Serotonin Depletion Research Articles

Boosting Serotonin Synthesis Is Not Sufficient to Improve Motor Coordination of Mecp2 Heterozygous Mouse Model of Rett Syndrome

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Mecp2 Het mice. Motor coordination was assessed in the accelerated rotarod during and after systemic administration of serotonin precursors for 2–3 weeks. Since no data are available, the effect of α-lactalbumin on tryptophan, serotonin and 5-hydroxyindoleacetic acid levels was evaluated in various brain regions in order to identify the dose of ALAC to evaluate on motor coordination. As compared to WT, Mecp2 Het mice show reduced levels of serotonin in the whole brain, hippocampus, brainstem and cerebral cortex, but not the striatum. Reduced levels of 5-hydroxyindoleacetic acid were observed in the hippocampus and brainstem. Doses of serotonin precursors increasing brain tryptophan and/or serotonin production and metabolism had no effect on motor coordination. The results indicate that boosting serotonin synthesis is not sufficient to improve motor coordination of Mecp2 Het mice.

Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.

Early-life manipulation of the serotonergic system exacerbates the harmful effects of sleep deprivation on cognitive functions.

Serotonin is a monoamine neurotransmitter that plays a main role in regulating physiologicaland cognitive functions. Serotonergic system dysfunction is involved in the etiology of various psychiatric and neurological disorders. Therefore, the present study was designed to investigate the effects of early-life serotonin depletion on cognitive disorders caused by sleep deprivation. Serotonin was depleted by para-chlorophenylalanine (PCPA, 100 mg/kg, s.c.) at postnatal days 10-20, followed by sleep deprivation-induced through the multiple platform apparatus for 24 h at PND 60. After the examination of the novel object recognition and passive avoidance memories, the hippocampi and prefrontal cortex were dissected to examine the brain-derived neurotrophic factor (BDNF) mRNA expression by PCR. Our findings showed that postnatal serotonin depletion and sleep deprivation impaired the novel object recognition and passive avoidance memories and changed the BDNF levels. In the same way, the serotonin depletion in early life before sleep deprivation exacerbated the harmful effects of sleep deprivation on cognitive function and BDNF levels. It can be claimed that the serotonergic system plays a main role in the modulation of sleep and cognitive functions.

The Involvement of the Serotonergic System in Ketamine and Fluoxetine Combination-induced Cognitive Impairments in Mice.

Glutamatergic N-methyl-D-aspartate (NMDA) receptors play vital roles in memory formation. Changes in the activity of these receptors influence memory processes. Ketamine is a noncompetitive NMDA receptor antagonist drug with promising mood-altering and pain-reducing effects in low doses. These effects are believed to be related to altered serotonergic transmission. The present study investigated the involvement of the serotonergic system in low-dose ketamine administrations' effects on memory acquisition, consolidation, and retrieval processes. Sixty-four male BALB/c mice were used in this experiment and separated into 8t groups. Mice were treated subchronically with a selective serotonin reuptake inhibitor, fluoxetine, and a serotonin depletion agent, p-chlorophenylalanine (pCPA). A serotonin antagonist, methiothepin, and ketamine were acutely administered 60 minutes before or after the behavioral tests. A passive avoidance (PA) test measured emotional memory acquisition, consolidation, and retrieval processes. Hippocampi malondialdehyde (MDA) levels were analyzed, and histopathological examinations were performed. Ketamine alone did not significantly affect memory encoding processes in the PA test, while the ketamine-fluoxetine combination disrupted memory consolidation. Fluoxetine negatively affected the memory acquisition process, which was normalized during the consolidation and retrieval trials. Drug applications did not significantly alter hippocampal MDA levels. In all ketamine-applied groups, histopathologic alterations were evident. Low-dose ketamine administration induces neurodegeneration, and it also impairs memory functions when combined with fluoxetine, indicating increased serotonergic transmission may be involved in the memory-impairing and neurotoxic effects of ketamine.

Poor Decision Making and Sociability Impairment Following Central Serotonin Reduction in Inducible TPH2-Knockdown Rats.

