Systemic low-grade inflammation associated with specific depressive symptoms:insights from network analyses of five independent NHANES samples

To the editor:Major depressive disorder(MDD)is a heterogeneous disorder with varying symptom presentations and underlying biological mechanisms.1 The mainstream neurobiological hypotheses of depression involve monoamine neurotransmitters,hypothalamic-pituitary-adrenal axis,immune-inflammation and the glutamate system.

Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson's disease

Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson＇s disease （PD）, whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection. Noradrenaline inhibits microglial activation and suppresses pro-inflamma- tory mediator production （e.g., tumor necrosis factor-a, interleukin-1β ＆ inducible nitric oxide synthase activity）, thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflamma- tory stimulus. Neighbouring astrocyte populations promote a neurotrophic environment in response to β2-adrenoceptor （β2-AR） stimulation via the production of growth factors （e.g., brain derived neurotrophic factor, cerebral dopamine neurotrophic factor ＆ glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system. More recent findings have demonstrated a role for the β2-AR in down-regulating expression levels of the human a-synuclein gene SNCA and relative a-synuclein protein abundance. Given that a-synuclein is a major protein constituent of Lewy body pathology, a hallmark neuropathological feature in Parkinson＇s disease, these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of a-synucleinopathies in the Parkinsonian brain. In essence, the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via （1） inhibiting nigral microglial activation ＆ pro-inflammatory mediator production, （2） promoting the synthesis of neurotrophic factors from midbrain astrocytes and （3） downregulating a-synuclein gene expression and protein abundance in a β2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial β2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

Differential effects of physical activity and sleep duration on cognitive function in young adults

Purpose: Although exercise and sleep duration habits are associated with cognitive function, their beneficial effects on cognitive function remain unclear. We aimed to examine the effect of sleep duration and daily physical activity on cognitive function, elucidating the neural mechanisms using near-infrared spectroscopy(NIRS).Methods: A total of 23 healthy young adults(age 22.0 ± 2.2 years) participated in this study. Exercise amount was assessed using a uniaxial accelerometer. We evaluated total sleep time(TST) and sleep efficiency by actigraphy. Cognitive function was tested using the N-back task, the Wisconsin Card Sorting Test(WCST), and the Continuous Performance Test—Identical Pairs(CPT-IP), and the cortical oxygenated hemoglobin levels during a word fluency task were measured with NIRS.Results: Exercise amount was significantly correlated with reaction time on 0- and 1-back tasks(r = —0.602, p = 0.002; r = —0.446, p = 0.033,respectively), whereas TST was significantly correlated with % corrects on the 2-back task(r = 0.486, p = 0.019). Multiple regression analysis,including exercise amount, TST, and sleep efficiency, revealed that exercise amount was the most significant factor for reaction time on 0- and 1-back tasks(b = —0.634, p = 0.002; b = —0.454, p = 0.031, respectively), and TST was the most significant factor for % corrects on the 2-back task(b = 0.542, p = 0.014). The parameter measured by WCST and CPT-IP was not significantly correlated with TST or exercise amount. Exercise amount, but not TST, was significantly correlated with the mean area under the NIRS curve in the prefrontal area(r = 0.492, p = 0.017).Conclusion: Exercise amount and TST had differential effects on working memory and cortical activation in the prefrontal area. Daily physical activity and appropriate sleep duration may play an important role in working memory.

Soluble Fiber Improves Management of Diarrhea in Elderly Patients Receiving Enteral Nutrition

Dietary fiber is a non-digestible carbohydrate providing beneficial effects for bowel health. The aim of this study was to evaluate the clinical effects of fiber supplementation in enteral feeding on elderly patients suffering from diarrhea. This study was conducted in 15 patients (7 men and 8 women, 79.0 ± 7.5 years) who had loose stools or diarrhea during enteral nutrition. The enteral formula was supplemented with soluble dietary fiber (5.2 g/day) for 3 weeks, which was then discontinued for 1 week to confirm its effects. The effects of soluble dietary fiber on stool frequency, the Bristol Stool Form Scale (which is designed to measure stool consistency), plasma diamine oxidase (DAO) activity, and concentrations of plasma short-chain fatty acids (SCFA) were evaluated. After supplementation with soluble dietary fiber, there were no significant differences in stool frequency but there was a significant improvement in stool consistency (P < 0.05). Furthermore, ingestion of soluble dietary fiber resulted in increased plasma DAO activity and significantly increased levels of plasma SCFA (P < 0.05). Supplementation with soluble dietary fiber may be beneficial for improving stool consistency in patients suffering from diarrhea during enteral nutrition. A further controlled trial is warranted to examine the preventive effects of soluble dietary fiber in patients suffering from diarrhea.

