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Background: Interactions between the serotonin (5-HT) and endocannabinoid (eCB) systems have been reported in the psychopathology of stress-related symptoms, while their interplay in regulating the relationship between childhood trauma and burnout remains unclear. In this study, we investigated the interaction of childhood trauma with genetic polymorphisms in these two systems in predicting burnout., Methods: Burnout, childhood trauma, and job stress were assessed using rating scales in 992 general occupational individuals. Genetic polymorphisms including HTR2A rs6313, 5-HTT rs6354 and FAAH rs324420, were genotyped. Linear hierarchical regression analysis and PROCESS macro in SPSS were used to examine two- and three-way interactions., Results: There were significant interactions of job stress × HTR2A rs6313 and childhood abuse × FAAH rs324420 on reduced personal accomplishment. Moreover, we found significant three-way interactions of childhood abuse × FAAH rs324420 × HTR2A rs6313 on cynicism and reduced personal accomplishment, childhood abuse × FAAH rs324420 × 5-HTT rs6354 on emotional exhaustion, and childhood neglect × FAAH rs324420 × 5-HTT rs6354 on reduced personal accomplishment. These results suggest that the FAAH rs324420 A allele carriers, when with some specific genetic polymorphisms of 5-HT system, would show more positive associations between childhood trauma and burnout., Conclusions: Genetic polymorphisms in the 5-HT and eCB systems may jointly moderate the impact of childhood trauma on burnout., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cannabidiol (CBD) is a phytocannabinoid devoid of psychostimulant properties and is currently under investigation as a potential antidepressant drug. However, the mechanisms underlying CBD's antidepressant effects are not yet well understood. CBD targets include a variety of receptors, enzymes, and transporters, with different binding-affinities. Neurochemical and pharmacological evidence indicates that both serotonin and BDNF-TrkB signalling in the prefrontal cortex are necessary for the antidepressant effects induced by CBD in animal models. Herein, we reviewed the current literature to dissect if these are independent mechanisms or if CBD-induced modulation of the serotonergic neurotransmission could mediate its neuroplastic effects through subsequent regulation of BDNF-TrkB signalling, thus culminating in rapid neuroplastic changes. It is hypothesized that: a) CBD interaction with serotonin receptors on neurons of the dorsal raphe nuclei and the resulting disinhibition of serotonergic neurons would promote rapid serotonin release in the PFC and hence its neuroplastic and antidepressant effects; b) CBD facilitates BDNF-TRKB signalling, especially in the PFC, which rapidly triggers neurochemical and neuroplastic effects. These hypotheses are discussed with perspectives for new drug development and clinical applications., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Peripartum mood and anxiety disorders (PMADs) affect 15-20% of peripartum women and are well known to disrupt infant caregiving. A recent study in humans reported that anxiety and depressive symptoms were alleviated by peripartum treatment with the probiotic, Lactocaseibacillus rhamnosus HN001. The current study determined the effects of chronic Lactocaseibacillus rhamnosus HN001 (HN001) treatment on postpartum affective and caregiving behaviors in a laboratory rodent model. Female rats were given probiotic overnight in their drinking water, or untreated water, from the first day of pregnancy through postpartum day 10. To determine whether the HN001 effects were influenced by a background of stress, half the females underwent chronic variable pregnancy stress and the other half remained undisturbed. The results revealed that, even without pregnancy stress, HN001 reduced postpartum anxiety-related behavior, increased variability in behavioral fragmentation when dams interacted with pups, increased time away from pups, and decreased prefrontal cortex norepinephrine (NE), dopamine (DA) and serotonin (5-HT). Probiotic plus stress consistently reduced the latency to float in the forced swim test, increased DA and 5-HT turnovers in the prefrontal cortex, increased hippocampal NE, and reduced hypothalamic DA. Fecal microbe alpha and beta diversities were lower postpartum than prepartum, which was prevented by the probiotic treatment and/or stress. Across the entire sample lower postpartum anxiety behavior was associated with lower fecal Bacteroides dorei. This study reveals novel information about how L. rhamnosus HN001 influences postpartum behavior and microbiota-gut-brain physiology in female laboratory rats, with implications for probiotic supplement use by pregnant and postpartum women., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exercise is known to reduce depression and anxiety symptoms. Although the cellular and molecular mechanisms underlying this effect remain unknown, exercise-induced increases in neurotransmitter release and hippocampal neurogenesis have been hypothesized to play key roles. One neurotransmitter that has been implicated in both antidepressant-like effects and the regulation of hippocampal neurogenesis is serotonin (5-HT). Complete loss of function of the brain 5-HT synthesis enzyme (tryptophan hydroxylase 2, Tph2) has been reported to prevent exercise-induced increases in neurogenesis and to block a subset of antidepressant-like responses to selective serotonin reuptake inhibitors (SSRIs), but whether partial loss of Tph2 function blocks the behavioral and neurogenic effects of exercise has not been established. This study used four tests that are predictive of antidepressant efficacy to determine the impact of 5-HT deficiency on responses to exercise in male and female mice. Our results demonstrate that low 5-HT impairs the behavioral effects of exercise in females in the forced swim and novelty-suppressed feeding tests. However, genetic reductions in 5-HT synthesis did not significantly impact exercise-induced alterations in cellular proliferation or immature neuron production in the hippocampus in either sex. These findings highlight the importance of brain 5-HT in mediating behavioral responses to exercise and suggest that individual differences in brain 5-HT synthesis could influence sensitivity to the mental health benefits of exercise. Furthermore, the observed disconnect between neurogenic and behavioral responses to exercise suggests that increased neurogenesis is unlikely to be the primary driver of the behavioral effects of exercise observed here., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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 V 1A 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prevalence of depression significantly increases during puberty and adolescence. Puberty is the period during which sexual maturity is attained, while adolescence persists beyond puberty and includes physiological, social, emotional, and cognitive maturation. A stressor that has been shown previously to induce depression is chronic sleep disruption. Probiotics can prevent stress-induced depression. However, it was unclear whether probiotics could prevent depression following chronic sleep disruption and what mechanism may be involved. Therefore, we investigated whether pubertal probiotic treatment could prevent depression-like behavior in mice following chronic sleep disruption. We also examined whether probiotic treatment could improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in chronically sleep-disrupted mice. We hypothesized that probiotic treatment would prevent depression-like behavior, improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in sleep-disrupted mice. Male and female mice (N=120) received cannula and electroencephalogram (EEG) electrode implants at postnatal day (PND) 26. Mice received Lacidofil® or Cerebiome® probiotics (PND 33-51) and were sleep-disrupted for the first 4 hours of the light phase (sleep period) (PND 40-51). Hippocampal L-lactate and glucose concentrations and sleep were measured over a 24-h period (PND 48-49). Depression-like behaviour was evaluated using tail suspension (PND 49) and forced swim tests (PND 50). Chronic sleep disruption increased depression-like behaviour and NREM duration in the dark phase, and reduced all metabolites and neuromodulating biomolecules measured within the brain. However, mice treated with probiotics did not display depression-like behaviour or decreased hippocampal L-lactate following chronic sleep disruption. Cerebiome prevented decreases to prefrontal serotonin and hippocampal glucose concentrations, while Lacidofil increased NREM duration in the latter half of the light phase. The current study not only replicates previous findings linking chronic sleep disruption to depression, but also demonstrates that pubertal probiotic treatment can mitigate the effects of chronic sleep disruption on depression-like behaviour and on the neural mechanisms underlying depression in a strain-dependent manner., Competing Interests: Declaration of Competing Interest We have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The trematode Acrolichanus auriculatus is a widely distributed intestine parasite of acipenserid fishes. For the first time the localization and distribution of the serotonergic nerve elements in A. auriculatus was studied using immunocytochemical method and confocal laser scanning microscopy. The study revealed the presence of biogenic amine, serotonin, in the central and peripheral nervous systems of A. auriculatus, that is in the neurons and neurites of the brain ganglia, brain commissure, the longitudinal nerve cords, and the connective nerve commissures. The innervation of the attachment organs, pharynx, oesophagus and distal regions of the reproductive system by the serotonergic nerve