Brain Serotonin Levels Research Articles

5-HIAA as a Potential Biological Marker for Neurological and Psychiatric Disorders.

Neurological and psychiatric disorders occur in about 6 percent of the global population indicating a significant amount of people suffering from neurological disorder on a varying range in day to day life. On an extensive view, there is a critical requirement for the development of an alternative biomarker for these conditions. The thwart found in developing a biomarker is the difficulty in identifying a serum biomarker as these are mostly limited to the central nervous system (CNS). Serotonin being a neurotransmitter synthesized in the raphe nuclei of the brain could serve as an alternative biomarker. Here, the limitation is that it’s quickly metabolized by the mitochondrial enzyme MAO to 5-hydroxy indole acetic acid (5HIAA). This subsequent metabolite can be used for the analysis of serotonin levels in brain by analysing its concentration in the cerebrospinal fluid (CSF). Many theories suggest that the variations in serotonin level could lead to the development of many neurological and psychiatric disorders like Alzheimer’s disease (AD), schizophrenia, depression and so on. A decreased level is noticed in these patients but this could either be due to decreased production or increased reuptake of serotonin from the neuronal synapses. For instance, we know that a patient with depression shows a significant reduction in the levels of 5HIAA, due to the location of the raphe nuclei within regions of memory and cognition. Similarly, it does shows variation in AD and mild cognitive disorder. Evolving of 5HIAA as a biomarker, could be more delicate and enhanced strategy for monitoring these disorders.

Role of Tryptophan in Microbiota-Induced Depressive-Like Behavior: Evidence From Tryptophan Depletion Study.

During the past decade, there has been a substantial rise in the knowledge about the effects of gut microbiota on host physiology and behavior, including depressive behavior. Initial studies determined that gut microbiota can regulate host tryptophan levels, which is a main serotonin precursor. A dysfunctional serotonergic system is considered to be one of the main factors contributing to the development of depression. Therefore, we hypothesized that regulation of brain tryptophan and serotonin can explain, at least partly, the effects of microbiota on depressive behavior. To test this hypothesis, we examined depressive-like behavior and brain levels of serotonin and tryptophan, of germ free (GF) and specific-pathogen free (SPF) mice under basal conditions, or after acute tryptophan depletion (ATD) procedure, which is a method to decrease tryptophan and serotonin levels in the brain. In basal conditions, GF mice exhibited less depressive-like behavior in sucrose preference, tail-suspension and forced swim tests, compared to SPF mice. In addition, in mice that were not subjected to ATD, GF mice displayed higher levels of tryptophan, serotonin and 5-hydroxyindoleacetic acid (the main degradation product of serotonin) in medial prefrontal cortex (mPFC) and hippocampus (HIPPO), compared to SPF mice. Interestingly, ATD increased depressive-like behavior of GF, but not of SPF mice. These behavioral changes were accompanied by a stronger reduction of tryptophan, serotonin and 5-hydroxyindoleacetic acid in mPFC and HIPPO in GF mice after ATD, when compared to SPF mice. Therefore, the serotonergic system of GF mice is more vulnerable to the acute challenge of tryptophan reduction, and GF mice after tryptophan reduction behave more similarly to SPF mice. These data provide functional evidence that microbiota affects depression-like behavior through influencing brain tryptophan accessibility and the serotonergic system.

Amelioration of fenitrothion induced oxidative DNA damage and inactivation of caspase-3 in the brain and spleen tissues of male rats by N-acetylcysteine

