Brain Serotonin System Research Articles

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.

Low-grade inflammation and serotonin 4 receptor binding in the healthy and the depressed brain

Inflammatory status affects healthy brain function and also low-grade inflammation putatively contributes to the pathophysiology of Major Depressive Disorder (MDD). This psychoneuro-immunological interplay is complex, bidirectional, and not fully understood. Also, it is not clear to what extent depressive states induce inflammation and/or if increased inflammation leads to depressive symptoms by affecting brain biology including serotonin signaling. The serotonin 4 receptor (5-HT4R) is an interesting new antidepressant target; direct stimulation has antidepressant-like, and pro-cognitive effects, and may also index serotonin tone at least in the adult healthy brain.Here, we investigate whether a peripheral marker of low-grade inflammation (hsCRP) is associated with 5-HT4R brain binding in both a healthy and in an unmedicated MDD group. 5-HT4R PET imaging data and hsCRP measures from 112 healthy and 79 unmedicated MDD individuals were available from the Cimbi database. We evaluated the associations between hsCRP level and 5-HT4R binding in three regions of interest (neocortex, hippocampus, and neostriatum) using multiple linear regression models adjusted for relevant covariates.We did not observe a statistically significant association between hsCRP and 5-HT4R binding. This applied to both the healthy and the MDD group.Our findings do not support a coupling between low-grade inflammation and brain 5-HT4R availability, which suggests that the serotonergic system is not sensitive to low-grade inflammation captured by hsCRP, neither in healthy nor in depressed states. Future studies are needed to test if the brain serotonin system is coupled to other inflammatory markers, for instance in conditions with high-grade and/or prolonged immunoactivation.

The role of brain serotonin signaling in excessive alcohol consumption and withdrawal: A call for more research in females

Alcohol Use Disorder (AUD) is a leading cause of death and disability worldwide, but current treatments are insufficient in fully addressing the symptoms that often lead to relapses in alcohol consumption. The brain's serotonin system has been implicated in AUD for decades and is a major regulator of stress-related behaviors associated with increased alcohol consumption. This review will discuss the current literature on the association between neurobiological adaptations in serotonin systems and AUD in humans as well as the effectiveness of serotonin receptor manipulations on alcohol-related behaviors like consumption and withdrawal. We will further discuss how these findings in humans relate to findings in animal models, including a comparison of systemic pharmacological manipulations modulating alcohol consumption. We next provide a detailed overview of brain region-specific roles for serotonin and serotonin receptor signaling in alcohol-related behaviors in preclinical animal models, highlighting the complexity of forming a cohesive model of serotonin function in AUD and providing possible avenues for more effective therapeutic intervention. Throughout the review, we discuss what is known about sex differences in the sequelae of AUD and the role of serotonin in these sequelae. We stress a critical need for additional studies in women and female animals so that we may build a clearer path to elucidating sex-specific serotonergic mechanisms and develop better treatments.

Two Adverse Early Life Events Induce Differential Changes in Brain CRH and Serotonin Systems in Rats along with Hyperphagia and Depression.

Different types of stress inflicted in early stages of life elevate the risk, among adult animals and humans, to develop disturbed emotional-associated behaviors, such as hyperphagia or depression. Early-life stressed (ELS) adults present hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is a risk factor associated with mood disorders. However, the prevalence of hyperphagia (17%) and depression (50%) is variable among adults that experienced ELS, suggesting that the nature, intensity, and chronicity of the stress determines the specific behavioral alteration that those individuals develop. We analyzed corticosterone serum levels, Crh, GR, Crhr1 genes expression in the hypothalamic paraventricular nucleus, amygdala, and hippocampus due to their regulatory role on HPA axis in adult rats that experienced maternal separation (MS) or limited nesting material (LNM) stress; as well as the serotonergic system activity in the same regions given its association with the corticotropin-releasing hormone (CRH) pathway functioning and with the hyperphagia and depression development. Alterations in dams' maternal care provoked an unresponsive or hyper-responsive HPA axis function to an acute stress in MS and LNM adults, respectively. The differential changes in amygdala and hippocampal CRH system seemed compensating alterations to the hypothalamic desensitized glucocorticoids receptor (GR) in MS or hypersensitive in LNM. However, both adult animals developed hyperphagia and depression-like behavior when subjected to the forced-swimming test, which helps to understand that both hypo and hypercortisolemic patients present those disorders. Different ELS types induce neuroendocrine, brain CRH and 5-hydroxytriptamine (5-HT) systems' alterations that may interact converging to develop similar maladaptive behaviors.

