Increased Serotonin Levels Research Articles

Apigenin reverses behavioural impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus

Objectives: Apigenin is the most common bioflavonoid known to be biologically active after systemic administration and show multiple pharmacological effects. The present study was designed to explore the role of apigenin in pentylenetetrazole (PTZ) kindling associated cognitive and behavioural impairments in the mouse model. Methods: The animals were kindled by injecting a sub-convulsive dose of PTZ (35 mg/kg) on every alternate day, followed by 20 days treatment with apigenin at two different doses (10 and 20 mg/kg). Seizure severity was assessed on every 5th, 10th, 15th, and 20th day during apigenin treatment after a PTZ injection, followed by analysis of cognitive and behavioural functions. Results: Apigenin treatment displayed insignificant effect on seizure severity in kindled mice at both the tested doses, in comparison to control. However, the treatment showed marked increase in per cent spontaneous alterations and decline in the anxiety index in T-maze and elevated plus maze tests, respectively. Apigenin-treated groups showed significant decrease in immobility period in both forced swim and tail suspension tests, without any change in the total locomotor activity in the open field test. Furthermore, increase in the hippocampus protein expression of brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and phosphorylated CREB, with increased serotonin level were also observed in the treated animals. Discussion: The results of the present study showed that apigenin treatment prevents cognitive deficit and reverses behaviour impairments, without altering seizures severity in kindled mice. The observed effects can be attributed to CREB-BDNF upregulation in the hippocampus.

Regulation of Tetrahydrobiopterin (BH4) Synthesis in the Nematode C. elegans

5,6,7,8‐tetrahydrobiopterin (BH4) is a cofactor required by the aromatic amino acid hydroxylases (AAAHs), nitric oxide synthases, and alkylglycerol monooxygenase (Werner et al., 2011, Biochem. J. 438: 397). Among the AAAHs are the rate‐limiting synthetic enzymes for serotonin and dopamine synthesis, and for conversion of phenylalanine (Phe) to tyrosine. In humans, the activity of phenylalanine hydroxylase (PAH) is essential for Phe catabolism; dysfunction of PAH, either from mutations in the PAH gene or in genes required for BH4 synthesis, results in phenylketonuria. Regulation of BH4 levels is important for many other physiological functions. The first and rate‐limiting step in BH4 de novo synthesis is performed by GTP Cyclohydrolase I (GTPCH1). Like in many biosynthesis pathways, this first enzyme is regulated by ‘end product feedback inhibition’ whereby BH4 inhibits GTPCH1 activity. In mammals, BH4 does not bind to GTPCH1 alone, but requires an additional protein called GTPCH1 feedback regulatory protein (GFRP) to inhibit GTPCH1. Crystal structures of rat GTPCH1 and GFRP with the BH4 analog BH2 show that the biopterin binds at the interface between the proteins (Maita et al., 2004, J Biol Chem 279: 51534). Phe increases BH4 production via GTPCH1 stimulation, also in a GFRP‐dependent fashion, similarly binding at the interface between GTPCH1 and GFRP. We have recently described the function and expression of genes required for BH4 synthesis and regeneration in the nematode C. elegans (Loer et al., 2015, Genetics 200: 237). Here we present work on the function of the gene gfrp‐1, which encodes a ortholog of mammalian GFRP, in the regulation of BH4 synthesis in C. elegans. Sequence analysis and structural predictions suggest the worm GFRP will function like the mammalian protein, binding both BH4 and Phe. In mammals, GTPCH1 and GFRP can also bind the selective inhibitor 2,4‐Diamino‐6‐hydroxypyrimidine (DAHP), which is structurally similar to both GTP (substrate) and BH4 (pathway end product). At low concentrations, DAHP apparently inhibits GTPCH1 like BH4 by binding with GFRP; this inhibition is GFRP‐dependent. At higher concentrations, DAHP acts as a competitive inhibitor, binding at the GTPCH1 active site like GTP; this inhibition is GFRP‐independent (Xie et al., 1998, J Biol Chem 273: 21091). Using a reduction‐of‐function mutant in the worm GTPCH1 gene [cat‐4(e3015) – S148N], we find that DAHP reduces BH4 production, as assessed by a significant reduction in serotonin immunoreactivity in whole worms. Treatment with Phe significantly increases serotonin levels in cat‐4(e3015) worms. We are currently assessing the effects of mutations in gfrp‐1 on serotonin levels (hence BH4 levels) in single mutants and cat‐4; gfrp‐1 double mutants, and whether the effects of DAHP and Phe on BH4 synthesis are GFRP‐dependent.Support or Funding InformationSupported by a Univ of San Diego Faculty Research Grant and an endowment from the Fletcher Jones Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice

The primary etiology of Parkinson’s disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs l-DOPA and apomorphine improved the NaDMDC-induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 h after the last infusion, and striatum 2 and 24 h after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system.