N-acetylcysteine (NAC) has largely been used as an effective chemo- protective agent owing to their beneficial effect in restoring several physiological parameters and relieving oxidative stress. Interestingly, it has been suggested that NAC mechanisms of action extend beyond being a precursor to the antioxidant glutathione and that they may involve several neurotropic and inflammatory pathways. Exposure to fenitrothion, an organophosphorus insecticide, promotes oxidative stress and induces several deleterious changes in the immune response and various tissues including cerebrum and spleen. The main objective of our study was to investigate ameliorative efficacy of N-acetylcysteine for immunological and neurological alterations and oxidative DNA damage induced by fenitrothion toxicity in cerebrum and spleen tissues of male rats. Our results revealed that oral exposure to fenitrothion for 30 days caused a reduction in the erythrocyte count in addition to leukocytosis, lymphocytosis, and neutrophilia. Also, this route of administration increased the serum levels of LDH, TNF-α, and IL-2 with reduction in serum immunoglobulins (IgG & IgM) concentrations. Furthermore, a significant downregulation in the antioxidant markers (GSH & SOD) with an elevation of free radical (MDA) levels were noticed. Regarding the brain, fenitrothion administration inhibited AchE activity and increased brain GABA, serotonin and dopamine levels. Moreover, it induced an elevation in oxidative DNA damage indicated by 8-hydroxy 2-deoxyguanosine (8OH2dG) and mRNA expression of pro-apoptotic genes, including Bax, and p53, but Bcl-2 expression was reduced. N-acetylcysteine co-treatment restored the normal physiological tone in most of these parameters. Immunostaining for GFAP and Caspase-3 markers in the brain and spleen tissues were increased respectively. In conclusion, N-acetylcysteine supplementation has an ameliorative effect against immunotoxic, neurotoxic and oxidative DNA damage induced by fenitrothion exposure.

Effect of Culcasia falcifolia on the biogenic amine levels in the brain tissue of pentylenetetrazole induced seizure in mice

In the present study the effect of the ethanol extract of Culcasia falcifolia on the neurotransmitter levels were evaluated. Pentylenetetrazole (PTZ) (60 mg/kg body weight, i. p) was administered to all the groups of mice to induce convulsions. After observing the convulsion, all groups rats were sacrificed, whole brain was dissected out and separated the forebrain. The brain tissue was homogenized and then centrifuged. The aqueous phase was taken for the assay. The reading was obtained using spectroflurimeter. The result of the present study shows that the ethanol extract of Culcasia falcifolia at the dose of 200 and 400 mg/kg body weight significantly increased the level of inhibitory neurotransmitter GABA and also showed significant increase in the levels of dopamine, noradrenalin and serotonin when compared to seizure control group (PTZ treated group) and was almost equivalent to control group. The findings of the study showed that the extract at 200 and 400 mg/kg body weight significantly (p<0.001) increased the levels of GABA, dopamine, serotonin and noradrenaline. The ethanol extract of Culcasia falcifolia exerted antiepileptic activity by decreasing seizure susceptibility to pentylenetetrazole-induced seizure in mice due to restoration of GABA, serotonin, dopamine and noradrenaline concentration levels in mice brain.

Association Between Sumatriptan Treatment During a Migraine Attack and Central 5-HT1B Receptor Binding

Triptans, the most efficient acute treatment for migraine attacks, are 5-HT1B/1D receptor agonists, but their precise mechanism of action is not completely understood. The extent to which triptans enter the central nervous system and bind to 5-HT1B receptors in the brain is unknown. To determine the occupancy of sumatriptan to central 5-HT1B receptors, and to investigate changes in brain serotonin levels during migraine attacks. This study of 8 patients in Denmark used a within-participant design and was conducted from April 20, 2015, to December 5, 2016. Participants were otherwise healthy patients with untreated episodic migraine without aura, aged between 18 and 65 years, and recruited from the general community. Data analysis was performed from January 2017 to April 2018. All participants underwent positron emission tomographic scans after injection of [11C]AZ10419369, a specific 5-HT1B receptor radiotracer. All participants were scanned 3 times: (1) during an experimentally induced migraine attack, (2) after a subcutaneous injection of 6-mg subcutaneous sumatriptan, and (3) on a migraine attack-free day. Scans 1 and 2 were conducted on the same study day. Each scan lasted for 90 minutes. The primary outcome was the nondisplaceable binding potential of [11C]AZ10419369 across 7 brain regions involved in pain modulation. The binding potential reflects receptor density, and changes in binding potential reflects displacement of the radiotracer. The occupancy of sumatriptan was estimated from the 2 scans before and after sumatriptan administration. Eight patients with migraine were included in the study; of these participants, 7 (87%) were women. The mean (SD) age of participants on study day 1 was 29.5 (9.2) years and on study day 2 was 30.0 (8.9) years. Sumatriptan was associated with statistically significantly reduced 5-HT1B receptor binding across pain-modulating regions (mean [SD] binding potential, 1.20 [0.20] vs 1.02 [0.22]; P = .001), corresponding to a mean (SD) drug occupancy rate of 16.0% (5.3%). Furthermore, during migraine attacks, as compared with outside of attacks, 5-HT1B receptor binding was statistically significantly associated with reduced in pain-modulating regions (mean [SD] binding potential, 1.36 [0.22] vs 1.20 [0.20]; P = .02). Treatment with sumatriptan during migraine attacks appeared to be associated with a decrease in 5-HT1B receptor binding, a finding that is most likely associated with the binding of sumatriptan to central 5-HT1B receptors, but the contribution of ongoing cerebral serotonin release to the lower binding cannot be excluded; the migraine attack-associated decrease in binding could indicate that migraine attacks are associated with increases in endogenous serotonin.