Serotonin is an essential neuromodulator for mental health and animals' socio-cognitive abilities. However, we previously found that a constitutive depletion of central serotonin did not impair rat cognitive abilities in stand-alone tests. Here, we investigated how a mild and acute decrease in brain serotonin would affect rats' cognitive abilities. Using a novel rat model of inducible serotonin depletion via the genetic knockdown of tryptophan hydroxylase 2 (TPH2), we achieved a 20% decrease in serotonin levels in the hypothalamus after three weeks of non-invasive oral doxycycline administration. Decision making, cognitive flexibility, and social recognition memory were tested in low-serotonin (Tph2-kd) and control rats. Our results showed that the Tph2-kd rats were more prone to choose disadvantageously in the long term (poor decision making) in the Rat Gambling Task and that only the low-serotonin poor decision makers were more sensitive to probabilistic discounting and had poorer social recognition memory than other low-serotonin and control individuals. Flexibility was unaffected by the acute brain serotonin reduction. Poor social recognition memory was the most central characteristic of the behavioral network of low-serotonin poor decision makers, suggesting a key role of social recognition in the expression of their profile. The acute decrease in brain serotonin appeared to specifically amplify the cognitive impairments of the subgroup of individuals also identified as poor decision makers in the population. This study highlights the great opportunity the Tph2-kd rat model offers to study inter-individual susceptibilities to develop cognitive impairment following mild variations of brain serotonin in otherwise healthy individuals. These transgenic and differential approaches together could be critical for the identification of translational markers and vulnerabilities in the development of mental disorders.

Exploring the role of inflammation in major depressive disorder: beyond the monoamine hypothesis.

Major depressive disorder affects approximately 8.4% of the United States population. The World Health Organization estimates that 280 million adults worldwide are suffering from depression. They have estimated that by 2030 it will be the second most serious condition. Current treatment relies on the monoamine hypothesis, however, one-third of patients with MDD do not respond to monoamine-based antidepressants. For years, it was hypothesized that the primary pathway of MDD involved serotonin as the main neurotransmitter. The monoamine hypothesis, a widely accepted theory, sought to explain the biological basis of MDD as being caused by the depletion of monoamine neurotransmitters, namely norepinephrine and serotonin. This hypothesis regarding monoamines as the pathophysiological basis of MDD led to the design and widespread use of selective serotonin reuptake inhibitors. However, given that only one-third of patients improve with SSRI it is reasonable to infer that the pathway involved is more complex than once hypothesized and there are more neurotransmitters, receptors, and molecules involved. The monoamine hypothesis does not explain why there is a delay in the onset of effect and action of SSRIs. Several studies have demonstrated that chronic stress is a risk factor for the development of MDD. Thus the monoamine hypothesis alone is not enough to fully account for the pathophysiology of MDD highlighting the need for further research involving the pathways of MDD. In this paper, we review the role of inflammation and cytokines on MDD and discuss other pathways involved in the development and persistence of depressive symptoms.

New bithiophene derivative attenuated Alzheimer’s disease induced by aluminum in a rat model via antioxidant activity and restoration of neuronal and synaptic transmission

BackgroundOne of the hypotheses that leads to an increased incidence of Alzheimer’s disease (AD) is the accumulation of aluminum in the brain’s frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. MethodologyAdult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3–6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. Main findingsAl disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-β plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. ConclusionTaking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-β plaques and phosphorylation of tau.

Altered circadian rhythms effects on anxiety, locomotor activity, serotonin and nitric oxide levels in the prefrontal cortex of juvenile and adult rats