The 2019 novel coronavirus disease(COVID-19) pandemic: A zoonotic prospective

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),a novel coronavirus(CoV),has recently emerged as a significant pathogen for humans and the cause for the recent outbreak of the 2019 novel coronavirus disease(COVID-19)throughout the globe.For developing any preventive measure,an understanding of the zoonotic pattern for this virus is a necessity.We should have a clear knowledge of its reservoir host,its distribution pattern and spreading routes.Information about zoonotic reservoirs and its transmission among them can help to understand the COVID-19 outbreaks.In this article,we discuss about the bats as the zoonotic reservoir of several CoV strains,co-existence of bats and CoV/viruses,the sequence similarity of SARS-CoV-2 with bat SARS-like CoV,the probable source of the origin of SARS-CoV-2 strain and COVID-19 outbreak,intermediate host of CoVs and SARS-CoV-2,human to human transmission and the possibility to maintain the zoonotic barriers.Our knowledge about the zoonotic reservoir of SARS-CoV-2 and its transmission ability may help develop the preventive measures and control for the future outbreak of CoV.

Oxidative stress bridges the gut microbiota and the occurrence of frailty syndrome

The incidence of frailty gradually increases with age.This condition places a heavy burden on modern society,of which the aging population is increasing.Frailty is one of the most complicated clinical syndromes;thus,it is difficult to uncover its underlying mechanisms.Oxidative stress(OS)is involved in frailty in multiple ways.The association between the gut microbiota(GM)and frailty was recently reported.Herein,we propose that OS is involved in the association between the GM and the occurrence of frailty syndrome.An imbalance between oxidation and antioxidants can eventually lead to frailty,and the GM probably participates in this process through the production of reactive oxygen species.On the other hand,OS can disturb the GM.Such dysbiosis consequently induces or exacerbates tissue damage,leading to the occurrence of frailty syndrome.Finally,we discuss the possibility of improving frailty by intervening in the vicious cycle between the imbalance of OS and dysbiosis.

G αi, and G βγ, subunits have opposite effects on dexmedetomidine-induced sedation

OBJECTIVE To explore the mechanism of G_(αi) and G_(βγ) subunits on dexmedetomidine(DMED)-induced sedation.METHODS Kunming mice were randomly placed into three groups(DMED group,DMED+dbcAMP/rolipram/gallein/M119 group,dbcAMP/rolipram/gallein/M119 group) to explore the regulation of dbcAMP/rolipram/gallein/M119 on DMED-induced sedation by establishing loss of righting reflex(LORR) model.DbcAMP/rolipram was intracerebroventricular injected and gallein/M119 was intraperitoneal injected 15 min before DMED intravenous injection.In CHO-α2 A-AR cells,after administration of DMED/gallein/M119,the regulation on the cAMP accumulation stimulated by Forskolin(FSK) was detected,so was the intracellular calcium ion concentration([Ca2 + ]i.The levels of pERK/pCREB were detected by Western Blot to explore the key signal molecules involved in DMED-induced sedation.RESULTS The ED50 of DMED-induced LORR(200.0 nmol·kg^(-1)) was increased to 375.0 or433.3 nmol·kg^(-1) by pre-treatment with cAMP analog dbcAMP(50 nmol/5μl per mouse) or phosphodies.terase 4 inhibitor rolipram(100 nmol/5μl per mouse).In addition,the ED50 of DMED-induced LORR was decreased to 113.6 or 136.5 nmol·kg^(-1) when pre-treated with G_(βγ) subunits inhibitor M119(100 mg·kg^(-1))or gallein(100 mg·kg^(-1)) respectively.Administration of dbcAMP,rolipram,gallein or M119 alone had little effect on LORR of mice.Gallein(10 μmol·L^(-1)) significantly inhibited forskolin-stimulated cAMP accumu.lation in CHO-α2A-AR cells.Compared with G_(βγ) subunits inhibitors or DMED alone,[Ca^(2+)]i and pERK1/2 significantly increased after co-administration of G_(βγ) subunits inhibitors with DMED.DbcAMP(5 μmol·L^(-1))or rolipram(5 μmol·L^(-1)) alone had little effect on ERK1/2 phosphorylation,but decreased DMEDinduced ERK1/2 phosphorylation after co-administration with DMED.G_(βγ) subunit inhibitors treatment increased DMED-induced phosphorylation of CREB,whereas dbcAMP or rolipram had little effect on pCREB induced by DMED.CONCLUSION G_(βγ) subunits might inhibit DMED-induced sedation through cAMP and pERK1/2 pathway,which was opposite to G_(αi) subuint.