elements is observed. The distribution of serotonergic neurons in A. auriculatus is schematically marked. The comparative analysis of findings obtained in A. auriculatus with those recorded for other digeneans reveals the presence of both conservative and distinctive features in the organization of the serotonergic nervous system in various representatives of trematodes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The anteroventral bed nucleus of stria terminalis (avBNST) is a limbic forebrain region involved in the regulation of anxiety, and expresses GABA B receptors, which are located at both pre- and post-synaptic sites. However, it is unclear how blockade of these receptors affects anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and increased GABA release and decreased glutamate release in the avBNST, as well as decreased level of dopamine (DA) in the basolateral amygdala (BLA). Intra-avBNST injection of pre-synaptic GABA B receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABA B receptor antagonist CGP35348 induced anxiety-like responses in both sham and 6-OHDA rats. Intra-avBNST injection of CGP36216 inhibited the GABAergic neurons and increased GABA/glutamate ratio in the avBNST and increased levels of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 produced opposite effects on the firing activity of avBNST GABAergic neurons and levels of the neurotransmitters in the avBNST and BLA. Moreover, the doses of the antagonists producing significant behavioral effects in 6-OHDA rats were lower than those in sham rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in 6-OHDA rats. Altogether, these findings suggest that pre- and post-synaptic GABA B receptors in the avBNST are implicated in PD-related anxiety-like behaviors, and degeneration of the nigrostriatal pathway enhances functions and/or upregulates expression of these receptors., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic stress is a major risk factor for psychiatric disorders. However, certain individuals may be at higher risk due to greater stress susceptibility. Elucidating the neurobiology of stress resilience and susceptibility may facilitate the development of novel strategies to prevent and treat stress-related disorders such as depression. Mounting evidence suggests that the serotonin (5-HT) system is a major regulator of stress sensitivity. In this study, we assessed the functions of 5-HT1A and 5-HT2A receptors within the lateral septum (LS) in regulating stress vulnerability. Among a group of male mice exposed to chronic social defeat stress (CSDS), 47.2% were classified as stress-susceptible, and these mice employed more passive coping strategies during the defeat and exhibited more severe anxiety- and depression-like behaviors during the following behavioral tests. These stress-susceptible mice also exhibited elevated neuronal activity in the LS as evidenced by greater c-Fos expression, greater activity of 5-HT neurons in both the dorsal and median raphe nucleus, and downregulated expression of the 5-HT1A receptor in the intermediate LS (LSi). Finally, we found the stress-induced social withdrawal symptoms could be rapidly relieved by LSi administration of 8-OH-DPAT, a 5-HT1A receptor agonist. These results indicate that 5-HT1A receptors within the LSi play an important role in stress vulnerability in mice. Therefore, modulation of stress vulnerable via 5-HT1A receptor activation in the LSi is a potential strategy to treat stress-related psychiatric disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Research has demonstrated that chronic stress experienced early in life can lead to impairments in memory and learning. These deficits are attributed to an imbalance in the interaction between glucocorticoids, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoid receptors in brain regions responsible for mediating memory, such as the hippocampus. This imbalance can result in detrimental conditions like neuroinflammation. The aim of this study was to assess the impact of sumatriptan, a selective agonist for 5-HT 1B/1D receptors, on fear learning capabilities in a chronic social isolation stress model in mice, with a particular focus on the role of the HPA axis., Methods: Mice were assigned to two opposing conditions, including social condition (SC) and isolated condition (IC) for a duration of five weeks. All mice underwent passive avoidance test, with their subsequent freezing behavior serving as an indicator of fear retrieval. Mice in the IC group were administered either a vehicle, sumatriptan, GR-127935 (a selective antagonist for 5-HT 1B/1D receptors), or a combination of sumatriptan and GR-127935 during the testing sessions. At the end, all mice were sacrificed and samples of their serum and hippocampus were collected for further analysis., Results: Isolation was found to significantly reduce freezing behavior (p<0.001). An increase in the freezing response among IC mice was observed following the administration of varying doses of sumatriptan, as indicated by a one-way ANOVA analysis (p<0.001). However, the mitigating effects of sumatriptan were reversed upon the administration of GR-127935. An ELISA assay conducted before and after the passive avoidance test revealed no significant change in serum corticosterone levels among SC mice. In contrast, a significant increase was observed among IC mice, suggesting hyper-responsiveness of the HPA axis in isolated animals. This hyper-responsiveness was ameliorated following the administration of sumatriptan. Furthermore, both the sumatriptan and SC groups exhibited a similar trend, showing a significant increase in the expression of hippocampal glucocorticoid receptors following the stress of the passive avoidance test. Lastly, the elevated production of inflammatory cytokines (TNF-α, IL-1β) observed following social isolation was attenuated in the sumatriptan group., Conclusion: Sumatriptan improved fear learning probably through modulation of HPA axis and hippocampus neuroinflammation., Competing Interests: Declaration of Competing Interest This study was the postgraduate thesis of Dr Kamyar Moradi under the supervision of Prof. Ahmad Reza Dehpour. This study was supported by a grant from Iran National Science Foundation (INSF) to Prof. Ahmad Reza Dehpour (Grant Number: 96002757). The funding organization had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the article and the decision to submit the article for publication. To the best of our knowledge, no conflict of interest, financial or other, exists. I have read and have abided by the statement of ethical standards for manuscripts submitted to Psychoneuroendocrinology., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The anteroventral bed nucleus of stria terminalis (avBNST) is a key brain region which involves negative emotional states, such as anxiety. The most neurons in the avBNST are GABAergic, and it sends GABAergic projections to the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN), respectively. The VTA and DRN contain dopaminergic and serotonergic cell groups in the midbrain which regulate anxiety-like behaviors. However, it is unclear the role of GABAergic projections from the avBNST to the VTA and the DRN in the regulation of anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and decreased level of dopamine (DA) in the basolateral amygdala (BLA). Chemogenetic activation of avBNST GABA -VTA or avBNST GABA -DRN pathway induced anxiety-like behaviors and decreased DA or 5-HT release in the BLA in sham and 6-OHDA rats, while inhibition of avBNST GABA -VTA or avBNST GABA -DRN pathway produced anxiolytic-like effects and increased level of DA or 5-HT in the BLA. These findings suggest that avBNST inhibitory projections directly regulate dopaminergic neurons in the VTA and serotonergic neurons in the DRN, and the avBNST GABA -VTA and avBNST GABA -DRN pathways respectively exert impacts on PD-related anxiety-like behaviors., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The serotonergic (5-HTergic) system is closely involved in the pathophysiology of mood and anxiety disorders and the responsibility of this system may differ for each symptom. In this study, we examined the relationship between the dysfunction of the 5-HTergic system and abnormal behaviors in the social defeat stress model, an animal model of mood and anxiety disorders and in mice with knockdown of Slc6a4, the gene encoding SERT. Monoamine content, serotonin (5-HT) release, 5-HT uptake, 5-HT transporter (SERT) protein levels, and behaviors were investigated in mice subjected to chronic social defeat stress and in mice with knockdown of Slc6a4, in 5-HTergic neurons projecting to the prefrontal cortex (PFC). Furthermore, DNA methylation of Slc6a4 was examined in mice subjected to chronic social defeat stress. Increased turnover, increased extracellular basal levels, decreased release and decreased uptake of 5-HT, and decreased SERT protein levels were observed in the PFC of the stressed mice. The decreased 5-HT uptake correlated with anxiety-like behavior characterized by decreased time spent in the open arms of the elevated plus maze. DNA methylation was increased in the CpG island of Slc6a4 in 5-HTergic neurons projecting to the PFC of the stressed mice. Similar to the stressed mice, mice with Slc6a4 knockdown in 5-HTergic neurons projecting to the PFC also showed decreased release and uptake of 5-HT in the PFC and increased anxiety-like behavior. Chronic stress may induce anxiety due to dysfunction in the prefrontal 5-HTergic system via decreased SERT expression in the PFC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT 5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT 5A receptor activation. We found an upregulation of 5-HT 5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT 5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT 5A receptor antagonist SB-699551. Moreover, application