AbstractBackgroundDementia and Alzheimer’s disease (AD) can be exacerbated by irregular sleep‐wake cycles, and age may be a risk factor. This study compared behavioral responses such as anxiety, motor coordination, and locomotion to altered circadian rhythms and serotonin, nitric oxide (NO), and malondialdehyde (MDA) levels in the prefrontal cortex of juvenile and adult rats.MethodA total of thirty female Wistar rats were grouped into three (n = 5) in the following juvenile (30‐45 days old) and adult (90‐120 days old) groups: (A) Control (12L:12D cycle),(B) 24‐hour LED light exposure(12L:12L cycle) and (C) 24‐hour dark cycle (12D:12D cycle). Experimental rats were kept in the stated cycle conditions using natural lighting, LED lighting, and a dark room, respectively, for 60 days. Data were analyzed using a two‐way ANOVA (GraphPad Prism 9), and statistical significance was measured at p<0.05.ResultFindings from the study revealed progressive weight loss in the sleep‐deprived juvenile (12L:12L) rats compared to adults (p<0.05) in the same and other groups. Also, anxiety‐like indices such as longer duration of time in the dark area of the light‐dark box, avoidance of open arm entries on the elevated plus maze, reduced line crossing activity in the open field box, etc. were markedly higher in the juvenile rats from the 12L:12L and 12D:12D groups respectively. When juvenile and adult 12L:12L and 12D:12D cycle rats data were compared to controls, severe depletion of serotonin (p<0.0001) and nitric oxide (p<0.01) levels were observed, while age‐dependent MDA levels were revealed across all groups.ConclusionA bi‐directional relationship was observed between age and circadian disruption effects with more severe outcomes in juveniles compared to adults and this hold interesting implications for the study of the biological clock mechanisms underlying anxiety, mood and sleep disorders in living systems.

The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats

BackgroundLiver cytochrome P450 (CYP) greatly contributes to the metabolism of endogenous substances and drugs. Recent studies have demonstrated that CYP expression in the liver is controlled by the central nervous system via hormonal pathways. In particular, the expression of hepatic CYPs is negatively regulated by the brain serotoninergic system. The present study aimed to investigate changes in the function of the main liver drug-metabolizing CYP enzymes as a result of serotonin depletion in the brain of aging rats, caused by knockout of brain tryptophan hydroxylase gene (TPH2-KO).MethodsThe hepatic CYP mRNA (qRT-PCR), protein level (Western blotting) and activity (HPLC), and serum hormone levels (ELISA) were measured in Dark Agouti wild-type (WT) male rats (mature 3.5-month-old and senescent 21-month-old) and in TPH2-KO senescent animals.ResultsThe expression/activity of the studied CYPs decreased with age in the liver of wild-type rats. The deprivation of serotonin in the brain of aging males decreased the mRNA level of most of the studied CYPs (CYP1A/2A/2B/3A), and lowered the protein level of CYP2C11 and CYP3A. In contrast, the activities of CYP2C11, CYP3A and CYP2C6 were increased. The expression of cytochrome b5 decreased in aging rats, but increased in TPH2-deficient senescent animals. The serum concentration of growth hormone declined in the aged and further dropped down in TPH2-deficient senescent rats.ConclusionsRat liver cytochrome P450 functions deteriorate with age, which may impair drug metabolism. The TPH2 knockout, which deprives brain serotonin, affects cytochrome P450 expression and activity differently in mature and senescent male rats.

Deciphering migraine pain mechanisms through electrophysiological insights of trigeminal ganglion neurons

Migraine is a complex neurological disorder that affects millions of people worldwide. Despite extensive research, the underlying mechanisms that drive migraine pain and related abnormal sensation symptoms, such as hyperalgesia, allodynia, hyperesthesia, and paresthesia, remain poorly understood. One of the proposed mechanisms is cortical spreading depression (CSD), which is believed to be involved in the regulation of trigeminovascular pathways by sensitizing the pain pathway. Another mechanism is serotonin depletion, which is implicated in many neurological disorders and has been shown to exacerbate CSD-evoked pain at the cortical level. However, the effects of CSD and serotonin depletion on trigeminal ganglion neurons, which play a critical role in pain signal transmission, have not been thoroughly studied. In this study, we aimed to investigate the association between CSD and serotonin depletion with peripheral sensitization processes in nociceptive small-to-medium (SM) and large (L) -sized trigeminal ganglion neurons at the electrophysiological level using rat models. We divided the rats into four groups: the control group, the CSD group, the serotonin depletion group, and the CSD/serotonin depletion group. We induced CSD by placing KCl on a burr hole and serotonin depletion by intraperitoneal injection of PCPA (para-chlorophenoxyacetic acid). We then isolated trigeminal ganglion neurons from all groups and classified them according to size. Using patch-clamp recording, we recorded the excitability parameters and action potential (AP) properties of the collected neurons. Our results showed that in SM-sized trigeminal ganglion neurons, the CSD-SM and CSD/serotonin depletion groups had a higher positive resting membrane potential (RMP) than the control-SM group (p = 0.001 and p = 0.002, respectively, post-hoc Tukey’s test). In addition, the gap between RMP and threshold in the CSD-SM group was significantly narrower than in the control-SM group (p = 0.043, post-hoc Tukey’s test). For L-sized neurons, we observed prolongation of the AP rising time, AP falling time, and AP duration in neurons affected by CSD (p < 0.05, pairwise comparison test). In conclusion, our study provides new insights into the underlying mechanisms of migraine pain and abnormal somatosensation. CSD and serotonin depletion promote the transmission of pain signals through the peripheral sensitization process of nociceptive small-to-medium-sized trigeminal ganglion neurons, as well as nociceptive and non-nociceptive large-sized trigeminal ganglion neurons.