Impact of living with bipolar patients: Making sense of caregivers' burden

The aim of the present review was to examine objective and subjective burdens in primary caregivers(usually family members) of patients with bipolar disorder(BD) and to list which symptoms of the patients are considered more burdensome by the caregivers. In order to provide a critical review about caregiver's burden in patients with bipolar disorder, we performed a detailed Pub Med, Bio Med Central, ISI Web of Science, Psyc INFO, Elsevier Science Direct and Cochrane Library search to identify all papers and book chapters in English published during the period between 1963 and November 2011. The highest levels of distress were caused by the patient's behavior and the patient's role dysfunction(work, education and social relationships). Furthermore, the caregiving role compromises other social roles occupied by the caregiver, becoming part of the heavy social cost of bipolar affective disorder. There is a need to better understand caregivers' views and personal perceptions of the stresses and demands arising from caring for someone with BD in order to develop practical appropriate interventions and to improve the training of caregivers.

Involvement of flumazenil-insensitive benzodiazepine binding site in benzodiazepine-induced anesthesia in zebrafish larvae

OBJECTIVE To identify the involvement of flumazenil-insensitive benzodiazepine(BZD) binding site in mediating BZD-induced immobility.The distribution of this nonclassical binding site and its key amino acid residues in GABAAreceptors(GABAARs) were also investigated.METHODS Using a zebrafish larvae locomotion model,we investigated the detailed dose-dependent effects of diazepam and other BZDs on zebrafish larvae behaviors,with a focus on their high-dose effects.We then evaluated the influence of the classical BZD antagonist flumazenil,GABAARs antagonist bicuculline,and the antagonist of a proposed BZD binding site in α4/6β3δ subtype receptor Ro15-4513 on BZDs induced immobility.Using wholecell patch clamp electrophysiological recordings on recombinant GABAARs,we investigated the modulation of diazepam alone or combined with flumazenil on GABA-elicited current in wildtype and mutated receptors.RESULTS Diazepam dose-dependently decreased the locomotor activities of zebrafish larvae at doses of 0.4,2,10,20,30,50 and 75 mg·L^(-1).The hypolocomotion(sedation-like state) induced by diazepam at10 and 20 mg·L^(-1) were effectively antagonized by flumazenil with EC150 of 0.086 mg·L-and1.295 mg·L^(-1),while the immobility(anesthesialike state) induced by diazepam at 30 mg·L^(-1) was abolished by bicuculline(3 mg·L^(-1)),but not affected by flumazenil(even at concentration up to150 mg·L^(-1)) or Ro15-4513(100 mg·L^(-1)).The immobility induced by clonazepam and lorazepam(100 mg·L^(-1)) was also resistant to flumazenil(100 mg·L^(-1)).In the α1β2γ2 subtype receptor expressed in HEK293 T cells,diazepam dose-dependently potentiated GABA-elicited current,and this potentiation was effectively antagonized by flumazenil(100 μmol·L^(-1)).However,in α1β2 subtype receptor,diazepam(150 μmol·L^(-1)) induced potentiation was insensitive to flumazenil(100 μmol·L^(-1)),but was abolished by the mutation of β2 N265 I.CONCLUSION These results provide direct in vivo evidence for the nonclassical binding sites,which may be located at the second transmembrane domain of GABAAR,mediate BZD-induced anesthesia.