Serotonin Receptors as a Potential Target in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide that has an increasing impact on aging societies. Besides its critical role in the control of various physiological functions and behavior, brain serotonin (5-HT) system is involved in the regulation of migration, proliferation, differentiation, maturation, and programmed death of neurons. At the same time, a growing body of evidence indicates the involvement of 5-HT neurotransmission in the formation of insoluble aggregates of β-amyloid and tau protein, the main histopathological signs of AD. The review describes the role of various 5-HT receptors and intracellular signaling cascades induced by them in the pathological processes leading to the development of AD, first of all, in protein aggregation. Changes in the functioning of certain types of 5-HT receptors or associated intracellular signaling mediators prevent accumulation of β-amyloid plaques and tau protein neurofibrillary tangles. Based on the experimental data, it can be suggested that the use of 5-HT receptors as new drug targets will not only improve cognitive performance in AD, but will be also important in treating the causes of AD-related dementia.

Effect of Prolonged Exposure to Short Daylight and a Tryptophan Hydroxylase Inhibitor on the Behavior and Brain Serotonin System in Danio rerio.

We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in D. rerio. Male and female D. rerio were exposed for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (p-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the "novel tank diving" test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (Tph1a, Tph1b, Tph2, and Mao) and receptors of 5-HT (Htr1aa, Htr2aa) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the "novel tank diving" test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased Tph1a and Tph2 gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of D. rerio.

The brain serotonin system in autism.

Autism spectrum disorders (ASDs) are among themost common neurodevelopmental diseases. These disorders are characterized by lack of social interaction, byrepetitive behavior, and often anxiety and learning disabilities. The brain serotonin (5-HT) system is known to becrucially implicated in a wide range of physiological functions and in the control of different kinds of normal and pathological behavior. A growing number of studies indicate the involvement of the brain 5-HT system in the mechanisms underlying both ASD development and ASD-related behavioral disorders. There are some review papers describing the role of separate key players of the 5-HT system in an ASD and/or autistic-like behavior. In this review, we summarize existing data on the participation of all members of the brain 5-HT system, namely, 5-HT transporter, tryptophan hydroxylase 2, MAOA, and 5-HT receptors, in autism in human and various animal models. Additionally, we describe the most recent studies involving modern techniques for invivo regulation of gene expression that are aimed at identifying exact roles of 5-HT receptors, MAOA, and 5-HT transporter inthe mechanisms underlying autistic-like behavior. Altogether, results of multiple research articles show that the brain 5-HT system intimately partakes in the control of some types of ASD-related behavior, and that specific changes in a function of a certain 5-HT receptor, transporter, and/or enzyme may normalize this aberrant behavior. These data give hope that some of clinically used 5-HT-related drugs have potential for ASD treatment.

Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation.

Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation.

Effect of Short Photoperiod on the Behavior and Brain Serotonin System in Zebrafish Danio rerio.

Reduced daylight duration causes the development of seasonal affective disorder (SAD; depression-like disorders characterized by depressed mood, apathy, bulimia, and weight gain) in sensitive individuals. Neurotransmitter serotonin (5-HT) is involved in the mechanism of SAD. Zebrafish (D. rerio) is a promising model for translational studies. We studied changes in the behavior, content of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the expression of genes encoding the key enzymes of 5-HT metabolism, tryptophan hydroxylases TPH1A, TPH1B, TPH2, monoamine oxidase (MAO), 5-HT transporter, and 5-HT1A and 5-HT2A receptors in the brain of zebrafish reared for 60 days under short (04:20 h) compared to those reared at normal (12:12 h) photoperiod. Exposure to short photoperiod decreased locomotor activity in the novel tank diving test, increased the level 5-HIAA, and reduced the level of Mao gene mRNA, but did not affect the level of 5-HT and expression of Tph1a, Tph1b, Tph2, Slc6a4a (transporter), Htr1aa, and Htr2aa (receptors) genes. Thus, zebrafish can be used as a promising model to study the involvement of 5-HT in the SAD mechanism.

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.

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.