of the GABA A receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABA A receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT 5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT 5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT 5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The etiology of idiopathic pain conditions, such as Provoked vulvodynia (PV), is multifactorial. The efficiency of venlafaxine, serotonin-noradrenaline reuptake inhibitor (SNRIs) in modulating vulvar pain led to the hypothesis that PV might involve central mechanisms. Here, we investigate whether vulvar pain is associated with gene-expression changes in mood, stress and pain systems, including amygdala (Amg), medial prefrontal cortex (mPFC), and periaqueductal gray matter (PAG). Additionally, we examined the analgesic and anxiolytic effects of venlafaxine. We found that the development of chronic vulvar pain in an animal model of PV is associated by overexpression of genes related to neuronal-activity and neuroinflammation in the Amg, mPFC, and PAG. Additionally, changes in the expression of GABA and serotonin synthesis, and reuptake were noted in the Amg and mPFC. Unsurprisingly, anxiety-like behavior and emotional-disorder were observed in rats with chronic vulvar pain. Nevertheless, treatment with venlafaxine (37.5 mg/kg) for one month significantly improves the vulvar hypersensitivity, as well as reduces the anxiety level. More critically, the long-term gene expression adaptation in serotonin receptor and synthesis, GABA synthesis, neuroplasticity, and neuroinflammation in the Amg, mPFC, and PAG, were modulated by venlafaxine in rats with vulvar pain. Our findings suggest that vulvar hypersensitivity induced by inflammation might associated with gene expression changes in brain areas that are involved in mood, stress and pain regulation. These changes probably play a role in central sensitization, and anxiety. Strikingly, enhancing the activity of serotonin and noradrenaline via venlafaxine treatment in rats with vulvar pain induces analgesic and anxiolytic effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hippocampal responses to selective 5-HT reuptake inhibitor (SSRI) have long been studied. However, its sub-regional involvements in mediating SSRI's pharmacological effects have not been fully addressed. The current study sought to investigate neurochemical, neurobiological and neurobehavioral changes in response to direct fluoxetine perfusion into the ventral and dorsal sub-regions of the hippocampus in C57BL/6 mice. Following fluoxetine perfusion, time courses of dialysate 5-HT, 5-HT transporter (5-HTT) protein (total, membrane and cytoplasmic fractions), locomotion, and immobility times in the forced swim test (FST) and tail suspension test (TST) were determined. At baseline, 5-HT uptake efficiency assessed by the no-net-flux microdialysis, and 5-HTT protein were measured as well. Results show that fluoxetine dose-dependently increased dialysate 5-HT, lowered membrane 5-HTT protein and increased cytoplasmic fraction without changing the total level, decreased immobility times in both the FST and TST, with greater responses all detected in the ventral sub-region compared to the dorsal sub-region. Fluoxetine didn't affect locomotor activity, ruling out the possibility that fluoxetine's effects on immobility maybe due to alteration in locomotion. Besides, lower 5-HT uptake efficiency and lower membrane 5-HTT protein level were found in the ventral sub-region at baseline. Together, the sub-regional differences at baseline and in responses to fluoxetine added powerful evidence to support the existence of two distinct 5-HT sub-systems in the hippocampus, with greater changes to fluoxetine detected in the ventral sub-system., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Buspirone is a pharmaceutical used to treat general anxiety disorder by acting on the dopaminergic and serotoninergic system. Buspirone, like many human pharmaceuticals, has been detected in municipal wastewater; however, the environmental exposure risks are unknown for this psychoactive compound. We studied the effects of buspirone on the behavior of zebrafish, focusing on locomotor and anxiolytic behavior. We also measured transcripts associated with oxidative stress, neurotoxicity, and serotonin signaling to identify potential mechanisms underlying the behavioral changes. Concentrations ranged from environmentally relevant (nM) to physiologically active concentrations typical of human pharmaceuticals (μM). Buspirone treatment did not impact survival, nor did it induce deformities in zebrafish treated for 7 days up to 10 μM. There was a positive relationship between locomotor activity and buspirone concentration in dark periods of the visual motor response test. In the light-dark preference test, both the average time per visit to the dark zone and the percent cumulative duration in the dark zone were increased by 1 μM buspirone. Transcript levels of ache, manf, and mbp were decreased in larvae, while the expression of gap43 was increased following exposure to buspirone, indicating potential neurotoxic effects. There was also reduced expression of serotonin-related genes encoding receptors, transporters, and biosynthesis enzymes (i.e., 5ht1aa, sertb, and tph1a). These data increase understanding of the behavioral and molecular responses in zebrafish following waterborne exposure to neuroactive pharmaceuticals like buspirone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Obesity has become a worldwide health challenge and commonly results from the intake of more calories than the body requires. The brain represents the master controller of food intake and as such has been the target of obesity medications. However, key mechanisms of druggable targets remain to be defined. Neurons within the arcuate nucleus of the hypothalamus co-expressing neuropeptide Y (NPY), agouti-related protein (AgRP) and GABA (NAG) are fundamental stimulators of hunger and food intake. NAG neurons also inhibit local satiety-promoting pro-opiomelanocortin (POMC) neurons. Agonists of the 1B subtype of metabotropic serotonin receptor (5-HT 1B R) reduce food intake in part through the inhibition of hunger-promoting NAG neurons. We first confirmed that 5-HT 1B R activation suppressed intake of a palatable Western diet in a mouse model of common dietary-induced obesity and genetically prone obesity. Next, we combined several electrophysiological approaches to analyse the effect of 5-HT 1B Rs in NAG neuron cell activity and GABA release. 5-HT 1B R activation reduced NAG neuron action potential frequency and neurotransmitter release. We found that 5-HT 1B R impact on GABA release from NAG neurons is mediated through voltage-gated Ca 2+ channels with a critical input from glutamate receptors of AMPA subtype (AMPARs). As a fundamental outcome, this type of interplay provides an uncommon example of metabotropic action of AMPARs which regulates inhibitory signalling due to modulation of GABA release. As a translational outcome, our results provide a key mechanism through which 5-HT 1B R drugs inhibit appetite-stimulating neurons within the brain to suppress food intake. This article is part of the Special Issue on "Ukrainian Neuroscience"., Competing Interests: Declaration of competing interest The authors declare that they don't have any conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A high prevalence of mental disorders following COVID-19 has been described. It is therefore essential to elucidate underlying biological mechanisms linking SARS-CoV-2 infection and mental health. The kynurenine and catecholamine metabolic pathways are modulated by inflammation and can affect systemic levels of serotonin and dopamine. Their activity may hence link physical disorders with mental health. We investigated factors that affect kynurenine and catecholamine pathway activity in SARS-CoV-2 infection and recovery., Methods: The cross-sectional SIMMUN (n = 165) and longitudinal INCOV cohort (n = 167, Su et al. 2022) were analyzed. Demographic and clinical characteristic, inflammatory markers, SARS-CoV-2 infection, symptoms of depression and anxiety (HADS), and mental stress (PSS-4) served as explanatory variables. Blood serotonin and markers of kynurenine (kynurenine/tryptophan ratio), and catecholamine pathway activity (dopamine 3-O-sulfate, phenylalanine/tyrosine ratio) were modeled by multi-parameter linear regression., Results: In the SIMMUN cohort, the inflammatory marker neopterin (β = 0.47 [95% CI: 0.34-0.61]), SARS-CoV-2-positivity (0.42 [0.16-0.68]), mental stress (0.18 [0.055-0.31]), and age (0.26 [0.12-0.39]) were positively associated with the kynurenine/tryptophan ratio. The phenylalanine/tyrosine ratio was lower in SARS-CoV-2-positive than uninfected participants (-0.38 [-0.68 to -0.08]). In the INCOV cohort, markers of inflammation were associated with lower serotonin (IL6: -0.22 [-0.38 to -0.053]) and dopamine 3-O-sulfate levels (interferon-gamma: -0.15 [-0.26 to -0.036]). Serotonin (0.76 [0.34-1.2]) and dopamine 3-O-sulfate levels (0.63 [0.28-0.99]) were higher during recovery than in acute SARS-CoV-2 infection., Conclusion: SARS-CoV-2 infection, inflammation, age and mental stress are key independent predictors of kynurenine pathway activity, which may influence serotonin availability. The catecholamine pathway was also affected in SARS-CoV-2 infection. Altered activity of these pathways may contribute to impaired mental health following COVID-19., Competing Interests: Declaration of Competing Interest Katharina Hüfner has received research grants from Austria Wirtschaftsservice (AWS) and the Science Fund of the Land Tirol as well as lecturer’s honoraria from Forum Medizinische Fortbildung (FOMF), the Hospital of Schwaz and the Austrian Society for Biological Psychiatry related to the topic of COVID-19. Piotr Tymoszuk owns the Data Science as a