Serotonin Synthesis Inhibitor Research Articles

Antidepressant-Like Effect of the Polymethoxylated Flavone Tangeretin from Citrus Peels: The Role of Serotonergic Mechanisms

Objective: Depression is a mood disorder characterized by a set of emotional, cognitive, physical and behavioral symptoms. Low response rate to antidepressant treatment in patients with depression, late onset of action, side effects due to long-term drug use, and pharmacogenetic variations limit the effectiveness and tolerability of these drugs and lead to compliance problems in patients. Therefore, studies on the discovery and development of new antidepressant drugs continue, and molecules of natural origin are becoming the focus of attention of researchers. Tangeretin, which is commonly found in citrus peels and has a pentamethoxyflavone structure, is an important member of flavonoids. Since it lacks a glycoside structure, it is easily absorbed from the intestines and can easily pass through the blood-brain barrier due to its lipophilic structure. Previous studies indicating that tangeretin may be effective on the central nervous system suggest that it may be possible for this phytochemical to have an effect on mood. Based on this idea, this study aimed to investigate the possible antidepressant-like effects of tangeretin and to elucidate the pharmacological mechanisms mediating this effect. Methods: Male Balb/c mice of the same age, weighing 30-35 g, were used for the experiments. The antidepressant-like effect of tangeretin (10, 20 ve 40 mg/kg, p.o.) was examined by tail suspension and modified forced swimming tests, while its effect on the motor coordination of experimental animals was evaluated using the Rota-rod method. Results: The data obtained revealed that doses of 10 and 20 mg/kg tangeretin decreased the immobility time of mice in tail suspension test and immobility number of mice in modified forced swimming tests compared to control animals not receiving tangeretin. These findings indicated that tangeretin showed an antidepressant-like activity comparable to the reference drug fluoxetine (30 mg/kg) when administered at doses of 10 and 20 mg/kg. Tangeretin, at the same doses, did not alter the climbing number of mice in modified forced swimming tests, but significantly increased their swimming number. The 40 mg/kg dose of this flavonoid did not cause a statistically significant effect in either test. While α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100 mg/kg i.p.) and ondansetron (a 5-HT3 receptor antagonist; 0.3 mg/kg i.p.) pretreatments did not change the antidepressant-like activity induced by 20 mg/kg dose of this flavonoid in the tail suspension tests; pretreatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100 mg/kg i.p., administered for 4-consecutive days), NAN-190 (a 5-HT1A receptor antagonist; 0.5 mg/kg i.p.) and ketanserin (a 5-HT2A/2C receptor antagonist; 1 mg/kg i.p.), reversed this activity. These findings indicated that tangeretin has antidepressant-like activity mediated by the serotonergic system and that 5-HT1A and 5-HT2A/5-HT2C serotonergic receptor subtypes participate in this effect. Conclusion: The findings of this study suggest that tangeretin may be a useful drug candidate in the treatment of depression. However, it is clear that for tangeretin to be considered an antidepressant agent, the antidepressant-like activity presented in this preclinical study must be confirmed by well-designed clinical studies conducted on various groups of patients with depressive disorders.

Development under predation risk increases serotonin-signaling, variability of turning behavior and survival in adult fruit flies Drosophila melanogaster.

The development of high-throughput behavioral assays, where numerous individual animals can be analyzed in various experimental conditions, has facilitated the study of animal personality. Previous research showed that isogenic Drosophila melanogaster flies exhibit striking individual non-heritable locomotor handedness. The variability of this trait, i.e., the predictability of left-right turn biases, varies across genotypes and under the influence of neural activity in specific circuits. This suggests that the brain can dynamically regulate the extent of animal personality. It has been recently shown that predators can induce changes in prey phenotypes via lethal or non-lethal effects affecting the serotonergic signaling system. In this study, we tested whether fruit flies grown with predators exhibit higher variability/lower predictability in their turning behavior and higher survival than those grown with no predators in their environment. We confirmed these predictions and found that both effects were blocked when flies were fed an inhibitor (αMW) of serotonin synthesis. The results of this study demonstrate a negative association between the unpredictability of turning behavior of fruit flies and the hunting success of their predators. We also show that the neurotransmitter serotonin controls predator-induced changes in the turning variability of fruit flies, regulating the dynamic control of behavioral predictability.