Measuring endogenous changes in serotonergic neurotransmission with [11C]Cimbi-36 positron emission tomography in humans

Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HT2AR) agonist radioligand [11C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [11C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HT1AR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [11C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HT2AR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [11C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HT2AR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI.

Transcranial photobiomodulation prevents anxiety and depression via changing serotonin and nitric oxide levels in brain of depression model mice: A study of three different doses of 810 nm laser.

The effectiveness of transcranial photobiomodulation (TPBM) in treating anxiety and depression disorders is a demonstrated and identified issue. However, the optimum therapeutic dose and the underlying mechanism of action are not fully understood. In this study, the therapeutic effects of three different near-infrared (NIR) doses on anxiety- and depression-like behaviors as well as cerebral levels of serotonin (5-HT) and nitric oxide (NO) were evaluated in a mouse model of chronic restraint stress (CRS). CRS procedure (3 hours/day, over 3 weeks) was performed as a typical stress model to study anxiety and depression along with laser treatment (3 times/week, over 3 weeks), which began simultaneously with CRS. A NIR diode laser (810 nm wavelength, 10 Hz) with the output power of 200 mW and power density of 4.75 W/cm2 was implemented to deliver three different doses of 4, 8, and 16 J/cm2 to the cerebral cortex of mice. Behavioral experiments including open field, tail suspension, and elevated plus maze tests as well as serum cortisol levels were assessed to evaluate the anti-anxiety and anti-depressive effects of NIR TPBM. The changes of 5-HT and NO levels in the prefrontal cortex (PFC) and hippocampus (Hipp) were assessed. CRS procedure induced anxiety- and depression-like behaviors, increased serum cortisol levels, decreased 5-HT and increased NO levels in the PFC and Hipp areas. NIR TPBM improved behavioral results, decreased serum cortisol levels, increased 5-HT and decreased NO concentrations in the PFC and Hipp. A dose of 8 J/cm2 of NIR TPBM showed the maximum effects on behavioral and molecular results, while a decline was observed from the optimum effects at both lower (4 J/cm2 ) and higher (16 J/cm2 ) doses. Our results demonstrated that NIR TPBM had an anti-anxiety and anti-depressive effect in CRS mice, which is probably linked to increasing 5-HT and decreasing NO levels in the PFC and Hipp areas. Also, the maximum anti-anxiety and anti-depressive effect was produced at dose of 8 J/cm2 . Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Serotonergic Regulation and Cognition after Stroke: The Role of Antidepressant Treatment and Genetic Variation