Service Tirol enterprise and works a free-lance data scientist and biostatistician. He has received an honorarium for statistical data analysis, bioinformatic and scientific writing services. Bernhard Holzner has intellectual property rights to the CHES software tool used for questionnaire data collection. Jens Lehmann reports consultancy for Evaluation Software Development GmbH, the software company developing CHES. All other authors report no conflicts of interest related to the current manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The anteroventral bed nucleus of the stria terminalis (avBNST) is widely acknowledged as a key brain structure that regulates negative emotional states, such as anxiety. At present, it is still unclear whether GABA A receptor-mediated inhibitory transmission in the avBNST is involved in Parkinson's disease (PD)-related anxiety. In this study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, increased GABA synthesis and release, and upregulated expression of GABA A receptor subunits in the avBNST, as well as decreased level of dopamine (DA) in the basolateral amygdala (BLA). In both sham and 6-OHDA rats, intra-avBNST injection of GABA A receptor agonist muscimol induced the following changes: (i) anxiolytic-like responses, (ii) inhibition of the firing activity of GABAergic neurons in the avBNST, (iii) excitation of dopaminergic neurons in the ventral tegmental area (VTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), and (iv) increase of DA and 5-HT release in the BLA, whereas antagonist bicuculline induced the opposite effects. Collectively, these findings suggest that degeneration of the nigrostriatal pathway enhances GABA A receptor-mediated inhibitory transmission in the avBNST, which is involved in PD-related anxiety. Further, activation and blockade of avBNST GABA A receptors affect the firing activity of VTA dopaminergic and DRN serotonergic neurons, and then change release of BLA DA and 5-HT, thereby regulating anxiety-like behaviors., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ionotropic receptors are ligand-gated ion channels triggering fast neurotransmitter responses. Among them, P2X and 5-HT 3 receptors have been shown to physically interact each other and functionally inducing cross inhibitory responses. Nevertheless, despite the importance of P2X4 and 5-HT 3A receptors that mediate for example neuropathic pain and psychosis respectively, complementary evidence has recently started to move forward in the understanding of this interaction. In this review, we discuss current evidence supporting the mechanism of crosstalking between both receptors, from the structural to the transduction pathway level. We expect this work may guide the design of further experiments to obtain a comprehensive view for the neuropharmacological role of these interacting receptors. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy"., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

The serotonin system plays a critical role in the modulation of impulsive aggression. Although serotonin transporters (SERT) are key in modulating synaptic serotonin levels, few studies have investigated the role of SERT levels in human impulsive aggression. The aim of this study was to investigate whether brain SERT levels are associated with trait impulsive aggression. We included 148 healthy individuals (mean age 29.3 ± 13.0, range 18-80 years, 91 females) who had undergone positron emission positron (PET) examinations with the SERT tracer [ 11 C]DASB and filled in self-report questionnaires of trait aggression, trait impulsivity and state aggression. We evaluated the association between cerebral SERT binding (BP ND ) and trait impulsive aggression in a latent variable model, with one latent variable (LV SERT ) modelled from SERT BP ND in frontostriatal and frontolimbic networks implicated in impulsive aggression, and another latent variable (LV IA ) modelled from various trait measures of impulsivity and aggression. The LV SERT was not significantly associated with the LV IA (p = 0.8). Post-hoc univariate analyses did not reveal any significant associations between regional SERT levels and trait aggression, trait impulsivity or state aggression, but we found that state aggression at the day of PET scan was significantly lower in L A /L A homozygotes vs S-carriers of the 5-HTTLPR gene (p = 0.008). We conclude that brain SERT binding was not related to variations in trait impulsive aggression or state aggression. Our findings do not support that SERT is involved in mediating the serotonergic effects on aggression and impulsivity, at least not in individuals with non-pathological levels of impulsive aggression., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest of relevance for the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The 5-hydroxytryptamine 7 receptor (5-HT 7 R) is one of the most recently cloned serotonin receptors which have been implicated in many physiological and pathological processes including drug addiction. Behavioral sensitization is the progressive process during which re-exposure to drugs intensified the behavioral and neurochemical responses to drugs. Our previous study has demonstrated that the ventrolateral orbital cortex (VLO) is critical for morphine-induced reinforcing effect. The aim of the present study was to investigate the effect of 5-HT 7 Rs in the VLO on morphine-induced behavioral sensitization and their underlying molecular mechanisms. Our results showed that a single injection of morphine, followed by a low challenge dose could induce behavioral sensitization. Microinjection of the selective 5-HT 7 R agonist AS-19 into the VLO during the development phase significantly increased morphine-induced hyperactivity. Microinjection of the 5-HT 7 R antagonist SB-269970 suppressed acute morphine-induced hyperactivity and the induction of behavioral sensitization, but had no effect on the expression of behavioral sensitization. In addition, the phosphorylation of AKT (Ser 473) was increased during the expression phase of morphine-induced behavioral sensitization. Suppression of the induction phase could also block the increase of p-AKT (Ser 473). In conclusion, we demonstrated that 5-HT 7 Rs and p-AKT in the VLO at least partially contribute to morphine-induced behavioral sensitization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: 5-hydroxytryptamine (5-HT, serotonin) is a major mediator in allergic reactions. The number of tolerogenic dendritic cell (tolDC) and regulatory T cell is reduced in allergic disorders. The mechanism is unclear. The objective of this study is to elucidate the role of 5-HT in interfering with tolDC generation and regulatory Type 1 T cell (Tr1 cell)., Methods: BALB/c mice were treated with 5-HT-containing nasal instillations. The frequency of tolDC and Tr1 cell was evaluated by flow cytometry., Results: Following treatment with 5-HT nasal instillations for one week, the frequency of tolDC and Tr1 cell was significantly reduced in the respiratory tissues. Higher levels of SOS1 were detected in DCs isolated from the airway tissues of mice treated with 5-HT. A complex of SOS1 and c-Maf was detected in DCs in response to 5-HT stimulation. The expression of IL-10 was suppressed by the presence of 5-HT. The induction of Tr1 cell by DC was substantially compromised by 5-HT., Conclusions: 5-HT inhibits the expression of IL-10 in DCs. DCs primed with 5-HT lose the ability to induce Tr1 cells., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mice exhibit IBD- and depressive-like phenotypes. A disturbed intestinal environment causes a decrease in serotonin and abnormal myelination in the brain, along with depressive-like behavior in rodents. However, the involvement of these factors in DSS-induced depressive-like behavior in mice remains unclear. In this study, we examined whether myelin proteins in the prefrontal cortex (PFC) and hippocampi were altered in DSS-treated mice, along with the changes in the serotonergic system in the PFC by western blotting and HPLC. The effects of brexpiprazole (Brx), a serotonin modulator, on DSS-induced depressive-like behavior using the tail-suspension test were evaluated. Subsequently, we investigated Brx's effects on the levels of myelin, nodal proteins, and neurotrophic molecules in the PFC with western blotting, and examined the altered node of Ranvier formation by immunohistochemistry. DSS-treated mice showed a reduction in myelin and nodal proteins, dysfunction of the serotonergic system, and impaired formation of the nodes of Ranvier in the PFC. Brx administration prevented the DSS-induced depressive-like behavior and demyelination in the PFC. However, the Brx-mediated effects were inhibited by the selective 5-HT 1A antagonist, WAY100635, or the selective TrkB antagonist, ANA-12. Brx decreased the phosphorylation of ERK, CREB, and TrkB along with the expression of BDNF in the PFC of DSS-treated mice. Moreover, the effects of Brx were blocked by WAY100635. These findings indicated that myelination regulated by the activation of the ERK1/2-CREB-BDNF-TrkB pathway in the PFC may be involved in mediating the antidepressant effects of Brx., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: Previously, we revealed a crucial role of 5-HT degradation system (5DS), consisting of 5-HT2A receptor (5-HT2AR), 5-HT synthases and monoamine oxidase A (MAO-A), in ischemia-reperfusion (IR)-caused organ injury. Whereas, platelet activating factor receptor (PAFR) also mediates myocardial ischemia-reperfusion injury (MIRI). Here, we try to clarify the relationship between 5DS and PAFR in mediating MIRI., Methods: H9c2 cell injury and rat MIRI were caused by hypoxia/reoxygenation (H/R) or PAF, and by ligating the left anterior descending coronary artery then untying, respectively. 