Antibiotic-induced microbial depletion enhances murine small intestinal epithelial growth in a serotonin-dependent manner.

Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacologic SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared to controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared to controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically.

Central serotoninergic system mediates Neuromedin S (NMS) induced hypophagia in layer-type chicken

According to previous studies, the serotonergic system plays a remarkable role in regulating meal intake, however, its role in the mediation of feeding caused by neuromodulin S (NMS) has not been investigated in birds. In the present research, 5 trials were considered in order to determine the links between these systems. In treatment 1, chickens received intracerebroventricular (ICV) infusion of NMS (0.25, 0.5, and 1 nmol). NMS (1 nmol), SB242084 (1.5 μg), a 5-HT2C receptor antagonist, and NMS + SB242084 were injected in the treatment 2. In subsequent treatments, instead of SB242084, 8-OH-DPAT (agonist of 5-HT1A receptor, 15.25 nmol), PCPA (serotonin synthesis inhibitor, 1.25 μg), and Fluoxetine (serotonin reuptake inhibitor, 10 μg) were applied. Then, total food consumption was recorded for 120 minutes. Based on observations, NMS dose-dependently attenuated meal intake (P<0.05). Hypophagia was diminished with NMS + SB242084 administration (P<0.05). ICV infusion of NMU + 8-OH-DPAT had no significant effect on the hypophagia (P≥0.05). The NMS-induced decreasing feed intake was attenuated with co-infusion of NMS+ PCPA (P< 0.05). Also, hypophagia was strengthened by NMS+ Fluoxetine co-infusion (P< 0.05). According to the results, the NMS-induced hypophagia is possibly mediated via 5-HT2c receptors in layer-type chickens.

S-adenosyl-l-methionine antidepressant-like effects involve activation of 5-HT1A receptors

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-HT1A 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-HT1A receptor activation.

Serotonin Activity Is Correlated with Intestinal Stem Cell Proliferation in Small Intestinal Crypts

INTRODUCTION: Increased serotonin activity enhances small intestinal (SI) mucosal growth and nutrient absorption, but the mechanism behind this observation is unknown. This study evaluated the effect of serotonin signaling on intestinal stem cell (ISC) number and proliferation in mouse SI crypts. We hypothesized that alterations in serotonin activity correspond to changes in ISC proliferation. METHODS: Lgr5-EGFP-reporter mice were administered intraperitoneal citalopram, a selective serotonin reuptake inhibitor (SSRI), to potentiate serotonin activity, or para-chlorophenylalanine (PCPA), to inhibit serotonin synthesis. Control animals received saline alone. After 14 days, mice were injected intraperitoneally with bromodeoxyuridine (BrdU) to label actively dividing cells, followed by SI harvest 1 hour later. Immunofluorescence staining and microscopy identified Lgr5-positive ISC and BrdU-positive proliferating cells in epithelial crypts. ISC proliferation was quantified by calculating the proportion of crypts per animal with ≥1 cell expressing Lgr5 and labeled with BrdU. RESULTS: Compared with controls, SSRI treatment was associated with more Lgr5-positive cells per crypt (4.8 ± 0.9 vs 3.1 ± 0.6 cells/crypt; p < 0.01), and PCPA treatment resulted in no difference (3.5 ± 1.3 vs 3.1 ± 0.6 cells/crypt; p = 0.11); 66.6% of crypts in control animals did not contain proliferating stem cells. SSRI treatment was associated with a greater number of crypts exhibiting ISC proliferation (60.0% vs 33.3%; p < 0.01), and PCPA treatment was associated with fewer crypts containing proliferating ISCs (16.7% vs 33.3%; p < 0.01) compared with controls (Figure).FigureCONCLUSION: Serotonin activity is directly correlated with ISC proliferation in SI crypts. Modulation of stem cell activity with SSRIs may have therapeutic potential in patients who undergo SI resection.

Serotonin modulation in the male Aedes aegypti ear influences hearing.