Introduction: Serotonin affects several brain functions including cognition. The serotonin transporter (SERT) regulates brain serotonin levels through reuptake into neurons. The gene encoding this transporter, the SERT gene, has several functional polymorphisms affecting the number of transporters and thereby the serotonin levels. SERT gene expression may be important for cognition and selective serotonin reuptake inhibitors (SSRI) may improve cognition post stroke. We therefore examined the association between SERT genotypes, cognitive function and early treatment with the SSRI citalopram among non-depressed Caucasian stroke patients. Patients and Methods: SERT gene polymorphisms in 270 non-depressed first-ever acute ischemic stroke patients randomized to citalopram, n = 130, or placebo, n = 140, were investigated. Patients were genotyped for a length polymorphism (L = long and S = short allele) and a single nucleotide polymorphism (A/G substitution) dividing the L-allele into L_A and L_G. According to these genotypes, patients were further grouped according to low (S/S, L_G/S and L_G/L_G), medium (S/L_A and L_G/L_A), or high functional gene expression (L_AL_A). Cognition was measured by the Symbol Digit Modalities Test (SDMT) at 1 and 6 months. Mean SDMT scores according to genotype and randomization groups were compared using multiple logistic regression adjusting for age, stroke severity, premorbid functional status, and vascular risk factors including smoking, hypertension, and diabetes. Results: Stratified by genotype groups, there were no statistically significant differences in SDMT scores between randomization groups. Placebo-treated patients with low SERT expression genotypes, however, tended to have lower mean SDMT scores (at 1 month: 30.2, SD 10.8) compared to citalopram-treated patients (33.6, SD 13.7). Within the placebo group, the low genotype expression patients had significantly lower adjusted mean SDMT scores at 1 month compared to the high genotype expression patients (adjusted mean difference of –6 points, CI –12.0 to –0.05). We found similar results at 6 months, although not statistically significant. The genotype expression was not associated with SDMT scores among citalopram-treated patients. Conclusion: There was no difference in cognition between citalopram and placebo-treated patients according to the genotype group. Our results indicate, however, that low expression SERT genotype may contribute to reduced cognitive function post stroke as placebo-treated patients with low SERT expression tended to score lower on the SDMT. The significant difference in SDMT scores between low and high expression patients was present only in the placebo-treated group, thereby warranting further exploration of the potential effect of early citalopram treatment on cognitive functioning. Our results are preliminary and need replication in larger-scale studies.

5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology.

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150mg/kg) in the plasma and brain associated with profound hyperthermia (+3.86±0.24°C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to [131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome.

Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224N on the right parietal bone by dropping a weight of 114.6g from a 20cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radioiodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35mg/kg, i.p.), pentobarbital (50mg/kg, i.p.), equithesin (3mL/kg, i.p.) and urethane (1g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.

Physiological and Behavioral Changes of Male Rats Following Social Isolation Stress During Early-Adolescence and Fluoxetine Exposure

Stress experiences during youth lead to abnormal behavior profile in adulthood, including an increase in aggression, depression and anxiety disorders in humans. The animals during early- adolescent period (PD 35) were divided into the following groups: Group 1- Control. Group II– social isolation stress for 42 days –Negative control. Group III –The animals were treated with 10 mg/kg of the fluoxetine for 21 days in combination with isolation stress for 21 days, all groups followed by behavioral studies, and assessed the biochemical effects of exposure to stress and stress with drug. The results showed there was significantly improvement in the open field test including significantly increased locomotor and exploratory activity with decreased anxiety and aggressive behavior after treatment with fluoxetine compared to stress group. The results were also noted significant increase in the levels of brain serotonin in stress with fluoxetine group compared to stress group, The results showed significantly decreased in levels of dopamine and monoamine oxidase A in brain tissue of rats treated with fluoxetine compared to stress group. While corticosterone, testosterone and LH levels in stress rats showed significantly increased compared to stress with fluoxetine group.