5-HT 2A R and PAFR antagonists [sarpogrelate hydrochloride (SH) and BN52021], MAO-A, AKT, mTOR and 5-HT synthase inhibitors (clorgyline, perifosine, rapamycin and carbidopa), and gene-silencing PKCε were used in experiments RESULTS: The mitochondrial ROS production, respiratory chain damage, inflammation, apoptosis and myocardial infarction were significantly prevented by BN52021, SH and clorgyline in H/R and PAF-treated cells and in IR myocardium. BN52021 also significantly suppressed the upregulation of PAFR, 5-HT 2A R, 5-HT synthases and MAO-A expression (mRNA and protein), and Gα q and PKCε (in plasmalemma) expression induced by H/R, PAF or IR; the effects of SH were similar to that of BN52021 except for no affecting the expression of PAFR and 5-HT 2A R. Gene-silencing PKCε suppressed H/R and PAF-induced upregulation of 5-HT synthases and MAO-A expression in cells; perifosine and rapamycin had not such effects; however, clorgyline suppressed H/R and PAF-induced phosphorylation of AKT and mTOR., Conclusion: MIRI is probably due to PAFR-mediated 5-HT 2A R activation, which further activates PKCε-mediated 5-HT synthesis and degradation, leading to mitochondrial ROS production., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Growing evidence from male rodent and human studies suggests that cannabidiol (CBD) modulates the expression of aversive memories and anxiety-related responses. The limited data on whether and how CBD influences these aspects in females could have therapeutic implications given the increased susceptibility of women to anxiety- and stress-related disorders relative to men. Female studies are also essential to examine inherent aspects that potentially contribute to differences in responsiveness to CBD. Here we addressed these questions in adult female rats. Contextually fear-conditioned animals acutely treated with CBD (1.0-10 mg/kg) were tested 45 min later. In subsequent experiments, we investigated the estrous cycle effects and the contribution of dorsal hippocampus (DH) serotonin 1A (5-HT1A) and cannabinoid types 1 (CB1) and 2 (CB2) receptors to CBD-induced effects on memory retrieval/expression. The effects of pre-retrieval systemic or intra-DH CBD administration on subsequent fear extinction were also assessed. Lastly, we evaluated the open arms avoidance and stretched-attend postures in females exposed to the elevated plus-maze after systemic CBD treatment. CBD 3.0 and 10 mg/kg administered before conditioned context exposure reduced females' freezing. This action remained unchanged across the estrous cycle and involved DH 5-HT1A receptors activation. Pre-retrieval CBD impaired memory reconsolidation and lowered fear during early extinction. CBD applied directly to the DH was sufficient to reproduce the effects of systemic CBD treatment. CBD 3.0 and 10 mg/kg reduced anxiety-related responses scored in the elevated plus-maze. Our findings demonstrate that CBD attenuates the behavioral manifestation of learned fear and anxiety in female rats., Competing Interests: Declaration of competing interest Francisco S. Guimarães is a co-inventor (Mechoulam R, JC, Guimaraes FS, AZ, JH, Breuer A) of the patent "Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023″ Def. US no. Reg. 62193296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to "develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease, and anxiety disorders." The other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

S-adenosyl-l-methionine (SAMe), a methyl donor, induces antidepressant effects in preclinical and clinical studies of depression. However, the mechanisms behind these effects have been poorly investigated. Since SAMe is involved in monoamine metabolism, this work aimed at 1) testing the effects induced by systemic treatment with SAMe in mice submitted to the forced swimming test (FST) and tail suspension test (TST); 2) investigating the involvement of serotonergic neurotransmission in the behavioral effects induced by SAMe. To do that, male Swiss mice received systemic injections (1 injection/day, 1 or 7 days) of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), SAMe (10, 25, 50, 100, and 200 mg/kg), or vehicle (10 ml/kg) and were submitted to the FST or TST, 30 min after the last injection. The effect of SAMe (50 mg/kg) was further investigated in independent groups of male Swiss mice pretreated with p-chlorophenylalanine (PCPA, serotonin synthesis inhibitor, 150 mg/kg daily, 4 days) or with WAY100635 (5-HT 1A receptor antagonist, 0.1 mg/kg, 1 injection). One independent group was submitted to the FST and euthanized immediately after for collection of brain samples for neurochemical analyses. Serotonin (5-HT) and noradrenaline (NA) levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, to investigate if the treatments used could induce any significant exploratory/motor effect which would interfere with the FST results, the animals were also submitted to the open field test (OFT). The administration of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), and SAMe (10 and 50 mg/kg) reduced the immobility time in the FST, an effect blocked by pretreatment with PCPA and WAY100635. None of the treatments increased the locomotion in the OFT. In conclusion, our results suggest that the antidepressant-like effects induced by SAMe treatment are dependent on serotonin synthesis and 5-HT 1A receptor activation., Competing Interests: Declaration of competing interest The authors have no competing interests to declare. S-adenosyl-l-methionine antidepressant-like effects involve activation of 5-HT1A receptors. All persons who meet authorship criteria are listed as authors, and all authors have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. Furthermore, the authors certify that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in Neurochemistry International., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

It is well known that overnutrition, overweight, and obesity in children can modulate brain mechanisms of plasticity, monoaminergic systems, and mitochondrial function. The immediate effect of overnutrition during the developmental period has not been thoroughly examined in rats until the present. This study sought to evaluate the impact on adult rats of early life overfeeding and fluoxetine treatment from post-natal day 1 (PND1) to post-natal day 21 (PND21) relative to mitochondrial function, oxidative balance, and expression of specific monoaminergic genes in the hippocampus. The following were evaluated: mitochondrial function markers, oxidative stress biomarkers, dopamine-and serotonin-related genes, and BDNF mRNA levels. Overfeeding during the lactation period deregulates cellular metabolism and the monoaminergic systems in the hippocampus. Strikingly, serotonin modulation by fluoxetine treatment protected against some of the effects of early overnutrition. We conclude that overfeeding during brain development induce detrimental effects in mitochondria and in the genes that regulate homeostatic status that can be the molecular mechanisms related to neurological diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We evaluated ventilation (V˙ E ), body temperature (T B ), oxygen consumption (V˙ O 2 ), respiratory equivalent (V˙ E / V˙ O 2 ), and monoamine concentrations of 14-day-old (14d) male and female chicks from eggs incubated at low (LT, 36 °C), control (CT, 37.5 °C) and high (HT, 39 °C) temperature during the early embryonic phase, to normoxia, hypercapnia and hypoxia under exposure to cold environment (20 °C). At normoxia, acute cold exposure did not affect the ventilatory variables, with the exception of HT males, in which cold prevented the reduced V˙ E observed under thermoneutral conditions. Exposure to 20 °C caused a decrease in T B in both sexes, and LT and HT females presented a greater hypothermic response. Hypercapnia combined with cold did not alter the ventilatory variables, but LT females and CT males and females showed a blunted CO 2 -induced hyperventilation due to a higher V˙ O 2 , compared to the same groups in thermoneutral conditions. Unlike with thermoneutral conditions, the blunted hypercapnic hyperventilation observed in the HT groups was not observed during cold challenge. CO 2 exposure promoted a similar decrease in T B in the thermoneutral and acutely cold exposed groups, while LT females under cold condition presented a blunted hypothermic response. During hypoxia, cold challenge attenuated the increase in V˙ E in LT females and HT males, due to changes in V T . Hypoxic metabolic depression was greater in LT females and males and HT males during cold exposure, while no change in V˙ E / V˙ O 2 was observed. The only alteration in monoaminergic concentration under cold challenge was an increase in brainstem 5-HIAA and 5-HIAA/5-HT ratio in HT females, and an enhanced 5-HT concentration in HT males. In summary, thermal manipulation during embryogenesis induces 14d old chicks to respond differently to cold stress with LT females and HT males being more sensitive., Competing Interests: Declaration of competing interest The authors have no competing interests to declare and have no relevant financial or non-financial interests to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adolescence is a period of risk for beginning tobacco addiction. Differential neural response to nicotine in adolescents vs. adults may help explain the increased vulnerability to nicotine self-administration seen with adolescent onset. We indexed the effects of acute nicotine ditartrate (0.4 mg/kg, salt weight) administration on dopamine (DA) and serotonin (5HT) as well as the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in several brain regions (nucleus accumbens, striatum and frontal cortex) of 6-week old (adolescent) and 10-week old (young adult) Sprague-Dawley rats. When nicotine was administered DA concentrations in the accumbens were significantly higher in adults than in adolescents, whereas there was no age-related difference without nicotine. However neither age group showed a significant effect of nicotine vs. age-matched controls. DA turnover in the accumbens was significantly greater in adolescent females in response to nicotine, but adult females did not show this effect and neither did males of either age group. DA turnover in the striatum was significantly higher in adolescents than adults regardless of nicotine administration. In the frontal cortex, there was a more complex effect. Without nicotine, adult male rats had higher DA concentrations than adolescent males, whereas female rats did not differ from adolescent to adult ages. When given nicotine, the age effect was no longer seen in males. However, there was not a significant effect of nicotine vs. age-matched controls in either age group. No age or nicotine effects were seen in females. 