Male Aedes aegypti (Ae. aegypti) mosquitoes rely on hearing to identify conspecific females for mating, with the male attraction to the sound of flying females (“phonotaxis”) an important behavior in the initial courtship stage. Hearing thus represents a promising target for novel methods of mosquito control, and hearing behaviors (such as male phonotaxis) can be targeted via the use of sound traps. These traps unfortunately have proven to be relatively ineffective during field deployment. Shifting the target from hearing behavior to hearing function could therefore offer a novel method of interfering with Ae. aegypti mating. Numerous neurotransmitters, including serotonin (5-hydroxytryptamine, or 5-HT) and octopamine, are expressed in the male ear, with modulation of the latter proven to influence the mechanical responses of the ear to sound. The effect of serotonin modulation however remains underexplored despite its significant role in determining many key behaviors and biological processes of animals. Here we investigated the influence of serotonin on the Ae. aegypti hearing function and behaviors. Using immunohistochemistry, we found significant expression of serotonin in the male and female Ae. aegypti ears. In the male ear, presynaptic sites identified via antibody labelling showed only partial overlap with serotonin. Next, we used RT-qPCR to identify and quantify the expression levels of three different serotonin receptor families (5-HT1, 5-HT2, and 5-HT7) in the mosquito heads and ears. Although all receptors were identified in the ears of both sexes, those from the 5-HT7 family were significantly more expressed in the ears relative to the heads. We then thoracically injected serotonin-related compounds into the mosquitoes and found a significant, reversible effect of serotonin exposure on the male ear mechanical tuning frequency. Finally, oral administration of a serotonin-synthesis inhibitor altered male phonotaxis. The mosquito serotonergic system and its receptors thus represent interesting targets for novel methods of mosquito, and thus disease, control.

Anxiolytic effect of Korean Red Ginseng through upregulation of serotonin and GABA transmission and BDNF expression in immobilized mice

BackgroundAnxiolytic properties of Korean Red Ginseng (KRG) have been previously reported. However, the exact mechanism(s) of action remains to be elucidated. The present study investigated the effect of KRG on immobilization-induced anxiety-like behaviors in mice and explored the involvement of the serotonin and GABA systems and BDNF in the anxiolytic action. MethodsMice were orally administered with KRG (200 mg/kg/day) for 4 weeks and immobilized once daily for 2 h. p-Chlorophenylalanine (p-CPA) was intraperitoneally injected on day 22-28, and flumazenil or bicuculline was injected on day 25-28. After behavioral evaluations, brains were dissected for biochemical analyses. ResultsKRG improved immobilization-induced anxiety-like behaviors in mice, as assessed by the elevated plus maze (EPM) and marble burying tests (MBT). The anxiolytic effect of KRG was comparable to that of fluoxetine, a reference drug clinically used for anxiety disorders. A serotonin synthesis inhibitor, p-CPA, blocked the effect of KRG in the EPM and MBT, indicating the requirement of serotonin synthesis for anxiolytic action. In addition, the anxiolytic effect of KRG was inhibited by bicuculline (a GABAA antagonist) in MBT, implying the involvement of GABA transmission. Western blotting analyses revealed that KRG upregulated the expression of tryptophan hydroxylase and GABAA receptor in the brain, which was blocked by p-CPA. Enhanced BDNF expression by KRG in the hippocampus was also indicated to mediate the anxiolytic action of KRG in immobilized mice. ConclusionKRG exhibited the anxiolytic effect in immobilized mice by multiple mechanisms of action, involving enhanced serotonin and GABA transmissions and BDNF expression.