Effects of High Levels of Deoxynivalenol and Zearalenone on Growth Performance, and Hematological and Immunological Parameters in Pigs

Background: Deoxynivalenol (DON) and zearalenone (ZEN) are common food contaminants produced by Fusarium sp. Mycotoxins are a potential health hazard because of their toxicological effects on both humans and farmed animals. Methods: We analyzed three groups of pigs: a control group (fed a standard diet), and the DON and ZEN groups, fed a diet containing 8 mg/kg DON and 0.8 mg/kg ZEN respectively, for four weeks. Results: DON and ZEN exposure decreased body weight (BW), average daily feed intake (ADFI), food conversion rate (FCR), and the serum levels of immunoglobulin (Ig)G and IgM. The total antioxidant levels significantly decreased in serum and increased in urine samples of both treatment groups. Additionally, DON and ZEN exposure increased serotonin levels in urine. Hematological parameters were not affected by the investigated toxins. Microscopic lesions were evident in sections of kidneys from either treatment group: we found sporadic interstitial nephritis in the DON group and renal glomerulus atrophy in the ZEN group. The expression levels of inflammatory cytokines and chemokine marker genes were reduced in tissues from DON- and ZEN-exposed pigs. Conclusions: chronic ingestion of high doses of DON and ZEN alters the immune response and causes organs damage, and might be associated with various diseases in pigs.

A nematode that can manipulate the behaviour of slugs

The ability of parasites to manipulate the behaviour of their hosts has evolved multiple times, and has a clear fitness benefit to the parasite in terms of facilitating growth, reproduction and transfer to suitable hosts. The mechanisms by which these behavioural changes are induced are poorly understood, but in many cases parasite manipulation of serotonergic signalling in the host brain is implicated. Here we report that Phasmarhabditis hermaphrodita, a parasite of terrestrial gastropod molluscs, can alter the behaviour of slugs. Uninfected slugs (Deroceras panormitanum, Arion subfuscus and Arion hortensis) avoid areas where P. hermaphrodita is present, but slugs infected with P. hermaphrodita are more likely to be found where the nematodes are present. This ability is specific to P. hermaphrodita and other nematodes (Steinernema carpocapsae and Heterorhabditis bacteriophora) do not induce this behavioural change. To investigate how P. hermaphrodita changes slug behaviour we exposed slugs to fluoxetine (a selective serotonin reuptake inhibitor) and cyproheptadine (a serotonin receptor antagonist). Uninfected slugs fed fluoxetine no longer avoided areas where P. hermaphrodita was present; and conversely, infected slugs fed cyproheptadine showed no increased attraction to areas with nematodes. These findings suggest that a possible mechanism by which P. hermaphrodita is able to manipulate parasite avoidance behaviour in host slugs is by manipulating serotonergic signalling in the brain, and that increased serotonin levels are potentially associated with a reduction in parasite avoidance.

Discovery of DSP-1053, a novel benzylpiperidine derivative with potent serotonin transporter inhibitory activity and partial 5-HT1A receptor agonistic activity

We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one. This optimization work led to the identification of the antidepressant candidate DSP-1053 as a potent SERT inhibitor with partial 5-HT1A receptor agonistic activity. DSP-1053 showed low CYP2D6 metabolic contribution and a robust increase in serotonin levels in the rat frontal cortex.

The Anti-Stress Effect of Mentha arvensis in Immobilized Rats.