Relationship between Dopamine and Serotonin on the Effect of Ginkgo biloba Extract in the Treatment of Obsessive Compulsive Disorder in Rodents

In this study, the effect of EGb-761, the standardized extract of Ginkgo biloba at dose levels of 50, 100 and 200 mg/kg was investigated on experimental models of obsessive compulsive disorder such as quinpirole-induced compulsive checking in rats and marble burying behaviour in mice. Water maze test was used to evaluate the effect on spatial memory and the underlying mechanisms were predicted based on rat brain dopamine and serotonin levels. EGb-761 at 100 and 200 mg/kg showed significant improvement against quinpirole-induced compulsions. A protective effect on memory task was observed in EGb-761-treated rats. This could be attributed to the increase in serotonin and decrease in the dopamine levels. The protective effect of EGb-761 in the treatment of obsessive compulsive disorder is apparent through the performance in the open field and marble burying behaviour.

Investigation of Antistress Activity of Operculina Terpethum Roots using Various Experimental Models

The root part of Operculina terpethum has been widely used in Ayurveda to treat variety of common and stress related disorders. The antistress effect of a seven-days treatment (100 and 200 mg / kg, p.o.) of the 80% ethanolic extract of Operculina terpethum root (OTRE) was evaluated by using the swimming endurance test, anoxic tolerance test, and biochemical changes in the cold-restraint stress test. The immunomodulatory activity was also evaluated for the same doses, and treatment of OTRE using the hem agglutination test. Diazepam 1 mg/kg was used as reference standard for the comparison. Both the doses of OTRE showed anti stress activity in all the tested models. 7 days pretreatment of OTRE (100 and 200 mg / kg, p.o.) treated animals showed a decrease in immobility time and an increase in anoxic tolerance time in swimming endurance and the anoxic tolerance tests, respectively. Pretreatment with OTRE significantly ameliorated the cold restraint stress induced variation in biochemical level such as increase in plasma cholesterol, triglyceride, glucose, total protein, and cortisol. Further, OTRE treatment significantly inhibited cold restraint stress induced alteration in brain noradrenaline, dopamine and serotonin levels. In mice immunized with sheep red blood cells, the treatment groups subjected to restraint stress prevented the humoral immune response to the antigen. The immune stimulating activity of the OTRE was indicated by an increase in the antibody titer in mice pre-immunized with sheep red blood cells and subjected to restraint stress. The findings of the present investigations indicate that the OTRE has significant anti stress activity, which may be due to the immune stimulating property and increased resistance, nonspecifically, against all experimental stress conditions.

Acute tryptophan loading decreases functional connectivity between the default mode network and emotion‐related brain regions

It has been shown that the functional architecture of the default mode network (DMN) can be affected by serotonergic challenges and these effects may provide insights on the neurobiological bases of depressive symptomatology. To deepen our understanding of this possible interplay, we used a double-blind, randomized, cross-over design, with a control condition and two interventions to decrease (tryptophan depletion) and increase (tryptophan loading) brain serotonin synthesis. Resting-state fMRI from 85 healthy subjects was acquired for all conditions 3 hr after the ingestion of an amino acid mixture containing different amounts of tryptophan, the dietary precursor of serotonin. The DMN was derived for each participant and session. Permutation testing was performed to detect connectivity changes within the DMN as well as between the DMN and other brain regions elicited by the interventions. We found that tryptophan loading increased tryptophan plasma levels and decreased DMN connectivity with visual cortices and several brain regions involved in emotion and affect regulation (i.e., putamen, subcallosal cortex, thalamus, and frontal cortex). Tryptophan depletion significantly reduced tryptophan levels but did not affect brain connectivity. Subjective ratings of mood, anxiety, sleepiness, and impulsive choice were not strongly affected by any intervention. Our data indicate that connectivity between the DMN and emotion-related brain regions might be modulated by changes in the serotonergic system. These results suggest that functional changes in the brain associated with different brain serotonin levels may be relevant to understand the neural bases of depressive symptoms.