P.0548 Tryptophan hydroxylase 2 deficiency modifies the effects of chronic fluoxetine treatment on the brain serotonin system and behavior in zebrafish

P.0548 Tryptophan hydroxylase 2 deficiency modifies the effects of chronic fluoxetine treatment on the brain serotonin system and behavior in zebrafish

Long-term effects of young-adult methamphetamine on dorsal raphe serotonin systems in mice: Role of brain-derived neurotrophic factor

To assess the long-term effects of chronic adolescent methamphetamine (METH) treatment on the serotonin system in the brain, we used serotonin-1A receptor (5-HT1A) and serotonin transporter (SERT) autoradiography, and quantitative tryptophan-hydroxylase 2 (TPH2) immunohistochemistry in the raphe nuclei of mice. Because of the modulatory role of brain-derived neurotrophic factor (BDNF) on the serotonin system and the effects of METH, we included both BDNF heterozygous (HET) mice and wildtype (WT) controls. Male and female mice of both genotypes were treated with an escalating METH dose regimen from the age of 6–9 weeks. At least two weeks later, acute locomotor hyperactivity induced by a 5 mg/kg D-amphetamine challenge was significantly enhanced in METH-pretreated mice, showing long-term sensitisation. METH pretreatment caused a small, but significant decrease of 5-HT1A receptor binding in the dorsal raphe nucleus (DRN) of males independent of genotype, but there were no changes in the median raphe nucleus (MRN) or in SERT binding density. METH treatment reduced the number of TPH2 positive cells in ventral subregions of the rostral and medial DRN independent of genotype. METH treatment selectively reduced DRN cell counts in BDNF HET mice compared to wildtype mice in medial and caudal ventrolateral subregions previously associated with panic-like behaviour. The data increase our understanding of the long-term and selective effects of METH on brain serotonin systems. These findings could be relevant for some of the psychosis-like symptoms associated with long-term METH use.

Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.

Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly

Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.

Investigation of the Brain Serotonin System Plasticity Using the Recombinant Mouse Lines Carring 1473G–Allele of Tryptophan Hydroxylase-2 Gene and Differing by the Distal Fragment of Chromosome 13 Containing 5-HT1A Receptor Gene

Abstract—In order to investigate the joint influence of C1473G polymorphism in the gene encoding the key enzyme for serotonin (5-HT) biosynthesis in brain – tryptophan hydroxylase-2, and the distal fragment (103,9-112,4 Мbp) of chromosome 13, including 5-HT1A serotonin receptor gene from catalepsy-prone CBA strain, on the brain 5-HT system, new recombinant mice strain B6-1473GG.CBA-CD13Mit76С (1473GG-76C) and B6-1473GG.CBA-D13Mit76В (1473GG-76B) on the base of C57BL/6 strain were created. The 1473GG-76C and 1473GG-76B lines carry a fragment of chromosome 13 containing Htr1a gene from the CBA and the C57BL/6 strains respectively. Both lines are homozygous by 1473G-allele, reducing the activity of TPH-2. It was shown that the 1473GG-76C line is characterized by increased levels of mRNA of Htr1a, Htr2a genes and Maoa gene (monoamine oxidase type A—the main enzyme of 5-HT degradation) in the midbrain, Htr1a gene in the cortex, Htr1a and Htr2a genes in the hippocampus as compared to 1473GG-76B. In addition, the 1473GG-76C line has increased expression of genes encoding the key regulators of Htr1a gene—FREUD-1 and FREUD-2. The mRNA level of the Cc2d1a gene encoding FREUD-1 was increased in the cortex, and the expression of the Cc2d1b gene encoding FREUD-2 was enhanced in the midbrain. Also, the 1473GG-76C line has increased 5-HT levels in the midbrain, hypothalamus and hippocampus. At the same time, the level of the main 5-HT metabolite, 5-HIAA, was decreased in the midbrain and cortex of these mice. The ratio of 5-HIAA/5-HT reflecting the intensity of 5-HT metabolism was reduced in all investigated structures of 1473GG-76C mice. Thus, the combination of 1473G-allelele of Tph2 gene with Htr1a gene from the CBA strain had a significant effect on the mRNA levels of the key genes of the 5-HT system and on 5-HT metabolism in the brain of 1473GG-76C mice.

Reward Contributions to Serotonergic Functions.

The brain serotonin systems participate in numerous aspects of reward processing, although it remains elusive how exactly serotonin signals regulate neural computation and reward-related behavior. The application of optogenetics and imaging techniques during the last decade has provided many insights. Here, we review recent progress on the organization and physiology of the dorsal raphe serotonin neurons and the relationships between their activity and behavioral functions in the context of reward processing. We also discuss several interesting theories on serotonin's function and how these theories may be reconciled by the possibility that serotonin, acting in synergy with coreleased glutamate, tracks and calculates the so-called beneficialness of the current state to guide an animal's behavior in dynamic environments.