Stress can lead to inflammation, accelerated aging, and some chronic diseases condition. Mentha arvensis (MA) is a traditional medicine having antioxidant and anti-inflammatory activities. The present study investigated the anti-stress role of MA and fermented MA (FMA) extract in immobilized rats. We studied the lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 cells and rats were immobilized for 2 h per day for 14 days using a restraining cage. MA (100 mg/kg) and FMA (100 mg/kg) were orally administered to rats 1 h prior to immobilization. Using high-performance liquid chromatography (HPLC) analysis, we determined the rosmarinic acid content of MA and FMA. The generation of malondialdehyde (MDA) and nitric oxide (NO) in RAW 246.7 cells were suppressed by both MA and FMA. In rats, MA and FMA notably improved the body weight, daily food intake, and duodenum histology. MDA and NO level were gradually decreased by MA and FMA treatment. MA and FMA significantly controlled the stress-related hormones by decreasing corticosterone and β-endorphin and increasing serotonin level. Moreover, protein expression levels of mitogen activated protein kinases (MAPK) and cyclooxygenase-2 (COX-2) were markedly downregulated by MA and FMA. Taken together, MA and FMA could ameliorate immobilized-stress by reducing oxidative stress, regulating stress-related hormones, and MAPK/COX-2 signaling pathways in rats. Particularly, FMA has shown greater anti-stress activities than MA.

Evaluation of oxytocin and serotonin levels in autism spectrum disorder

Objective Autism spectrum disorder (ASD) is a complex neurological and developmental disorder that affects how a person acts and interacts, communicates with others, and learns. Endocrine and neuropeptide factors are some among the list of possible etiologic or predisposing contenders. Abnormalities in the brain serotonin system are reported in ASD, including evidence of altered serotonin synthesis and receptor binding, as well as dystrophic serotonergic axons. Blood oxytocin levels are also a focus of ASD research. This work aimed to assess oxytocin and serotonin levels as biomarkers in individuals with ASD. Participants and methods Serotonin and oxytocin levels, as biochemical parameters related to neurochemistry, were determined in the sera of 40 autistic patients (29 males and 11 females). They were categorized as mild to moderate and severe as indicated by their Childhood Autism Rating Scale and as low average intelligence, slow learner, and mentally retarded according to their intelligence quotients. The parameters were then compared with that of 40 age-matched and sex-matched control samples (30 males and 10 females). Results Our patients showed a highly significant increase in serotonin levels and a highly significant decrease in oxytocin levels as compared to controls. Diagnostic validity test was carried out for both serotonin and oxytocin and showed excellent results. A correlation done between serotonin and oxytocin levels among the patient group showed significant negative correlation. Conclusion Our results significantly reinforce the reliability of increased serotonin blood levels and decreased oxytocin levels as biomarkers in ASD, providing possible indications potentially useful for their inclusion in multimarker diagnostic panels for clinical use. Identifying relationships between identified ASD biomarkers may be a useful approach to connect the different findings of multiple systems in this heterogeneous disorder and to find the causesof ASD and to identify potential interventions.

Serotonergic dysregulation is linked to sleep problems in Parkinson's disease.

IntroductionSleep disturbances are common non-motor symptoms in Parkinson's disease (PD). Experimental studies suggest involvement of the serotonergic system in the regulation of sleep and arousal. Using [11C]DASB positron emission tomography, a marker of serotonin transporter availability, we investigated whether sleep dysfunction is associated with serotonergic dysfunction in PD.MethodsWe studied 14 PD patients with sleep dysfunction, 14 PD without sleep dysfunction, and 12 healthy controls. Groups were matched for age, disease duration, severity of motor symptoms, daily intake of levodopa equivalent units, body-mass-index, depression and fatigue. [11C]DASB non-displaceable binding potential (BPND) was calculated for regions with a role in the regulation of sleep and arousal.Results[11C]DASB BPND was reduced by 32–49% in PD patients with sleep dysfunction, and 14–25% in PD without sleep dysfunction, compared to healthy controls. PD patients with sleep dysfunction had lower [11C]DASB BPND in caudate (P < 0.01), putamen (P < 0.001), ventral striatum (P < 0.001), thalamus (P < 0.05), hypothalamus (P < 0.001) and raphe nuclei (P < 0.01), compared to PD without sleep dysfunction. Higher severity of sleep symptoms (assessed with Parkinson Disease Sleep Scale) correlated with lower [11C]DASB binding in caudate (r = 0.77; P < 0.001), putamen (r = 0.84; P < 0.001), ventral striatum (r = 0.86; P < 0.001), thalamus (r = 0.79; P < 0.001), hypothalamus (r = 0.90; P < 0.001) and raphe nuclei (r = 0.83; P < 0.001).ConclusionsOur findings demonstrate that sleep dysfunction in PD is associated with reduced serotonergic function in the midbrain raphe, basal ganglia and hypothalamus. Strategies to increase serotonin levels in the brain could be a promising approach to treat sleep dysfunction in PD, and may also have relevance in other neurodegenerative disorders.