Impact of space allowance on performance traits, brain neurotransmitters and blood antioxidant activity of New Zealand White rabbits

The objective of this trial was to investigate the effect of space allowance on performance, welfare-related parameters and the levels of brain neurotransmitters in growing male rabbits. In a cage housing system, a total of 96 weaned rabbits were accommodated on three space allowance conditions (S1 = 1425 cm2/rabbit; S2 = 850 cm2/rabbit; S3 = 625 cm2/rabbit), with 8 replicate cages per each group. Rabbits in the S1 and S2 groups showed better daily feed intake and feed conversion ratio compared with the high stocking density group (p = 0.004 and 0.018, respectively). Compared to the highest stocking density group (S3), rabbits in the S1 and S2 groups showed significantly lower serum cortisol, MDA and GSSH level (p = 0.026, 0.018 and 0.009, respectively). The concentration of dopamine in brain tissues was significantly decreased in the S3 group compared with other experimental groups (P = 0.001). However, there was no significant effect of space allowance on the brain AChE level (P = 0.277). Brain serotonin and GABA levels showed a significant decrease in rabbits reared with a limited space allowance (S3) compared with S1 and S2 groups (P = 0.001 and 0.038, respectively). The level of brain MDA was significantly increased in the S3 group compared with the S1 group (P = 0.006). However, there were no detectable differences in the brain ATP level in rabbits reared with different space allowance (P = 0.693). In conclusion, the current study indicates that the 850 cm2/rabbit stocking density has resulted in a better feed intake, and welfare-related conditions compared with the 625 cm2/rabbit. Furthermore, the limited space allowance may impair the most important brain neurotransmitters in male rabbits.

Antidepressant-Like and Neuroprotective Effects of Ethanol Extract from the Root Bark of Hibiscus syriacus L.

Hibiscus syriacus L. (Malvaceae) is an important ornamental shrub in horticulture and has been widely used as a medical material in Asia. The aim of this study was to assess the antidepressant and neuroprotective effects of a root bark extract of H. syriacus (HSR) and to investigate the underlying molecular mechanisms. Using an animal model of restraint stress, we investigated the effects of HSR on depressive-like behaviors and on the expression levels of serotonin, corticosterone, and neurotrophic factors in the brain. The mice were exposed to restraint stress for 2 h per day over a period of 3 weeks and orally treated with HSR (100, 200, or 400 mg/kg/day). We also examined the neuroprotective effect of HSR using corticosterone-treated human neuroblastoma SK-N-SH cells. The cells were incubated with the extract for 24 h, followed by corticosterone stimulation for 1 h, and then cell viability assay, cellular ATP assay, mitochondrial membrane potential (MMP) assay, cellular reactive oxygen species (ROS) assay, and western blotting were used to investigate the neuroprotective effects of HSR. Administration of HSR not only reduced the immobility times of the restraint-stressed mice in the forced swimming and tail suspension tests, but also significantly increased sucrose preference in the sucrose preference test. In addition, HSR significantly reduced the plasma levels of corticosterone and increased the brain levels of serotonin. The extract also increased the phosphorylation level of cyclic AMP response element-binding (CREB) protein and the expression level of brain-derived neurotrophic factor (BDNF). The in vitro assays showed that HSR pretreatment increased cell viability and ATP levels, recovered MMP, decreased ROS levels, and increased the expression of CREB and BDNF in corticosterone-induced neurotoxicity. Taken together, our data suggest that HSR may have the potential to control neuronal cell damage and depressive behaviors caused by chronic stress.

Effects of Melatonin Administration in Different Time Modes on Morphofunctional Indices of the Hypothalamic Serotonergic Neurons in Obese Rats