Thienorphine induces analgesia by binding κ -and δ-, or by partially binding μ-opioid receptor,thus further regulating cAMP-PKA activity

OBJECTIVE Thienorphine,a new oripavine derivative,has shown to possess stronger antinociceptive effects and better oral bioavailability compared to buprenorphine.The present study examines the effect of thienorphine on c AMP-dependent protein kinase A(PKA) activity in CHO cells expressing μ-,κ-,δ-and ORL1 receptors.In addition,we further examined its analgesic effect in vivo.METHODS The effect of thienorphine on cA MP-dependent PKA redistribution and cA MP inhibition were analyzed in CHO-PKAcatEGFP cells.PKA redistribution assays in CHO-PKAcatEGFP cells stably expressing μ-,κ-,δ-and ORL1 receptors were analyzed by high-throughput screening system to elucidate the efficacy of agonists or antagonists on opioid receptors.Moroever,the antinociceptive effects of thienorphine in vivo were examined using hot plate test.RESULTS Briefly,the maximum inhibition of thienorphine on PKA activity was about 36%,100%,100%and 12% in CHO-μ/κ/δ/ORL1-PKAcatE GFP cel s,respectively.In addition,thienorphine concentrationdependently inhibited the PKA activity with EC50 value of(22.7±18.1) nmol·L^(-1) in CHO-κ-PKAcatE GFP cels and(12.4±7.7) nmol·L^(-1) in CHO-δ-PKAcatE GFP cells.Thienorphine induced approximately 50%antinociceptive effect in mice lacking μ receptors compared to their wild-type controls(P<0.05).Also,the κ and δ selective antagonist nor-binaltorphimine,naltrindole decreased approximately 50%-60% in % MPE of theinorphine in μ-KO mice,respectively.The ORL1 receptor selective antagonist J113397 had no effect in %MPE of theinorphine in μ-KO mice.CONCLUSION Thienorphine induces analgesia through bindingκ-and δ-,or by partially binding μ-opioid receptor,thus further regulating the cAMP-PKA activity.Therefore,thienorphine may be used in acute or chronic pain with minimal addictive potential.

Mouse strain differences in selective serotonin reuptake inhibitors sensitivity correlates with serotonin transporter binding and function

OBJECTIVE Selective serotonin reuptake inhibitors(SSRIs) bind 5-HT transporters,leading to the accumulation of 5-HT and amelioration of depression.Although different mouse strain showed different sensitivity to SSRIs in mouse models of depression,the reason for these strain differences remains unclear.Here,therefore,in the present study,we examined immobility time and locomotor activity in two mouse strains,namely,C57BL/6 J and DBA/2 J mice,and the effects of the SSRIs fluoxetine.Furthermore,we analyzed 5-HT transporter binding and reuptake inhibition in both strains to explore their relationship with the immobility and locomotor activity effects of the three SSRIs in these two mouse strains.METHODS Strain differences in SSRI effects in the tail suspension test(TST) and forced swimming test(FST).To initiate our studies,we sought to confirm that SERT strain variation did not alter SERT protein expression,5-HT recognition,or uptake activity when expressed in C57BL/6 J and DBA/2 J mice.Radioligand binding assays were conducted to determine the affinity of the SSRIs for the 5-HT transporters in the two mouse strains.RESULTS SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2 J but not C57BL/6 J mouse strains,whereas fluoxetine showed opposite results.Paroxetine reduced immobility time similarly in both strains.The affinity of citalopram for the 5-HT transporter in DBA/2 J mice was 700-fold higher than that for in C57BL/6 J mice,whereas the affinity of fluoxetine in C57BL/6 J mice was 100-fold higher than that in the DBA/2 J mouse.Furthermore,High citalopram concentrations were required to [3 H]5-HT uptake in C57BL/6 J but not DBA/2 J mouse cortical synaptosomes,whereas fluoxetine also showed opposite results.CONCLUSION Immobility duration depends on 5-HT transporter binding levels,leading to apparent strain differences in immobility time in FST and TST.Furthermore,differences in 5-HT transporter binding may cause variations in SSRI responses on behaviors.SERT mutation mice maintained sensitivity to paroxetine,an antidepressant that is unaffected by the mouse mutation.Therefore,the background strain of these mice likely contributes to the acute behavioral actions of SSRIs in immobility time.These differences may help to explain some of the discrepancies in studies that used these strains of mice to examine the role of 5-HT in mouse models of depression.Future studies should investigate additional neural substrates and molecular mechanisms underlying strain variations in mouse models of depression to help identify genetic predispositions to this disorder in humans.

