) inhibitor, Citalopram on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. MitoPark (MP) mice at 20 weeks of age, subjected to a 14-day administration of L-DOPA/Carbidopa, displayed dyskinesia, referred to as LID. Subsequent investigations explored the effects of 5-HT-modifying agents, such as 5-HTP and Citalopram, on abnormal involuntary movements (AIMs), locomotor activity, neurochemical signals, serotonin transporter activity, and protein expression in the DA-denervated striatum of LID MP mice. 5-HTP exhibited duration-dependent suppressive effects on developing and established LID, especially related to abnormal limb movements observed in L-DOPA-primed MP mice. However, Citalopram, predominantly suppressed abnormal axial movement induced by L-DOPA in LID MP mice. We demonstrated that 5-HTP could decrease L-DOPA-upregulation of DA turnover rates while concurrently upregulating 5-HT metabolism. Additionally, 5-HTP was shown to reduce the expressions of p-ERK and p-DARPP-32 in the striatum of LID MP mice. The effect of Citalopram in alleviating LID development may be attributed to downregulation of SERT activity in the dorsal striatum of LID MP mice. While both single injection of 5-HTP and Citalopram effectively mitigated the development of LID, the difference in mitigation of AIM subtypes may be linked to the unique effects of these two serotonergic agents on L-DOPA-derived DA and 5-HT metabolism.

Focal pharmacological manipulation of serotonin signaling in the amygdala does not alter social behavior.

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of drugs that increase serotonin signaling is associated with decreased social interactions. However, in primates, the direct involvement of serotonin signaling in the amygdala, particularly in affiliative social interaction, remains unexplored. Here, we examined the effects of serotonin manipulations within the amygdala on social behavior in eight pairs of familiar male macaques. We microinfused drugs targeting the serotonin system into either the basolateral (BLA) or central (CeA) amygdala and measured changes in social behavior. Surprisingly, the results demonstrated no significant differences in social behavior following the infusion of a selective serotonin reuptake inhibitor, 5-HT1A agonist or antagonist, 5-HT2A agonist or antagonist, or 5-HT3 agonist or antagonist into either the BLA or CeA. These findings suggest that serotonin signaling in the amygdala does not directly contribute to the regulation of social behavior between familiar conspecifics. Future research should explore alternative mechanisms and potential interactions with other brain regions to gain a comprehensive understanding of the complex neural circuitry governing social behavior.

Structure-function interrelationships and associated neurotransmitter profiles in drug-naïve benign childhood epilepsy with central-temporal spikes patients.

To explore the interrelationships between structural and functional changes as well as the potential neurotransmitter profile alterations in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI data from 20 drug-naïve BECTS patients and 33 healthy controls (HCs) were acquired. Parallel independent component analysis (P-ICA) was used to identify covarying components among gray matter volume (GMV) maps and fractional amplitude of low-frequency fluctuations (fALFF) maps. Furthermore, we explored the spatial correlations between GMV/fALFF changes derived from P-ICA and neurotransmitter maps in JuSpace toolbox. A significantly positive correlation (p < 0.001) was identified between one structural component (GMV_IC6) and one functional component (fALFF_IC4), which showed significant group differences between drug-naïve BECTS patients and HCs (GMV_IC6: p < 0.01; fALFF_IC4: p < 0.001). GMV_IC6 showed increased GMV in the frontal lobe, temporal lobe, thalamus, and precentral gyrus as well as fALFF_IC4 had enhanced fALFF in the cerebellum in drug-naïve BECTS patients compared to HCs. Moreover, significant correlations between GMV alterations in GMV_IC6 and the serotonin (5HT1a: p < 0.001; 5HT2a: p < 0.001), norepinephrine (NAT: p < 0.001) and glutamate systems (mGluR5: p < 0.001) as well as between fALFF alterations in fALFF_IC4 and the norepinephrine system (NAT: p < 0.001) were detected. The current findings suggest co-altered structural/functional components that reflect the correlation of language and motor networks as well as associated with the serotonergic, noradrenergic, and glutamatergic neurotransmitter systems. The relationship between anatomical brain structure and intrinsic neural activity was evaluated using a multimodal fusion analysis and neurotransmitters which might provide an important window into the multimodal neural and underlying molecular mechanisms of benign childhood epilepsy with central-temporal spikes. Structure-function relationships in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients were explored. The interrelated structure-function components were found and correlated with the serotonin, norepinephrine, and glutamate systems. Co-altered structural/functional components reflect the correlation of language and motor networks and correlate with the specific neurotransmitter systems.