5HT in the accumbens was significantly increased by nicotine administration in adults but not in adolescents. Altered neural responsivity of adolescents to nicotine-induced neural effects particularly in accumbens DA and 5HT may be related to the increased nicotine dose concentrations they self-administer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Propionate is an effective mould inhibitor widely used as a food preservative. In this study, we used zebrafish to explore the adverse effects of long-term exposure to low concentrations of sodium propionate and the underlying molecular mechanisms (from larvae to adult). When exposed for 3 months, we found that blood glucose, total cholesterol, and triglyceride levels increased, and zebrafish developed a hyperglycaemic state. New tank test results showed depression in zebrafish reduced 5-hydroxytryptamine levels in the brain and damaged the dopamine system. At the same time, the results of the color preference test showed that zebrafish had cognitive impairments. In addition, Hypothalamic-Pituitary-Adrenal axis analysis revealed abnormal gene expression, increased cortisol levels, and reduced glucocorticoid receptor mRNA levels, which were consistent with depressive behavior. We also observed abnormal transcription of inflammatory and apoptotic factors. Overall, we found that chronic exposure to sodium propionate induces depressive symptoms. This may be related to the activation of the HPA axis by the hyperglycaemic state, thereby inducing inflammation and disrupting the dopaminergic system. In summary, this study provides theoretical and technical support for the overlap of the emotional pathogenesis associated with diabetes., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The serotonergic system is involved in diverse cognitive functions including memory. Of particular importance to daily life are declarative memories that contain information about personal experiences, general facts, and events. Several psychiatric or neurological diseases, such as depression, attention-deficit-hyperactivity disorder (ADHD), and dementia, show alterations in serotonergic signalling and attendant memory disorders. Nevertheless, understanding serotonergic neurotransmission and its influence on memory remained a challenge until today. In this systematic review, we summarize recent psychopharmacological studies in animals and humans from a psychological memory perspective, in consideration of task-specific requirements. This approach has the advantage that comparisons between serotonin (5-HT)-related neurochemical mechanisms and manipulations are each addressing specific mnemonic circuits. We conclude that applications of the same 5-HT-related treatments can differentially affect unrelated tasks of declarative memories. Moreover, the analysis of specific mnemonic phases (e.g., encoding vs. consolidation) reveals opposing impacts of increased or decreased 5-HT tones, with low 5-HT supporting spatial encoding but impairing the consolidation of objects and verbal memories. Promising targets for protein synthesis-dependent consolidation enhancements include 5-HT 4 receptor agonists and 5-HT 6 receptor antagonists, with the latter being of special interest for the treatment of age-related decline. Further implications are pointed out as base for the development of novel therapeutic targets for memory impairment of neuropsychiatric disorders., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Male and females appear equally capable of showing habituated hypothalamic-pituitary-adrenal (HPA) axis output responses to repeated exposures of the same challenge. Whether this reflects, within males and females, common mechanisms of decreased neuronal activity within stress responding, afferents to the paraventricular hypothalamic nucleus (PVH), the final common pathway to the HPA axis, has not been examined. Here we compared in adult male and female rats the extent to which declines in HPA axis responses to repeated restraint are met by habituated cellular (Fos) responses, in addition to changes in serotonin (5-hydroxytryptamine; 5-HT) expression and signaling, which normally stimulates the HPA axis. Thus, alterations in this component of HPA axis drive could provide an underlying basis for sex differences in adaptive responses. Males and females showed reliable declines in ACTH and corticosterone responses after 10 daily episodes of repeated restraint, recapitulated, in largest part, by similar regional patterns of Fos habituation, including within the PVH, several stress sensitive cell groups of the limbic forebrain, as well as within the raphe nucleus. Serotonin staining in the dorsal raphe and terminal profiles in the forebrain continued to reflect a higher pre-synaptic capacity for the 5-HT system in females. The sexual dimorphism encountered within the lateral septum and medial preoptic area of control animals was less distinguished in the repeat condition, however, whereas 5-HT varicosities in the PVH increased after repeated restraint only in females. Relative to their singly restrained counterparts, males displayed an increase in 5-HT 1 A receptor expression in the raphe nucleus after repeated restraint, whereas females showed a decrease in 5-HT 1 A mRNA levels in the hippocampus and in the zona incerta, representing the most proximal of cell groups expressing the 5-HT 1 A receptor in the vicinity of the PVH. In conclusion, similar regional profiles of cellular habituation in males and females suggest common CNS substrates of neuroendocrine adaptation. However, this process may be met by underlying sex differences in serotonergic control, given the respective roles for pre- and postsynaptic 5-HT 1 A receptors in mediating serotonin availability and signal transfer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Among the enzymes that support brain metabolism, cytochrome P450 (CYP) enzymes occupy an important place. These enzymes catalyze the biotransformation pathways of neuroactive endogenous substrates (neurosteroids, neurotransmitters) and are necessary for the detoxification processes. The aim of the present study was to assess changes in the CYP2D activity and protein level during the aging process and as a result of serotonin deficiency in the female brain. The CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) female rats (mature 15-week-old and senescent 18-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent female rats. The CYP2D activity in mature WT Dark Agouti females was independent of the changing phases of the estrous cycle. In senescent WT females rats, the CYP2D activity and protein level were decreased in the cerebral cortex, hippocampus, cerebellum and liver, but increased in the brain stem. In the other examined structures (frontal cortex, hypothalamus, thalamus, striatum), the enzyme activity did not change. In aging TPH2-deficient females, the CYP2D activity and protein levels were decreased in the frontal cortex, hypothalamus and brain stem (activity only), remaining unchanged in other brain structures and liver, relative to senescent WT females. In summary, the aging process and TPH2 deficit affect the CYP2D activity and protein level in female rats, which may have a negative impact on the compensatory capacity of CYP2D in the synthesis of serotonin and dopamine in cerebral structures involved in cognitive and emotional functions. In the liver, the CYP2D-catalyzed drug metabolism may be diminished in elderly females. The results in female rats are compared with those obtained previously in males. It is concluded that aging and serotonin deficiency exert sex-dependent effects on brain CYP2D, which seem to be less favorable in females concerning CYP2D-mediated neurotransmitter synthesis, but beneficial regarding slower neurosteroid metabolism., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neuroleptics have to be used for a long time to produce a therapeutic effect. Cytochrome P450 2D (CYP2D) enzymes mediate alternative pathways of neurotransmitter synthesis (i.e. tyramine hydroxylation to dopamine and 5-methoxytryptamine O-demethylation to serotonin), and metabolism of neurosteroids. The aim of our present study was to examine the influence of chronic treatment with the new atypical neuroleptic asenapine on CYP2D in rat brain. In parallel, liver CYP2D was investigated for comparison. Asenapine added in vitro to microsomes of control rats competitively, but weakly inhibited the activity of CYP2D (brain: K i  = 385 μM; liver: K i  = 36 μM). However, prolonged administration of asenapine (0.3 mg/kg sc. for 2 weeks) significantly diminished the activity and protein level of CYP2D in the frontal cortex, nucleus accumbens, hippocampus and cerebellum, but did not affect the enzyme in the hypothalamus, brain stem, substantia nigra and the remainder of the brain. In contrast, asenapine enhanced the enzyme activity and protein level in the striatum. In the liver, chronically administered asenapine reduced the activity and protein level of CYP2D, and the CYP2D1 mRNA level. In conclusion, prolonged administration of asenapine alters the CYP2D expression