The antidepressant-like effect of trans-astaxanthin involves the serotonergic system.

The antidepressant-like effect of trans-astaxanthin, a compound present rich in algae, was evaluated through behavioral and neurochemical methods. Results showed that trans-astaxanthin treatment significantly decreased the immobility time in force swim test and tail suspension test, but did not influence locomotor activity. Trans-astaxanthin treatment did not effectively antagonize hypothermia and ptosis induced by reserpine. However, pre-treatment with para-chlorophenylalanine abolished the anti-immobility effect of trans-astaxanthin in force swim and tail suspension test. These results suggested that the mechanism of antidepressant-like effect of trans-astaxanthin may involve the serotonergic system, but not noradrenaline system. This hypothesis was confirmed by neurochemical assays which showed that trans-astaxanthin increased serotonin levels in the hippocampus, frontal cortex, striatum and hypothalamus. Furthermore, our data suggested that trans-astaxanthin decreased indoleamine 2, 3-dioxygenase activity in the hippocampus, frontal cortex and hypothalamus. Inhibition of indoleamine 2,3-dioxygenase activity subsequently decreased the kynurenine/tryptophan ratio and increased the serotonin/tryptophan ratio in these brain regions. Taken together, these findings indicate that the antidepressant-like effect of trans-astaxanthin involves the serotonergic system.

Elevated Serotonin Interacts with Angiotensin-II to Result in Altered Valve Interstitial Cell Contractility and Remodeling.

While the valvulopathic effects of serotonin (5HT) and angiotensin-II (Ang-II) individually are known, it was not clear how 5HT and Ang-II might interact, specifically in the context of the mechanobiological responses due to altered valve mechanics potentiated by these molecules. In this context, the hypothesis of this study was that increased serotonin levels would result in accelerated progression toward disease in the presence of angiotensin-II-induced hypertension. C57/BL6J mice were divided into four groups and subcutaneously implanted with osmotic pumps containing: PBS (control), 5HT (2.5ng/kg/min), Ang-II (400ng/kg/min), and 5HT+Ang-II (combination). Blood pressure was monitored using the tail cuff method. Echocardiography was performed on the mice before surgery and every week thereafter to assess ejection fraction. After three weeks, the mice were sacrificed and their hearts excised, embedded and sectioned for analysis of the aortic valves via histology and immunohistochemistry. In separate experiments, porcine valve interstitial cells (VICs) were directly stimulated with 5HT (10-7M), Ang-II (100nM) or both and assayed for cellular contractility, cytoskeletal organization and collagen remodeling. After three weeks, average systolic blood pressure was significantly increased in the 5HT, Ang-II and combination groups compared to control. Echocardiographic analysis demonstrated significantly reduced ejection fraction in Ang-II and the combination groups. H&E staining demonstrated thicker leaflets in the combination groups, suggesting a more aggressive remodeling process. Picrosirius red staining and image analysis suggested that the Ang-II and combination groups had the largest proportion of thicker collagen fibers. VIC orientation, cellular contractility and collagen gene expression was highest for the 5HT+Ang-II combination treatment compared to all other groups. Overall, our results suggest that 5HT and Ang-II interact to result in significantly detrimental alteration of function and remodeling in the valve.

Effects of the 5-HT6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex

Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT6 receptor (Ki 0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis. Idalopirdine (10mg/kg p.o.) increased extracellular levels of dopamine, noradrenaline and glutamate in the mPFC and showed a trend to increase serotonin levels. No effect was observed on acetylcholine levels. The AChEI donepezil (1.3mg/kg s.c.) significantly increased the levels of acetylcholine. Pretreatment with idalopirdine 2h prior to donepezil administration potentiated the effect of donepezil on extracellular acetylcholine levels. The idalopirdine potentiation of donepezil-induced increase in acetylcholine levels was also observed during local infusion of idalopirdine (6µg/ml) into the mPFC by reverse dialysis. The data from the current study may provide a mechanistic model for the pro-cognitive effects observed with administration of idalopirdine in donepezil-treated patients with Alzheimer's disease observed in the phase 2 studies (Wilkinson et al. 2014).