Wnt1/β-catenin signaling up-regulates spinal VGLUT2 expression to maintain neuropathic pain in mice

OBJECTIVE The present study was aimed to investigate the role of Wnt/β-catenin sig.naling in spinal VGLUT2 regulation and neuropathic pain.METHODS To elucidate the association be.tween VGLUT2 and neuropathic pain,we determined the expression and distribution characteristics of VGLUT2 in mice subjected to spared nerve injury(SNI),and then observed the effects of two VGLUT2 targeting shRNAs on mechanical allodynia and glutamate release.The effects of Wnt/β-catenin signal.ing on VGLUT2 expression and pain behavior were investigated by using Wnt agonist,Wnt1,and Wnt/β-catenin pathway inhibitor XAV939 in SNI mice.RESULTS SNI surgery induced significant up-regula.tion of VGLUT2 on postoperative days 7,14,and 21.Double immunofluorescence labeling of VGLUT2 with NeuN,MAP2,Iba-1,or GFAP showed that VGLUT2 was mainly expressed in neurons in the dor.sal horn of the spinal cord after SNI(NeuN,MAP2).Intrathecal administration of VGLUT2 shRNAs be.fore or after SNI surgery significantly decreased mechanical allodynia and glutamate release.Mean.while,Wnt1/β-catenin signaling increased significantly after SNI surgery.Over-expression of β-catenin in PC12 cells increased VGLUT2 protein level,intrathecal administration of Wnt agonist or Wnt1 signifi.cantly increased VGLUT2 protein expression in spinal cord,while Wnt/β-catenin pathway inhibitor XAV939 decreased VGLUT2 expression in PC12 cells and spinal cord.Additionally,intrathecal admin.istration of XAV939 7 days after SNI significantly attenuated mechanical allodynia in mice,which was in accordance with down-regulation of VGLUT2 protein levels.VGLUT2 shRNAs significantly attenuat.ed Wnt agonist or Wnt1 induced mechanical allodynia.CONCLUSION Wnt1/β-catenin signaling path.way up-regu-lates the spinal VGLUT2 expression,and this regulation is involved in neuropathic pain behavior.

Regulation ofβ2-adrenoceptors in brain glia:implications for neuroinflammatory and degenerative disorders

Noradrenaline:Within the central nervous system(CNS),the primary source of the catecholamine neurotransmitter noradrenaline is the locus coeruleus(LC)in the pontine tegmentum,with LC neurons projecting to almost all regions of the brain and spinal cord.Following its release from LC neurons,noradrenaline has wide ranging effects.For example,noradrenaline is the endogenous agonist for G-coupledα-andβ-adrenoceptors that are expressed on many cell types,including neurons and glia,in both the peripheral nervous system and CNS.It is via these receptors that noradrenaline exerts its anti-inflammatory and neurotrophic effects in the brain.Noradrenaline additionally has adrenoceptor-independent neuroprotective actions,and as such plays a role in free radical scavenging and reducing oxidative stress(Feinstein et al.,2016).

The effects of oral smokeless tobacco administration on endurance performance

Background: Smokeless tobacco is widely used by athletes to enhance performance. Nicotine is a central nervous system stimulant and acts on cardiocirculatory and metabolic systems, involving tissue blood flow and circulatory vasoreactivity. The aim of this study was to investigate the effects of the oral smokeless tobacco(Swedish snus(SS)) on the perception of fatigue and time to exhaustion(TTE) during moderate-intensity aerobic exercise.Methods: Fourteen healthy non-tobacco male users were recruited for a double-blind, controlled crossover design(SS vs. snus placebo(SP)).Subjects were tested for 3 sessions: experimental session 1(Exp1) consisted of an incremental test to determine the maximal aerobic power output(Wmax), whereas Exp2 and Exp3 consisted of exercising at 65%Wmaxuntil exhaustion in SS or SP conditions. During Exp2 and Exp3, muscle and cerebral oxygenation was assessed by means of near-infrared spectroscopy, and the rating of perceived exertion(RPE) was recorded.Results: Comparing SS with SP tests, significant differences(p < 0.05) were found in the values of cerebral(～3%) and muscular tissues oxygenation(～4%) in the first 30 min of exercise. The RPE values were not significantly different between the 2 conditions(SS vs. SP). No significant difference was found in TTE(SS: 54.25 § 21.84 min; SP: 50.01 § 17.03 min).Conclusion: This study showed that muscular and cerebral oxygenation increased significantly with snus administration during an endurance exercise until exhaustion, but this did not affect fatigue perception and TTE. The results showed that snus could not be considered an ergogenic substance in non-tobacco users.