Serotonin and dopamine depletion in distinct brain regions may cause anxiety in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice as a model of early Parkinson's disease.

In this study, we aimed to evaluate the association of early anxious behavior with serotonin, dopamine, and their metabolites in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. Forty C57BL/6 male mice were randomly divided into the control group (n = 20) and the model group (n = 20). Mice in the model group were injected intraperitoneally with MPTP. The light-dark box (LDB) and elevated plus-maze were used to monitor anxious behavior. The association of early anxious behavior with neurotransmitters in the prefrontal cortex, hippocampus, and striatum was evaluated. In our murine model, MPTP induced a decreased level of 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the prefrontal cortex, hippocampus, and striatum (all P < 0.05); however, it only induced a decreased level of dopamine and its metabolite homovanillic acid (HVA) in the striatum (both P < 0.001), with a negative correlation in the hippocampus and a positive correlation in the cortex and striatum. In the LDB, 5-hydroxytryptamine levels in the cortex and dopamine and HVA levels in the striatum were negatively correlated with anxious behavior. Moreover, in the elevate plus-maze, 5-hydroxytryptamine and 5-HIAA in the cortex and dopamine and HVA in the striatum were positively correlated with the ratio of the time spent in open arms. In the murine model of early Parkinson's disease, the balance between dopamine and 5-hydroxytryptamine systems varied among brain regions. The depletion of 5-hydroxytryptamine in the cortex and dopamine in the striatum may be associated with anxiety behaviors in MPTP-treated mice.

Para-Chlorophenyl Alanine Induces Aggressive Behavior by Serotonin Depletion in Male Rats and Increases Tryptophan Hydroxylase two and GABAA α1 mRNA Expression in the Olfactory Bulb

Para-Chlorophenyl Alanine Induces Aggressive Behavior by Serotonin Depletion in Male Rats and Increases Tryptophan Hydroxylase two and GABAA α1 mRNA Expression in the Olfactory Bulb

Seizures Cause Prolonged Impairment of Ventilation, CO2 Chemoreception and Thermoregulation.

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1a R1407X/+ (Dravet syndrome; DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.

Effects of Dopamine and Serotonin Depletion on Reward and Aversion Processes in the Human Brain

Effects of Dopamine and Serotonin Depletion on Reward and Aversion Processes in the Human Brain

Phytotherapeutic alternatives for neurodegenerative dementias: Scientific review, discussion and therapeutic proposal.

The incidence and prevalence of age-related neurodegenerative dementias have been increasing. There is no curative therapy and conventional drug treatment can cause problems for patients. Medicinal plants traditionally used for problems associated with ageing are emerging as a therapeutic resource. The main aim is to give a proposal for use and future research based on scientific knowledge and tradition. A literature search was conducted in several searchable databases. The keywords used were related to neurodegenerative dementias, ageing and medicinal plants. Boolean operators and filters were used to focus the search. As a result, there is current clinical and preclinical scientific information on 49 species used in traditional medicine for ageing-related problems, including neurodegenerative dementias. There are preclinical and clinical scientific evidences on their properties against protein aggregates in the central nervous system and their effects on neuroinflammation, apoptosis dysregulation, mitochondrial dysfunction, gabaergic, glutamatergic and dopaminergic systems alterations, monoamine oxidase alterations, serotonin depletion and oestrogenic protection. In conclusion, the potential therapeutic effect of the different medicinal plants depends on the type of neurodegenerative dementia and its stage of development, but more clinical and preclinical research is needed to find better, safer and more effective treatments.