Polygene by environment interactions predicting depressive outcomes.

Depression is a major public health problem with a continued need to uncover its etiology. Current models of depression contend that gene-by-environment (G × E) interactions influence depression risk, and further, that depression is polygenic. Thus, recent models have emphasized two polygenic approaches: a hypothesis-driven multilocus genetic profile score (MGPS; "MGPS × E") and a polygenic risk score (PRS; "PRS × E") derived from genome-wide association studies (GWAS). This review for the first time synthesizes current knowledge on polygene by environment "P × E" interaction research predicting primarily depression-related outcomes, and in brief, neurobiological outcomes. The "environment" of focus in this project is stressful life events. It further discusses findings in the context of differential susceptibility and diathesis-stress theories-two major theories guiding G × E work. This synthesis indicates that, within the MGPS literature, polygenic scores based on the serotonin system, the HPA axis, or across multiple systems, interact with environmental stress exposure to predict outcomes at multiple levels of analyses and most consistently align with differential susceptibility theory. Depressive outcomes are the most studied, but neuroendocrine, and neuroimaging findings are observed as well. By contrast, vast methodological differences between GWAS-based PRS studies contribute to mixed findings that yield inconclusive results.

Arginine vasopressin activates serotonergic neurons in the dorsal raphe nucleus during neonatal development in vitro and in vivo

Birth stress is a risk factor for psychiatric disorders and associated with exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. In perinatal hippocampus, AVP activates GABAergic interneurons which leads to suppression of spontaneous network events and suggests a protective function of AVP on cortical networks during birth. However, the role of AVP in developing subcortical networks is not known. Here we tested the effect of AVP on the dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system in male and female neonatal rats, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. We show that AVP is strongly excitatory in neonatal DRN: it increases excitatory synaptic inputs of 5-HT neurons via V1A receptors in vitro and promotes their action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of these neurons. Furthermore, we identified two major firing patterns of neonatal 5-HT neurons in vivo, tonic regular firing and low frequency oscillations of regular spike trains and confirmed that these neurons are also activated by AVP in vivo. Finally, we show that the sparse vasopressinergic innervation in neonatal DRN originates exclusively from cell groups in medial amygdala and bed nucleus of stria terminalis. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own functional development and affect the maturation of cortical target regions, which may increase the risk for psychiatric conditions later on.

Mitigation and mechanism of low dose linoleic acid on depression caused by disorder of gut microbiome

ABSTRACT Objectives Depression is a widely prevalent mental disorder, and nutritional interventions play an increasingly important role in its treatment. In this paper, effects of linoleic acid (LA) on depressive behavior in mice induced by gut microbiome disorders were investigated. Methods Fifty C57BL/6J male mice were randomly separated into five groups, control group (CK), ceftriaxone sodium group (CRO), low-dose linoleic acid group (LLA, 1 g/kg), medium-dose linoleic acid group (MLA, 2 g/kg), and high-dose linoleic acid group (HLA, 5 g/kg). In the LLA, MLA, and HLA groups, mice were treated with ceftriaxone sodium (CRO) to induce depressive behaviors, followed by LA administration. Behavioral tests were used to evaluate depressive behavior. High-throughput sequencing and Hematoxylin–eosin (H&E) staining in gut microenvironment were carried out. ELISA kits were used to measure brain inflammatory factors, and 5-hydroxy-tryptamine (5-HT). Gas chromatography and western blot were used to determine fatty acids compositions and the enzymes expression involved in lipid metabolism in brain respectively. Results The results showed that 10 weeks CRO treatment contribute to depressive behavior, gut microbiome disturbance, and serotonin system disturbance. LLA and MLA improved the depressive-like behavior, and significantly increased the levels of 5-HT1A, 5-HTT and 5-HT in the hippocampus. LLA was found to improve the diversity of gut microbiome and alleviate colon tissue damage. Meantime, LLA increased the content of linoleic acid, improved the expression of FADS2 and COX-2, increased IL-10 levels, and decreased IL-6 levels in the brain. Discussion LA alleviated depressive behavior in mice by improving the gut microenvironment, regulate fatty acid metabolism, and modulate inflammation.