Telotristat ethyl reverses myxomatous changes in mice mitral valves

RationaleMyxomatous mitral valve degeneration is a common pathological manifestation of mitral valve regurgitation, with or without valvular prolapse. In addition to similarities between naturally occurring and serotonergic valve degeneration, an increasing body of evidence has recently suggested that serotonin signaling is a regulator of degenerative valvulopathies. Studies have found that serotonin can be synthesized locally by valvular cells and serotonin receptors in turn may be activated to promote signaling. Recently, telotristat ethyl (TE) has been introduced as a treatment for carcinoid disease, by selectively inhibiting tryptophan hydroxylase 1, the rate-limiting enzyme in peripheral serotonin synthesis. TE provides a unique tool to test inhibition of serotonin synthesis in vivo, without impacting brain serotonin, to further confirm the role of local serotonin synthesis on heart valves.ObjectiveTo confirm the link between serotonin and myxomatous valvular disease in vivo.Methods and resultsA hypertension-induced myxomatous mitral valve disease mouse model was employed to test the effect of TE on valvular degeneration. Circulating serotonin and local serotonin in valve tissues were tested by enzyme immunoassay and immunohistochemistry, respectively. TE was administrated in two modes: (1) parallel with angiotensin II (A2); (2) post A2 treatment. Myxomatous changes were successfully recapitulated in hypertensive mice, as determined by ECM remodeling, myofibroblast transformation, and serotonin signaling activation. These changes were at least partially reversed upon TE administration.ConclusionThis study provides the first evidence of TE as a potential therapeutic for myxomatous mitral disease, either used to prevent or reverse myxomatous degeneration.

Antidepressant-like effect of tofisopam in mice: A behavioural, molecular docking and MD simulation study.

Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology. In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect. The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies. Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors. This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems.

Possible interaction of central noradrenergic, serotoninergic and oxytocin systems with nesfatin-1 induced hypophagia and feeding behavior in newborn broiler

There are some differences between mammals and birds in terms of central food intake regulation. In avian species, the hypophagic role of nesfatin-1 has not been investigated with other neurotransmitters. Therefore, this study aimed to determine the alteration of feeding behavior following intracerebroventricular (ICV) injection of nesfatin-1 and its possible interaction with central noradrenergic, serotoninergic, and oxytocin systems in newborn broiler chicks. In experiment 1, birds received ICV injection of phosphate-buffered saline (PBS), prazosin (α1 receptors antagonist, 10 nmol), nesfatin-1 (40 ng), and co-administration of prazosin and nesfatin-1. Experiments 2–10 were similar to experiment 1, except that yohimbine (α2 receptors antagonist, 13 nmol), metoprolol (β1 receptors antagonist, 24 nmol), IC1118,551 (β2 receptors antagonist for, 5nmol), SR59230R (β3 receptors antagonist, 20 nmol), fluoxetine (serotonin reuptake inhibitor, 10 µg), PCPA (serotonin synthesis inhibitor, 1.5 µg), 8-OH-DPAT (5-HT1A receptors agonist, 15.25 nmol), SB242084 (5-HT2C receptors antagonist,1.5 µg) and tocinoic acid (oxytocin receptors antagonist, 2 µg) were injected instead of prazosin. Immediately after the injection, food consumption and behavioral traits were recorded. Nesfatin-1 decreased food consumption (P < 0.05). Nesfatin-1 along with ICI118551 decreased food consumption (P < 0.05). The nesfatin-1- induced hypophagia were reduced by the simultaneous injection of PCPA and nesfatin-1 (P < 0.05). Nesfatin-1induced hypophagia were decreased by the simultaneous injection of SB242084 (P < 0.05). The nesfatin-1 -induced hypophagia were abolished by the simultaneous injection of the tocinoic acid and nesfatin-1 (P < 0.05). ICV injection of the nesfatin-1 decreased the number of steps, jumps, exploratory food, and pecks (P < 0.05) with no effect on drink pecks (P > 0.05). Nesfatin-1 significantly decreased standing time and increased both sitting time and rest time (P < 0.05). Nesfatin-1 could play an important role in feeding behavior, and its hypophagic effects were mediated by β2 adrenergic, 5-HT2C serotoninergic, and oxytocin receptors in neonatal chickens.

Antidepressant, anti-amnesic and vasoprotective effect of Bombax costatum Pellegr. & Vuillet aqueous stem bark extract on chronic mild unpredictable stress induced in rat