Constitutive depletion of brain serotonin differentially affects rats’ social and cognitive abilities

Central serotonin appears a promising transdiagnostic marker of psychiatric disorders and a modulator of some of their key behavioral symptoms. In adult male Tph2 -/- rats, constitutively lacking central serotonin, we tested individual's cognitive, social and non-social abilities and characterized group's social organization under classical and ethological testing conditions. Using unsupervised machine learning, we identified the functions most dependent on serotonin. Although serotonin depletion did not affect cognitive performances in classical testing, in the home-cage it induced compulsive aggression and sexual behavior, hyperactive and hypervigilant stereotyped behavior, reduced self-care and exacerbated corticosterone levels. This profile recalled symptoms of impulse control and anxiety disorders. Serotonin appeared essential for behavioral adaptation to dynamic social environments. Our animal model challenges the essential role of serotonin in decision-making, flexibility, impulsivity, and risk-taking. These findings highlight the importance of studying everyday life functions within the dynamic social living environment to model complexity in animal models.

(+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission

The antidepressant-like activity of (+)-catharanthine and (-)-18-methoxycoronaridine [(-)-18-MC] was studied in male and female mice using forced swim (FST) and tail suspension tests (TST). The underlying molecular mechanism was assessed by electrophysiological, radioligand, and functional experiments. The FST results showed that acute administration (40 mg/kg) of (+)-catharanthine or (-)-18-MC induces similar antidepressant-like activity in male and female mice at 1 h and 24 h, whereas the TST results showed a lower effect for (-)-18-MC at 24 h. Repeated treatment at lower dose (20 mg/kg) augmented the efficacy of both congeners. The FST results showed that (-)-18-MC reduces immobility and increases swimming times without changing climbing behavior, whereas (+)-catharanthine reduces immobility time, increases swimming times more markedly, and increases climbing behavior. To investigate the contribution of the serotonin and norepinephrine transporters in the antidepressant effects of (+)-catharanthine and (-)-18-MC, we conducted in vitro radioligand and functional studies. Results obtained demonstrated that (+)-catharanthine inhibits norepinephrine transporter with higher potency/affinity than that for (-)-18-MC, whereas both congeners inhibit serotonin transporter with similar potency/affinity. Moreover, whereas no congener activated/inhibited/potentiated the function of serotonin receptor 3A or serotonin receptor 3AB, both increased serotonin receptor 3A receptor desensitization. Depletion of serotonin decreased the antidepressant-like activity of both congeners, whereas norepinephrine depletion only decreased (+)-catharanthine’s activity. Our study shows that coronaridine congeners induce antidepressant-like activity in a dose- and time-dependent, and sex-independent, manner. The antidepressant-like property of both compounds involves serotonin transporter inhibition, without directly activating/inhibiting serotonin receptors 3, while (+)-catharanthine also mobilizes norepinephrinergic neurotransmission.

Beneficial effects of enriched environment on behavior, cognitive functions, and hippocampal brain-derived neurotrophic factor level following postnatal serotonin depletion in male rats.

The neurotransmitter serotonin (5-HT) is one of the most important modulators of neural circuitry and has a critical role in neural development and functions. Previous studies indicated that changes in serotonergic system signaling in early life critically impact mental health, behavior, the morphology of hippocampal neurons, and cognitive functions across the lifespan. The enriched environment (EE) has indicated beneficial effects on behavior and cognitive functions in the developmental period of life, but its impacts on cognitive impairments and behavioral changes following postnatal serotonin depletion are unknown. Therefore, the present study aimed to evaluate the influences of the EE housing (postnatal days [PNDs] 21-60) following postnatal serotonin depletion (by para-chlorophenylalanine [PCPA], 100 mg/kg, s.c, in PNDs 10-20) on anxiety-related behaviors, cognitive functions, and brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus of male rats. Memory and behavioral parameters were examined in early adulthood and after that, the hippocampi of rats were removed to determine the BDNF mRNA expression by PCR (PNDs 60-70). The findings of the present work indicated that adolescent EE exposure alleviated memory impairment, decreased BDNF levels, and anxiety disorders induced by experimental depletion of serotonin. Overall, these results indicate that serotonergic system dysregulation during the developmental periods can be alleviated by adolescent EE exposure.