Activity of etv5a and etv5b genes in the hypothalamus of fasted zebrafish is influenced by serotonin

Serotonin has been implicated in the inhibition of food intake in vertebrates. However, the mechanisms through which serotonin acts has yet to be elucidated. Recently, ETV5 (ets variant gene 5) has been associated with obesity and food intake control mechanisms in mammals. We have analyzed a putative physiological function of the two etv5 paralogous genes (etv5a and etv5b) in neuronal food intake control in adult zebrafish that have been exposed to different nutritional conditions. A feeding assay was established and fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), was applied. Gene expression changes in the hypothalamus were determined using real-time PCR. Fasting induced an up-regulation of etv5a and etv5b in the hypothalamus, whereas increased serotonin levels in the fasted fish counteracted the increase in expression. To investigate potential mechanisms the expression of further food intake control genes was determined. The results show that an increase of serotonin in fasting fish causes a reduction in the activity of genes stimulating food intake. This is in line with a previously demonstrated anorexigenic function of serotonin. Our results suggest that obesity-associated ETV5 has a food intake stimulating function and that this function is modulated through serotonin.

4 Study on the antidepressant-like effects of Yuzhi Jieyu tea and its composition ratio in vivo

Objectives Cornus officinalis Sieb. et Zucc. pulp (COP) and Gardenia jasminoides Ellis fruit (GJF) are both medicinal and edible herbs with a good taste. Yuzhi Jieyu tea (YZJYT) is mainly prepared using COP and GJF teabags and boiling water. The present study aimed to investigate the antidepressant-like effects of YZJYT and its composition ratio in vivo for the first time. Methods Male mice were treated with YZJYT (4 g/kg) at different ratios and fluoxetine hydrochloride (10 mg/kg) once a day for 7 consecutive days by intragastric administration. The forced swim test (FST), tail suspension test (TST), open field test (OFT) and reserpine reversal test 1 hour after the last administration were used to evaluate the antidepressant-like effects and the composition ratio of YZJYT, and brain tissues were used for serotonin determination through enzyme-linked immunoassay. Results YZJYT (COP:GJF ratio ranging from 1:2 to 4:1) administration exerted antidepressant-like effects in mice, as indicated by the reduced duration of immobility in the FST and TST, but it had no effect on locomotor activity in the OFT. YZJYT treatment significantly counteracted the decrease in rectal temperature induced by reserpine. Furthermore, YZJYT increased levels of serotonin (5-HT) in the brains of mice. These antidepressant-like effects of YZJYT are essentially similar to the effects of the clinical antidepressant fluoxetine hydrochloride. Conclusions These findings indicate that YZJYT exerts an antidepressant-like effect when the composition ratio of COP:GJF ranges from 1:2 to 4:1, and suggest its mechanisms may be partially involved in the central serotonergic system. Acknowledgments This research was financially supported by project grants from the Funding Scheme for Young Key Teachers of Colleges and Universities in Henan Province (Grant No. 2014GGJS-072), the Science and Technology Project of Zhengzhou (Grant No. 20150309) and the Students’ Creative Learning project in Henan University of Chinese Medicine (Grant No. YXCX [2013] 3).

HBK-14 and HBK-15 with antidepressant-like and/or memory-enhancing properties increase serotonin levels in the hippocampus after chronic treatment in mice