in the brain structures and in the liver. Through affecting the CYP2D activity in the brain, asenapine may modify its pharmacological effect. By increasing the CYP2D expression/activity in the striatum, asenapine may accelerate the synthesis of dopamine (via tyramine hydroxylation) and serotonin (via 5-methoxytryptamine O-demethylation), and thus alleviate extrapyramidal symptoms. By reducing the CYP2D expression/activity in other brain structures asenapine may diminish the 21-hydroxylation of neurosteroids and thus have a beneficial influence on the symptoms of schizophrenia. In the liver, by reducing the CYP2D activity, asenapine may slow the biotransformation of concomitantly administered CYP2D substrates (drugs) during continuous treatment of schizophrenia or bipolar disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Δ 9 -tetrahydrocannabinol (THC) is the main phytocannabinoid present in the Cannabis sativa. It can produce dose-dependent anxiolytic or anxiogenic effects in males. THC effects on anxiety have scarcely been studied in females, despite their higher prevalence of anxiety disorders. Cannabidiol, another phytocannabinoid, has been reported to attenuate anxiety and some THC-induced effects. The present study aimed to investigate the behavioral and neurochemical effects of THC administered alone or combined with CBD in naturally cycling female rats tested in the elevated plus-maze. Systemically administered THC produced biphasic effects in females, anxiolytic at low doses (0.075 or 0.1 mg/kg) and anxiogenic at a higher dose (1.0 mg/kg). No anxiety changes were observed in males treated with the same THC dose range. The anxiogenic effect of THC was prevented by co-administration of CBD (1.0 or 3.0 mg/kg). CBD (3.0 mg/kg) caused an anxiolytic effect. At a lower dose (1.0 mg/kg), it facilitated the anxiolytic effect of the low THC dose. The anxiogenic effect of THC was accompanied by increased dopamine levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). In contrast, its anxiolytic effect was associated with increased mPFC serotonin concentrations. The anxiolytic effect of CBD was accompanied by increased mPFC serotonin turnover. Together, these results indicate that female rats are susceptible to the biphasic effects of low THC doses on anxiety. These effects could depend on mPFC and NAc dopaminergic and serotoninergic neurotransmissions. CBD could minimize potential THC high-dose side effects whereas enhancing the anxiolytic action of its low doses in females., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not known how blockade of GABA B receptors in the region affects anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to hyperactivity of LHb neurons and decreased the level of extracellular dopamine (DA) in the basolateral amygdala (BLA) compared to sham-lesioned rats. Intra-LHb injection of pre-synaptic GABA B receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABA B receptor antagonist CGP35348 induced anxiety-like responses in both groups. Further, intra-LHb injection of CGP36216 decreased the firing rate of the neurons, and increased the GABA/glutamate ratio in the LHb and release of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 increased the firing rate of the neurons and decreased the GABA/glutamate ratio and release of DA and 5-HT in sham-lesioned and the lesioned rats. However, the doses of the antagonists producing these behavioral effects in the lesioned rats were lower than those in sham-lesioned rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in the lesioned rats. Collectively, these findings suggest that pre-synaptic and post-synaptic GABA B receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway up-regulates function and/or expression of these receptors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Triadimefon (TDF) is a pesticide used in agricultural crops to control powdery mildews, rusts and other fungal pests. It exerts its fungicidal activity through the inhibition of ergosterol biosynthesis, impairing the formation of the cell membrane. For vertebrates, one of its side effects is the binding to the dopamine transporter increasing the levels of synaptic dopamine, similarly to cocaine. In addition, it has been demonstrated that TDF affects the abundance of other monoamines in the brain, specifically serotonin. It is well known that drugs which alter the dopaminergic and serotonergic systems produce behavioral changes and participate in the development of addictions in mammals. In this work we have used the conditioned place preference paradigm to assess, for the first time, the rewarding properties of TDF in zebrafish. We found out that TDF triggers both, preference and aversion depending on the dosage used during conditioning. We observed that 5 mg/L produced aversion to the pattern previously paired with TDF. However, 15 mg/L induced the opposite behavior, showing that zebrafish seek out those environments which had previously been paired with the higher dose of TDF. These results are congruent with our previous findings, where we showed that 5 mg/L reduced the levels of serotonin, usually linked to anxious behaviors (a negative cue), whereas higher concentrations of TDF increased extracellular dopamine, the main currency of the reward system. Interestingly, both doses of TDF induced circling behavior, a feature usually seen in glutamatergic antagonists., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fluoxetine (FLX), a commonly used selective serotonin reuptake inhibitor, is often used to treat depression during pregnancy. However, prenatal exposure to FLX has been associated with a series of neuropsychiatric illnesses. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral abnormalities in offspring. Thus, the present study aimed to explore whether prenatal FLX exposure causes long-term neurobehavioral effects, and identify the underlying mechanism between FLX and abnormal behaviors. In our study, 12/mg/kg/day of FLX or equal normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX = 30, NS = 27) on gestation day 11 till birth. We assessed the physical development and behavior of offspring, and in vivo magnetic resonance spectroscopy (MRS) was conducted to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Our results showed that the offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety-like behavior, and impaired social interaction. Moreover, down-regulation of 5-HT and SERT expression were identified in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1H-MRS in the PFC of offspring. Finally, a proteomic study revealed sex-dependent differential protein expression. These findings may have translational importance suggesting that using SSRI medication alone in pregnant mothers may result in developmental delay in their offspring. Our results also help guide the choice of outcome measures in identifying of molecular and developmental mechanisms., (Copyright © 2021. Published by Elsevier Ltd.)

Patients deprived of cigarettes exhibit increased pain sensitivity during perioperative periods, yet the underlying neuroanatomical and molecular bases of this hypersensitivity are unclear. The present study showed that both the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were significantly decreased in a rat model of nicotine withdrawal. These rats showed less tryptophan hydroxylase 2 (TPH2) positive neurons and reduced TPH2 expression in the nucleus raphe magnus (NRM), and thus resulted in decreased 5-hydroxytryptamine (5-HT) levels in cerebrospinal fluid. Intrathecal injection of 5-HT or NRM microinjection of TPH-overexpression adeno-associated virus alleviated nicotine withdrawal-induced hyperalgesia, whereas 5-HT receptor pharmacological blockade by methysergide (a 5-HT receptor antagonist) exacerbated hypersensitivity and diminished the difference between the two groups. Together, these data indicate that hyperalgesia after nicotine withdrawal is mediated by declined descending serotonergic pathways in the NRM. This provides a new perspective to improve the postoperative pain management of patients, especially the smokers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Parkinson's disease is a multifactorial neurodegenerative disease. The cellular pathology includes dopamine depletion, decrease in mitochondrial complex I enzyme activity, lysosomal glucocerebrosidase enzyme activity and glutathione levels. The SH-SY5Y human neuroblastoma cell line is one of the most widely used cell line models for Parkinson's disease. However, the consensus on its suitability as a model in its proliferative or differentiated state is lacking. In this study, we characterized and compared the biochemical processes most often studied in PD. This in proliferative and differentiated phenotypes of SH-SY5Y cells and several differences were found. Most notably, extracellular dopamine metabolism was significantly higher in differentiated SH-SY5Y. Furthermore, there was a greater variability in glutathione levels in proliferative phenotype (+/- 49%) compared to differentiated (+/- 16%). Finally, enzyme activity assay revealed significant increase in the lysosomal enzyme glucocerebrosidase activity in differentiated phenotype. In contrast, our study has found similarities between the two phenotypes in mitochondrial electron transport chain activity and tyrosine hydroxylase protein expression. The results of this study demonstrate that despite coming from the same cell line, these cells possess some key differences in their biochemistry. This highlights the importance of careful characterization of relevant disease pathways to assess the suitability of cell lines, such as SH-SY5Y cells, for modelling PD or other diseases, i.e. when using the same cell line but different differentiation states., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Within the hindbrain, serotonin (5-HT) functions as a modulator of the central