Ethnopharmacological relevanceBombax costatum Pellegr. & Vuillet is used traditionally in Northern Cameroon to treat memory impairment, anxiety, insomnia and depression. Aim of the studyInvestigating the effect of Bombax costatum stem bark aqueous extract (BC) on depression associated with amnesia and vascular disorder, using a chronic mild unpredictable stress (CMUS) model in rats for 30 days. Materials and methodsSucrose Preference Test (SPT), Forced Swimming Test (FST), corticosteronemia, brain serotonin and dopamine level were evaluated as indices of antidepressant-like effect. The Novel Object Recognition Task (NOR), the Morris Water Maze (MWM) and acetylcholinesterase activity in the hippocampus were also used to verify memory integrity. Oxidative and nitrosative stress markers, the lipid profile and atherogenic index were estimated in blood serum to assess vasoprotective effect. Chlorophenylalanine and haloperidol, were used to delineate the extract's mechanism of action. ResultsCMUS induced a decrease in sucrose preference and swimming time in the SPT and FST respectively while BC (27.5 and 55 mg/kg) increased sucrose preference and swimming time. Increments in these parameters were however reversed by the treatment of rats with chlorophenylalanine a serotonin synthesis inhibitor and haloperidol a D2 receptor antagonist. An increase in blood corticosterone level, prefrontal cortex malondialdehyde and nitric oxide concentrations were reversed by the extract. Moreover, BC increased the time spent in the target quadrant of the MWM test and the discrimination index in the NOR test. This was associated with an increase in hippocampus superoxide dismutase and catalase levels, a decrease in acetylcholine esterase level, total blood cholesterol and atherogenicity index compared to CMUS group. ConclusionThirty days CMUS induces a depressive state in rats. BC reverses this condition when administered alongside stress exposure. This antidepressive effect is associated with antiamnesic, antioxidant and vasoprotective actions, suggesting its use as a potential candidate in the management of major depressive disorder.

Establishment of a novel animal model of depression by inhibiting serotonin synthesis using &lt;i&gt;in vivo&lt;/i&gt; gene editing

Establishment of a novel animal model of depression by inhibiting serotonin synthesis using &lt;i&gt;in vivo&lt;/i&gt; gene editing

Role of serotonin in modulating the development and function of adult-born neurons in the olfactory bulb.

Role of serotonin in modulating the development and function of adult-born neurons in the olfactory bulb.

Cardamonin Modulates Neuropathic Pain through the Possible Involvement of Serotonergic 5-HT1A Receptor Pathway in CCI-Induced Neuropathic Pain Mice Model.

Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin’s effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/77 receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system.

5-HT1A Serotonergic, α-Adrenergic and Opioidergic Receptors Mediate the Analgesic Efficacy of Vortioxetine in Mice.

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

EVALUATION OF INVOLVEMENT OF NEURO-CHEMICAL MECHANISM IN VALERIANA WALLICHII INDUCED ANTIDEPRESSANT EFFECT IN MICE

Objective: Valeriana (V) wallichii DC is found among the ground flora of Himalayan regions and used as herbal medicine for CNS disorders in Indian systems of medicine. In the study, aimed to investigation of involvement of neuro-chemical-systems in V. wallichii induced antidepressant effects in mice.&#x0D; Methods: The antidepressant activity of aqueous alcoholic extracts of V. wallichii was measured by using Forced Swim Test and Tail Suspension Test in mice, whereas locomotor activity was observed by Actophotometer. Involvement of adrenergic, dopaminergic and serotonergic receptors in V. wallichii induced antidepressant effects in mice were also observed.&#x0D; Results: Sub-acute administration of V. wallichii in mice showed significant (P&lt;0.05) increase in the antidepressant activity similar to the Imipramine, but did not show at lower doses in FST. Whereas, pretreatment of adrenergic receptor antagonist, dopaminergic receptor antagonist and serotonin synthesis inhibitor prevented V. wallichii induce anti-depressant effect in mice. Lower doses of hydoalcoholic extract of V. wallichii did not interfering the locomotor activity in mice during the sub-acute administration, but at a higher dose significantly (P&lt;0.05) decreases the locomotor activity.&#x0D; Conclusion: Hence, it is concluded that the antidepressant effect of V. wallichii in mice may mediate via adrenergic, dopaminergic and serotonergic systems.

Serotonin depletion reduces both acquisition and expression of context-conditioned fear

Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear. Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300mg/kg daily×3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only. The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear. Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.

Serotonin Synthesis Inhibition by Para-Chlorophenylalanine Impairs Defensive Reactions of Aversive Learning and Long-term Sensitization in Terrestrial Snails

Serotonin Synthesis Inhibition by Para-Chlorophenylalanine Impairs Defensive Reactions of Aversive Learning and Long-term Sensitization in Terrestrial Snails

Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401.

An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.