5-HT1A and 5-HT7 receptor ligands might have antidepressant-like properties and improve cognitive function. We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT1A and 5-HT7 receptor antagonists in various behavioral tests in rodents. As a continuation of our previous experiments, in this study we aimed to investigate whether chronic administration of 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15) caused antidepressant-like effects and elevated serotonin levels in the murine hippocampus. We also evaluated cholinolytic properties and the influence of acute administration of both compounds on cognitive function in mice. To assess antidepressant-like properties and the influence on learning and memory we used forced swim test and step-through passive avoidance task in mice, respectively. Both compounds showed antidepressant-like properties and significantly elevated serotonin levels in the hippocampus after chronic treatment (HBK-14 – 2.5 mg/kg; HBK-15 – 0.625 and 1.25 mg/kg). HBK-15 administered chronically antidepressant-like activity at lower dose (0.625 mg/kg) than the dose active after acute treatment (1.25 mg/kg). None of the compounds affected locomotor activity of mice. HBK-15 possessed very weak cholinolytic properties, whereas HBK-14 did not show any effect on muscarinic receptors. Only HBK-15 (0.625 mg/kg) presented memory-enhancing properties and ameliorated cognitive impairments caused by scopolamine (1 mg/kg). Our results indicate that 5-HT1A and 5-HT7 antagonists might have potential in the treatment of depression and possess positive influence on cognitive function.

Spermatorrhea and Loss of Libido Induced by Topiramate: First Case Report and Review of Literature

Topiramate (TPM) is a broad-spectrum antiepileptic drug used for a variety of clinical conditions, including migraine prophylaxis and mood disorders. Spermatorrhea accompanied by loss of libido severely lowers quality of life for men, but had never been reported as a possible adverse effect of TPM. Here, we present a case of a 39-year-old Chinese man who was diagnosed with partial epilepsy and treated with TPM (100 mg/d). Eleven days after initiating TPM treatment, he began to experience spermatorrhea every 2 to 3 days, accompanied by loss of libido, lack of energy, lassitude, irascibility, weakness, poor appetite, frequent urination, and nocturia. The symptoms continued for 2 months. After withdrawal of TPM, symptoms disappeared and did not recur. This is the first case report of TPM-induced spermatorrhea and loss of libido in China. Spermatorrhea and loss of libido are probably rare adverse effects of TPM treatment. When these symptoms occur in a patient taking TPM, the possibility that they are adverse effects to this drug should be considered, and switching the patient to a different drug may be a good option. The underlying mechanism by which TPM induces spermatorrhea may be related to increased serotonin level, and loss of libido may be related to changes in serotonin and hormone levels.

Attention deficit-hyperactivity disorder suffers from mitochondrial dysfunction

BackgroundPathophysiology of attention-deficit hyperactivity disorder (ADHD) is not known, and therefore the present study investigated mitochondrial defects, if any in cybrids created from patients and control population. MethodsTo investigate mitochondrial pathology in ADHD, cybrids cell lines were created from ADHD probands and controls by fusing their platelets with ρ0-cells prepared from SH-SY5Y neuroblastoma cell line. Cellular respiration, oxidative stress, mitochondrial membrane potential and morphology were evaluated employing oxygraph, mitochondria-specific fluorescence staining and evaluation by FACS, and immunocytochemistry. HPLC-electrochemical detection, quantitative RT-PCR and Blue Native PAGE were employed respectively for assays of serotonin, mitochondrial ATPase 6/8 subunits levels and complex V activity. ResultsSignificantly low cellular and mitochondrial respiration, ATPase6/8 transcripts levels, mitochondrial complex V activity and loss of mitochondrial membrane potential and elevated oxidative stress were observed in ADHD cybrids. Expression of monoamine oxidizing mitochondrial enzymes, MAO-A and MAO-B levels remained unaffected. Two-fold increase in serotonin level was noted in differentiated cybrid-neurons. ConclusionsSince cybrids are shown to replicate mitochondrial defects seen in post-mortem brains, these observed defects in ADHD cybrids strongly suggest mitochondrial pathology in this disorder. General significanceMitochondrial defects are detected in ADHD cybrids created from patients' platelets, implying bioenergetics crisis in the mitochondria could be a contributory factor for ADHD pathology and/or phenotypes.