Selective Serotonin Reuptake Inhibitors and Associated Bleeding Risks: A Narrative and Clinical Review.

Major Depressive Disorder (MDD) is a major cause of disability worldwide and is associated with serious lasting impairment. A leading hypothesis of the pathophysiology of MDD is the monoamine deficiency hypothesis which suggests that depression is caused by depletion of serotonin, norepinephrine, or dopamine in the central nervous system. Serotonin is the most widely studied neurotransmitter in the pathophysiology of depression, with studies showing that reduced central serotonin synthesis leads to depressive symptoms in individuals at risk for depression. Selective Serotonin Reuptake Inhibitors (SSRI) inhibit serotonin reuptake and subsequently increase the amount of serotonin available in synapses. Common side effects of SSRIs include increased suicidality of patients under the age of 25, sexual dysfunction, anxiety, dizziness, weight gain, gastrointestinal distress, and headache. Other side effects include prolonging the QT interval, coagulopathy, and the risk of serotonin syndrome, as well as SSRI discontinuation syndrome. Sites of increased bleeding related to SSRI use have been reported to occur in the upper gastrointestinal tract, as well as intracranially. Based on the current literature, three studies have found that SSRIs are not associated with increased bleeding and/or increased perioperative risk, while others have demonstrated that SSRIs are associated with an increased risk in perioperative use. The inhibition of serotonin reuptake can affect platelet aggregation since platelets also express the serotonin transporter. SSRIs can result in decreased storage of serotonin in platelet dense granules. Increased serotonin can also increase gastric acid secretion, which increases the risk for ulceration. SSRIs in combination with NSAIDs also show a significantly increased risk of upper GI bleeding. Some studies show an increased bleeding risk from 30% to 70% when taking a combination of vitamin K antagonists and SSRIs in hospitalized patients. Related to the high prevalence of conditions that are treated with SSRIs, the bleeding risk associated with this class of medication merits further study.

Network pharmacology and pharmacological evaluation for deciphering novel indication of Sishen Wan in insomnia treatment

BackgroundInsomnia is the most frequent sleep disorder worldwide and is a prominent risk factor for mental and physical health deterioration. The clinical application of common pharmacological treatments for insomnia is far from satisfactory due to their various adverse effects. In recent years, drugs developed from natural herbs have become potential alternative therapies for insomnia. Sishen Wan (SSW), a traditional Chinese medicine (TCM) used for centuries to treat diarrheal disease, consists of multiple neurologically active herbs with sleep-regulating potential that may have therapeutic effects on insomnia. However, its hypnotic and sleep-regulating effects have not been evaluated in clinical practice or laboratory experiments. PurposeTo investigate the anti-insomnia effects of SSW and explore its possible mechanisms using preclinical models. Study design and methodsThe sedative effect of the SSW formula was investigated using network pharmacology analysis that was validated using various pharmacological approaches, including the evaluation of locomotor activity (LMA), pentobarbital-induced sleep time, and electroencephalography/electromyogram (EEG/EMG)-based sleep profiling in normal rats. Several animal models of insomnia, including sleep deprivation, serotonin depletion, and cage-changing models, have been used to further assess the anti-insomnia effects of SSW. Furthermore, the potential underlying mechanisms of action of SSW were predicted using bioinformatics methods and verified using in vivo and in silico experiments. ResultsThe results showed that SSW reduced LMA and prolonged pentobarbital-induced sleep time in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement (NREM) sleep in normal rats, indicating a solid sedative effect. In animal models of insomnia, SSW alleviated sleep disturbance by increasing NREM sleep time, shortening NREM sleep latency, and inhibiting sleep fragmentation, suggesting a possible curative effect of SSW on insomnia. Finally, through functional enrichment analysis and in vivo and in silico experiments, 5-HT1A was identified as the key target of the anti-insomnia effect of SSW. Moreover, (S)-propranolol, nuciferine, zizyphusine, and N,N-dimethyl-5-methoxytryptamine may be the active compounds of SSW responsible for its anti-insomnia effect. ConclusionThis study extended the possible indication scope for SSW, which provides a potential therapeutic TCM that may be used for insomnia treatment, as well as a reference scheme for the discovery of novel indications of TCM.