Serotonin transporter protein in autopsied brain of chronic users of cocaine.

The long-held speculation that the brain serotonin system mediates some behavioral effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioral (e.g., mood) abnormality in chronic users of the drug. Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n = 9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n = 15) and, as a separate drug of abuse group, in chronic heroin users (n = 11). We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 among the control and drug abuse groups. In the cocaine users, no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid. Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.

Brain 5‐HT deficiency prevents antidepressant‐like effects of high fat diet and blocks high fat diet‐induced GSK3β phosphorylation in the hippocampus

Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remain highly controversial. Some argue that depression and/or anxiety lead to increased consumption of ‘comfort foods’ to reduce negative affect and that chronic consumption of these foods promotes obesity. Alternatively, it has been suggested that chronic excessive consumption of highly palatable foods, such as those high in fats, could induce negative affective states in susceptible individuals. However, the genetic factors that influence food consumption and behavioral responses to high fat diets (HFDs) remain largely unknown. The brain serotonin (5‐HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5‐HT exacerbates depression‐ and anxiety‐like behavior induced by stress and blocks reductions in depression‐like behavior induced by antidepressants, but the effects of brain 5‐HT deficiency on responses to HFD have not been explored. The current work used genetically modified mice to evaluate the effects of low brain 5‐HT on behavioral and molecular alterations induced by chronic exposure to HFD. Real‐time PCR was used to measure mRNA expression, and Western blotting was used to study protein phosphorylation. Our results reveal that HFD decreases depression‐like behavior and increases some anxiety‐like behaviors in wild‐type mice. However, genetic brain 5‐HT deficiency blocks HFD‐induced reductions in forced swim immobility and prevents HFD‐induced increases in hippocampal GSK3β phosphorylation. These effects occur despite the fact that low 5‐HT does not influence HFD‐induced changes in body weight or anxiety‐like behavior in the novel open field test or the elevated plus maze. Together, our results suggest that although brain 5‐HT deficiency does not alter HFD intake, low brain 5‐HT prevents therapeutic‐like responses to HFD and blocks the inhibition of GSK3 by HFD. Although GSK3 inhibition has been shown to lead to antidepressant‐like effects, whether GSK3 inhibition is required for the antidepressant‐like effects of HFD has not been established. Nonetheless, our results indicate that brain 5‐HT plays a major role in mediating some of the effects of HFD, which could help explain the complex relationships between obesity and mental illness.

Эффекты острого стресса у мышей, различающихся чувствительностью 5-НТ 1А -рецепторов к хронической активации с помощью 8-OH-DPAT

Recently the B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) recombinant mouse lines have been created, which differ in the sensitivity of the 5-HT1A-receptor to chronic activation by an 8-OH-DPAT (8-hydroxy-2- (di-n-propylamino) tetralin). 5-HT1A-receptor is the key regulator of the brain serotonin (5-HT) system that is implicated in the regulation of stress response. In this work, it was found that acute emotional stress (immobilization of 40 min) increases the expression of the c-fos gene, which is a marker of the response to stress, in the brain of both lines. The stress-induced increase c-fos expression in the striatum, hypothalamus, and cortex of B6-M76C mice was more pronounced. The reaction to emotional stress led to an increase in the ratio of the serotonin metabolite - 5-HIAA (5-hydroxyinodolacetic acid) to 5-HT in the midbrain and hippocampus in both lines. An increased 5-HIAA/5-HT ratio was detected in the hypothalamus B6-M76C and cortex B6-M76B of mice after stress. Moreover, the reaction to stress led to decrease in the level of norepinephrine in the hippocampus and hypothalamus in B6-M76C mice. The levels of dopamine, norepinephrine, epinephrine and the dopamine/norepinephrine ratio in the adrenal glands increased in response to the stress effect only in B6-M76C. The present study showed that the sympathoadrenal system is more sensitive to acute stress in the B6-M76C mice. Reaction to stress in B6-M76C mice leads to an increase in the content of norepinephrine and epinephrine in adrenal tissue. An increase in the adrenal dopamine/norepinephrine ratio may indicate a more rapid transition of catecholamine biosynthesis intermediates (dopamine) to norepinephrine and further epinephrine due to the acceleration of the biosynthetic process in response to stress in B6-M76C mice. In addition, an increased sensitivity of the hypothalamic neurons to the action of stress in B6-M76C was shown. Thus, B6-M76C mice are of significant interest for the study of the hypothalamic-pituitary-adrenal system with an overactive response to stress, and can contribute to the identification of new biomarkers for clinical studies