Potential Differences in Psychedelic Actions Based on Biological Sex.

The resurgence of interest in psychedelics as treatments for psychiatric disorders necessitates a better understanding of potential sex differences in response to these substances. Sex as a biological variable (SABV) has been historically neglected in medical research, posing limits to our understanding of treatment efficacy. Human studies have provided insights into the efficacy of psychedelics across various diagnoses and aspects of cognition, yet sex-specific effects remain unclear, making it difficult to draw strong conclusions about sex-dependent differences in response to psychedelic treatments. Compounding this further, animal studies used to understand biological mechanisms of psychedelics predominantly use one sex and present mixed neurobiological and behavioral outcomes. Studies that do include both sexes often do not investigate sex differences further, which may hinder the translation of findings to the clinic. In reviewing sex differences in responses to psychedelics, we will highlight the direct interaction between estrogen (the most extensively studied steroid hormone) and the serotonin system (central to the mechanism of action of psychedelics), and the potential that estrogen-serotonin interactions may influence the efficacy of psychedelics in female participants. Estrogen influences serotonin neurotransmission by affecting its synthesis and release, as well as modulating the sensitivity and responsiveness of serotonin receptor subtypes in the brain. This could potentially influence the efficacy of psychedelics in females by modifying their therapeutic efficacy across menstrual cycles and developmental stages. Investigating this interaction in the context of psychedelic research could aid in the advancement of therapeutic outcomes, especially for conditions with sex-specific prevalence.

Primary somatosensory cortex CB1 and 5‑HT1A receptors interaction in the penicillin model of epilepsy.

Cannabinoid and serotonin systems regulate many biological processes. The aim of the present study was to investigate the functional interaction between the cannabinoid and serotonergic systems of the primary somatosensory region (S1) of the brain in epileptiform activity caused by penicillin. The ACEA (an agonist of CB1 receptor), AM‑251 (an antagonist of CB1 receptor), 8‑OH‑DPAT (an agonist of 5‑HT1A receptor) and WAY‑100635 (an antagonist of 5‑HT1A receptor) were administered into the S1 after the same site administration of penicillin in urethane‑anesthetized rats. Electrocorticographic recording was done for a 90‑min period. The spike waves number and amplitude were recorded in 15‑min intervals. Areas under the curve (AUC) of the above‑mentioned spike alterations was calculated in 90 min. Spike waves with frequency of 30/min and amplitude of 1.3 mV were appeared after penicillin microinjection. The ACEA (50 ng), 8‑OH‑DPAT (500 ng) and ACEA (10 ng) plus 8‑OH‑DPAT (100 ng) reduced epileptiform activity. The AM‑251 (50 ng) and WAY‑100365 (500 ng) prevented the reducing effects of ACEA (50 ng) and 8‑OH‑DPAT (500 ng). The AM‑251 alone increased spike waves frequency. The AUC results supported the effects of the above‑mentioned treatments. The results showed that activating CB1 and 5‑HT1A receptors in the S1 may reduce the epileptiform activity caused by penicillin. Therefore, alone and together activation of central CB1 and 5‑HT1A receptors might be considered in the management of epilepsy treatment.