We examined the effects of introduction of melatonin in different time modes on morphofunctional parameters of serotonergic neurocytes of the rat hypothalamic arcuate nucleus (cross-sectional area of the neurocyte nuclei, content of serotonin vesicles per neuron, and number/density of serotonergic neurons); general levels of tryptophan and serotonin in the rat brain were also estimated. Experimental animal groups included rats with normal body mass and rats with obesity induced by a high-calorie diet; three different modes of melatonin introduction were used (single introductions by gavage in the morning, similar introductions in the evening, and continuous introduction with drinking water, i.e., distributed in time). Animals with high-calorie diet-induced obesity were characterized by a greater mean area of cross-sections of the neurocyte nuclei, a smaller number of serotonin-positive neurocytes, and smaller numbers of serotonin-containing vesicles in each neurocyte of the arcuate nucleus. The levels of serotonin and its precursor tryptophan in the brain were also smaller in the above (obese) rats. Introductions of melatonin into rats fed a high-calorie diet provided relative smoothing of the abovementioned changes: the dimensions of the neurocyte nuclei became close to the control values. The number of serotonin-positive neurons increased (only at evening and time-distributed introductions), the number of serotonin-containing vesicles was greater (exclusively at distributed melatonin introductions), and the general contents of serotonin and tryptophan in the brain also increased (at evening and distributed introductions). The mode of continuous distributed introduction of melatonin with drinking water was found to be most effective. Thus, introductions of melatonin improve the functional state of serotonergic neurocytes in the hypothalamic arcuate nucleus of rats with moderate pathological manifestations of obesity; the intensity of melatonin-induced morphofunctional shifts depends noticeably on the time mode of its introduction.

Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans

Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive–compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

The role of serotonin and its receptors on the anticonvulsant effect of curcumin in pentylenetetrazol-induced seizures

AimCurcumin, derived from turmeric, has been demonstrated to be effective in controlling seizures, although the exact mechanism is yet unknown. In this study, the role of serotonin and its receptors in the anticonvulsant effect of curcumin was evaluated in mice. Main methodsTotal 110 mice were randomly divided into 11 groups (n = 10). In the first to the fourth groups, the role of curcumin (150 mg/kg, i.p) and serotonin (PCPA (100 mg/kg); was used to deplete the brain serotonin levels) was investigated. The fifth group first received NAD-299 (4 mg/kg, sc), RS-102221 (5 mg/kg, i.p), SDZ205-557 Hydrochloride (1 mg/kg, i.p), and SB 26997 (10 mg/kg, i.p), then curcumin. The sixth group received NAD-299, curcumin. The animals in the seventh to ninth groups received 5-HT2C, 5-HT4, and 5-HT7 antagonists, respectively, with curcumin. The tenth group received HTR2C antagonist and the eleventh group received HTR4 antagonist. In all animals 25 min after curcumin PTZ (80 mg/kg; i.p) was injected. Key findingsPCPA not only inhibited the anticonvulsant action of curcumin, but also reversed some of its anticonvulsant effect. The 5-HT1A, 5-HT2C and 5-HT4 antagonists diminished but 5-HT7 antagonist strengthened the anticonvulsant effect of curcumin. Evaluation of gene expression using real-time PCR confirmed that only 5-HT7 gene expression was reduced after curcumin injection. SignificanceAccording to these results, it may be suggested that curcumin exerts anticonvulsive effects by increasing the serotonin levels in the brain that influence receptors, including 5-HT1A, 5-HT2C, and 5-HT4 and likely through the reduction of 5-HT7 gene expression.

Seasonality, alarm pheromone and serotonin: insights on the neurobiology of honeybee defence from winter bees

Honeybees maintain their colony throughout the cold winters, a strategy that enables them to make the most of early spring flowers. During this period, their activity is mostly limited to thermoregulation, while foraging and brood rearing are stopped. Less is known about seasonal changes to the essential task of defending the colony against intruders, which is regulated by the sting alarm pheromone. We studied the stinging responsiveness of winter bees exposed to this scent or a control (solvent). Surprisingly, winter bees, while maintaining their responsiveness in control conditions, did not increase stinging frequency in response to the alarm pheromone. This was not owing to the bees not perceiving the pheromone, as shown by calcium imaging of the antennal lobes. As the alarm pheromone is thought to act through an increase in brain serotonin levels, ultimately causing heightened defensiveness, we checked if serotonin treatments would affect the stinging behaviour of winter bees. Indeed, treated winter bees became more inclined to sting. Thus, we postulate that loss of responsiveness to the sting alarm pheromone is based on a partial or total disruption of the mechanism converting alarm pheromone perception into high serotonin levels in winter bees.