glucagon-like peptide-1 (GLP-1) system. This interaction between 5-HT and GLP-1 is achieved via 5-HT2C and 5-HT3 receptors and is relevant for GLP-1-mediated feeding behavior. The central GLP-1 system is activated by various stressors, activates the hypothalamic pituitary adrenocortical (HPA) axis, and contributes to stress-related behaviors. Whether 5-HT modulates GLP-1's role in the stress response in unknown. We hypothesized that the serotonergic modulation of GLP-1-producing neurons (i.e., PPG neurons) is stimuli-specific and that stressed-induced PPG activity is one of the modalities in which 5-HT plays a role. In this study, we investigated the roles of 5-HT2C and 5-HT3 receptors in mediating the activation of PPG neurons in the nucleus tractus solitarius (NTS) following exposure to three different acute stressors: lithium chloride (LiCl), noncontingent cocaine (Coc), and novel restraint stress (RES). Results showed that increased c-Fos expression in PPG neurons following LiCl and RES-but not Coc-is dependent on hindbrain 5-HT2C and 5-HT3 receptor signaling. Additionally, stressors that depend on 5-HT signaling to activate PPG neurons (i.e., LiCl and RES) increased c-Fos expression in 5-HT-expressing neurons within the caudal raphe (CR), specifically in the raphe magnus (RMg). Finally, we showed that RMg neurons innervate NTS PPG neurons and that some of these PPG neurons lie in close proximity to 5-HT axons, suggesting RMg 5-HT-expressing neurons are the source of 5-HT input responsible for engaging NTS PPG neurons. Together, these findings identify a direct RMg to NTS pathway responsible for the modulatory effect of 5-HT on the central GLP-1 system-specifically via activation of 5-HT2C and 5-HT3 receptors-in the facilitation of acute stress responses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Synapsins (Syns) are a family of phosphoproteins associated with synaptic vesicles (SVs). Their main function is to regulate neurotransmitter release by maintaining a reserve pool of SVs at the presynaptic terminal. Previous studies reported that the deletion of one or more Syn genes in mice results in an epileptic phenotype and autism-related behavioral abnormalities. Here we aimed at characterizing the behavioral phenotype and neurobiological correlates of the deletion of Syns in a Syn triple knockout (TKO) mouse model. Wild type (WT) and TKO mice were tested in the open field, novelty suppressed feeding, light-dark box, forced swim, tail suspension and three-chamber sociability tests. Using in vivo electrophysiology, we recorded the spontaneous activity of dorsal raphe nucleus (DRN) serotonin (5-HT) and ventral tegmental area (VTA) dopamine (DA) neurons. Levels of 5-HT and DA in the frontal cortex and hippocampus of WT and TKO mice were also assessed using a High-Performance Liquid Chromatography. TKO mice displayed hyperactivity and impaired social and anxiety-like behavior. Behavioral dysfunctions were accompanied by reduced firing activity of DRN 5-HT, but not VTA DA, neurons. TKO mice also showed increased responsiveness of DRN 5-HT-1A autoreceptors, measured as a reduced dose of the 5-HT-1A agonist 8-OH-DPAT necessary to inhibit DRN 5-HT firing activity by 50%. Finally, hippocampal 5-HT levels were lower in TKO than in WT mice. Overall, Syns deletion in mice leads to a reduction in DRN 5-HT firing activity and hippocampal 5-HT levels along with behavioral alterations reminiscent of human neuropsychiatric conditions associated with Syn dysfunction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In modern societies, there is a strive to improve the quality of life related to risk of crimes which inevitably requires a better understanding of brain determinants and mediators of aggression. Neurobiology provides powerful tools to achieve this end. Pre-clinical and clinical studies show that changes in regional volumes, metabolism-function and connectivity within specific neural networks are related to aggression. Subregions of prefrontal cortex, insula, amygdala, basal ganglia and hippocampus play a major role within these circuits and have been consistently implicated in biology of aggression. Genetic variations in proteins regulating the synthesis, degradation, and transport of serotonin and dopamine as well as their signal transduction have been found to mediate behavioral variability observed in aggression. Gene-gene and gene-environment interactions represent additional important risk factors for aggressiveness. Considering the social burden of pathological forms of aggression, more basic and translational studies should be conducted to accelerate applications to clinical practice, justice courts, and policy making., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ongoing activity in nociceptors, a driver of spontaneous pain, can be generated in dorsal root ganglion neurons in the absence of sensory generator potentials if one or more of three neurophysiological alterations occur - prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Previous work showed that acute, sustained exposure to serotonin (5-HT) hyperpolarized AP threshold and potentiated DSFs, leading to ongoing activity if a separate source of maintained depolarization was present. Cellular signaling pathways that increase DSF amplitude and promote ongoing activity acutely in nociceptors are not known for any neuromodulator. Here, isolated DRG neurons from male rats were used to define the pathway by which low concentrations of 5-HT enhance DSFs, hyperpolarize AP threshold, and promote ongoing activity. A selective 5-HT 4 receptor antagonist blocked these 5-HT-induced hyperexcitable effects, while a selective 5-HT 4 agonist mimicked the effects of 5-HT. Inhibition of cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), attenuated 5-HT's hyperexcitable effects, but a blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels had no significant effect. 5-HT 4 -dependent PKA activation was specific to DRG neurons that bind isolectin B4 (a nonpeptidergic nociceptor marker). 5-HT's effects on AP threshold, DSFs, and ongoing activity were mimicked by a cAMP analog. Sustained exposure to 5-HT promotes ongoing activity in nonpeptidergic nociceptors through the G s -coupled 5-HT 4 receptor and downstream cAMP signaling involving both PKA and EPAC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pomegranate (Punica granatum) fruit is of particular interest because of its high nutritional value and therapeutic actions. Recently, we showed that an aqueous extract of pomegranate (AE-PG) given by oral route induced antidepressant-like actions mediated by estrogen receptors (ERs) suggesting its potential to function as an alternative to estrogen therapy replacement in menopause-related depression treatment. Orally administered AE-PG allows the biotransformation of ellagitannins into active estrogenic compounds through the intestinal microbiota. However, it is necessary to know if compounds that do not need to be biotransformed by the intestinal microbiota are involved in the antidepressant-like effects. Therefore, the first aim of this study was to determine if AE-PG produces an antidepressant-like effect when administered intraperitoneally. Also, to determine the participation of specific ER-subtypes (α or β) and to analyze the role of the serotonergic system. Young female Wistar rats were ovariectomized as a surgical model of menopause. The intraperitoneal administration of AE-PG (1 mg/kg; i. p.) was evaluated in the forced swimming test and open field tests. Also, the ERα antagonist (TPBM; 50 μg/rat; s. c.) or the ERβ antagonist (PHTPP; 25 μg/rat; s. c.) were administered with AE-PG to analyze the participation of the specific ERs. Finally, the effect of the serotonin neurotoxin 5,7-DHT (200 μg/rat; i. c.v.) on the antidepressant-like effect of the AE-PG was studied in independent experimental groups. RESULTS: showed that AE-PG administered by intraperitoneal route induced antidepressant-like effects. This result suggests that gut microbiota biotransformation is not necessary to exert its actions. The mechanism of action involves the activation of the ERβ and the serotonergic system. Altogether, this information contributes to the elucidation of the antidepressant action of the pomegranate fruit, which could be further considered as an alternative treatment for depression during menopause., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1-10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1-15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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

Brain cytochrome P450 (CYP) contributes to the local metabolism of endogenous substrates and drugs. The aim of present study was to ascertain whether the cytochrome P450 2D (CYP2D) activity changes with ageing and in cerebral serotonin deficit. Kinetics of 5-methoxytryptamine O-demethylation to serotonin was studied and the CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) rats (mature 3.5-month-old and senescent 21-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent rats. The CYP2D activity and protein level decreased in the frontal cortex of senescent WT rats, but increased in senescent TPH2-deficient rats (compared to senescent WT). In contrast, in the hippocampus, hypothalamus and striatum the CYP2D activity/protein level increased with ageing, but did not change in senescent TPH2-deficient animals (compared to senescent WT). The activity and protein level of liver CYP2D was lower in senescent WT rats than in the mature animals and further decreased in senescent TPH2-deficient rats. In conclusion, ageing and TPH2-deficit affect the CYP2D activity and protein level, which may have a positive impact on neurotransmitter synthesis in brain structures involved in cognitive, emotional or motor functions, but a negative effect on drug metabolism in the liver., (Copyright © 2020 Elsevier Ltd. All rights reserved.)