Ginsenosides attenuate d-galactose- and AlCl3-inducedspatial memory impairment by restoring the dysfunction of the neurotransmitter systems in the rat model of Alzheimer's disease

Ethnopharmacological relevancePanax ginseng C.A.Mey. is a traditional Chinese herbal medicine, which has been used to treat Alzheimer's disease (AD) for thousands of years. Ginsenoside is one of the major compounds found in P. ginseng. This study aimed to explore the attenuation of spatial memory impairment by ginsenosides and its correlation with restoring the dysfunction of the neurotransmitter systems in AD model rats to understand the mechanism underlying the anti-AD effect of P. ginseng. Materials and methodsIn this study, the AD model was established by combining d-galactose (d-gal) with AlCl3 (Al) for 60 days. From day 30, the ginsenosides group was intragastrically administered with ginsenosides for 30 days. The ethology of rats was tested through the Morris water maze test(MWM). Histopathological changes in the hippocampus of rats were observed through hematoxylin and eosin staining. The expressions of amyloid β peptide (Aβ) and phospho-tau (p-tau) in the hippocampus and cortex of rats were detected by immunohistochemistry. A liquid chromatography–mass spectrometry assay was used to measure neurotransmitter concentrations in the hippocampus, cortex, and blood. ResultsGinsenosides could significantly decrease the escape latency time and the average latency time in the place navigation test and increase the times of crossing the platform area, the percentage of residence time, and the distance in the original platform quadrant in the spatial probe test. Ginsenosides could repair the damage of the hippocampus and reduce the expressions of Aβ and p-tau. Ginsenosides could also increase γ-aminobutyric acid, acetylcholine, and dopamine levels and decrease glutamate and aspartic acid levels in the hippocampus and cortex and increase glycine and serotonin levels in the blood. ConclusionsAfter effectively administrated, ginsenosides attenuate d-gal- and Al-induced spatial memory impairment. The possible mechanism of the beneficial effect is restoring the dysfunction of various neurotransmitters.

Effects of Anodal Transcranial Direct Current Stimulation and Serotonergic Enhancement on Memory Performance in Young and Older Adults.

In the absence of effective therapies for dementia and its precursors, enhancing neuroplasticity by means of non-invasive brain stimulation such as anodal transcranial direct current stimulation (atDCS) might be a promising approach to counteract or delay the onset of cognitive decline, but effect sizes have been moderate so far. Previous reports indicate that increasing serotonin levels may enhance atDCS-induced neuroplasticity. However, evidence for serotonergic modulation of atDCS effects on memory is still lacking. Here, we conducted a double-blind, randomized, sham-/placebo-controlled trial to investigate the impact of a selective serotonin reuptake inhibitor (SSRI; single dose of 20 mg citalopram) and atDCS over the right temporoparietal cortex (1 mA, 20 min) on memory formation. Twenty young and 20 older subjects completed an object-location learning task in each of the four conditions: sham+placebo, sham+SSRI, atDCS+placebo, and atDCS+SSRI. Outcome measures were performance in immediate (primary outcome) and delayed cued recall. While we found an SSRI effect, but no statistically significant effect of atDCS on immediate recall scores, young and older adults benefited most from the combined application (comparisons: atDCS+SSRI>atDCS+placebo and atDCS+SSRI>sham+placebo). Thus, our data provide evidence that atDCS improves memory formation if serotonergic neurotransmission is enhanced simultaneously. Further studies are needed to assess whether these findings extend to clinical populations with memory impairment and translate into clinically relevant improvements after long-term serotonergic enhancement and repeated stimulation.

Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo.

BackgroundThe aggregation of amyloid-β (Aβ) into insoluble plaques is a hallmark pathology of Alzheimer’s disease (AD). Previous work has shown increasing serotonin levels with selective serotonin re-uptake inhibitor (SSRI) compounds reduces Aβ in the brain interstitial fluid (ISF) in a mouse model of AD and in the cerebrospinal fluid of humans. We investigated which serotonin receptor (5-HTR) subtypes and downstream effectors were responsible for this reduction.ResultsAgonists of 5-HT4R, 5-HT6R, and 5-HT7R significantly reduced ISF Aβ, but agonists of other receptor subtypes did not. Additionally, inhibition of Protein Kinase A (PKA) blocked the effects of citalopram, an SSRI, on ISF Aβ levels. Serotonin signaling does not appear to change gene expression to reduce Aβ levels in acute timeframes, but likely acts within the cytoplasm to increase α-secretase enzymatic activity. Broad pharmacological inhibition of putative α-secretases increased ISF Aβ and blocked the effects of citalopram.ConclusionsIn total, these studies map the major signaling components linking serotonin receptors to suppression of brain ISF Aβ. These results suggest the reduction in ISF Aβ is mediated by a select group of 5-HTRs and open future avenues for targeted therapy of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0112-5) contains supplementary material, which is available to authorized users.