S4A-5 Screening ofμOpioid Receptor-Interacting Proteins and Effects of ABIN-1 on Receptor Function

Aim:To determine the proteins that interact with the carboxyl-terminal of theμopioid receptor(MOR-C)after chronic morphine exposure.Methods:The brain cDNA library of chronic morphine treatment rats was screened using rat MOR-C to investigate the regulator of opioids dependence in the present study.The brain cDNA library from chronic morphine-dependent rats was constructed using the SMART(Switching Mechanism At 5′end of RNA Transcript)technique.Bacterial two-hybrid system was used to screening the rat MOR-C interacting proteins from the cDNA library.RT-qPCR and immunoblotting were used to determine the variation of MOR-C interacting proteins in rat brain after chronic morphine treatment.Column overlay assays,immunocytochemistry and coimmunoprecipitation were used to demonstrate the interaction of MOR-C and p75NTR-associated cell death executor(NADE)or A20-binding inhibitor of nuclear factor kB(ABIN-1).Results:21 positive proteins,including 19 known proteins were screened to interact with rat MOR-C.Expression of several of these proteins was altered in specific rat brain regions after chronic morphine treatment.Among these proteins,ABIN-1 and NADE were confirmed to interact with rat MOR-C by in vitro proteinprotein binding and coimmunoprecipitation in Chinese hamster ovary(CHO)cells and rat brain with or without chronic morphine treatment.Saturation binding studies showed that ABIN-1 had no effect on MOR binding.However,the interaction of ABIN-1 and MOR inhibited the activation of G proteins induced by DAMGO([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin).MOR phosphorylation,ubiquitination,and internalization induced by DAMGO were decreased in Chinese hamster ovary cells that coexpressed MOR and ABIN-1.The suppression of forskolinstimulated adenylylcyclase by DAMGO was also inhibited by the interaction of ABIN-1with MOR.In addition,extracellular signal-regulated kinase activation was also negatively regulated by overexpression of ABIN-1.These data suggest that ABIN-1 is a negative coregulator of MOR activation,phosphorylation,and internalization in vitro.ABIN-1 also inhibited morphine-induced hyperlocomotion in zebrafish larvae(AB strain).By utilization of an antisense morpholino oligonucleotide(MO)gene knockdown technology,the ABIN-1MO-injected zebrafish larvae showed a significant increase(approximately 60%)in distance moved compared with control MO-injected larvae after acute morphine treatment(P≤0.01).Conclusion:Understanding the rat MOR-C interacting proteins and the proteins variation under chronic morphine treatment may be critical for determining the pathophysiological basis of opioid tolerance and addiction.Among these proteins,ABIN-1 negatively regulates MOR function in vitro and in vivo.Other MOR-C interacting proteins’influence on the opioid tolerance and addiction need further study.

S1-2 The 5-HT6 Receptor-Related Mechanism for the Cognition-Enhancing Properties of Hypidone Hydrochloride(YL-0919),A Novel Protential Antidepressant

Hypidone hydrochloride(YL-0919),the 5-HT1A/6 agonists and 5-HT reuptake inhibitor,is a novel potent antidepressant with original chemical structure.Previous studies confirmed that YL-0919 has significant antidepressant-and anxiolytic-like effects.Compared with first-line antidepressants,YL-0919 possesses rapid-onset and cognition-enhancing advantages without causing sexual disorders.Recently,it has been found that it has high affinity with 5-HT6 receptor.Objective:To study the target characteristics of YL-0919 to 5-HT6 receptors,and to explore the relationship between the 5-HT6 receptor and the cognition-enhancing,antidepressant/anxiolytic-like effects of YL-0919 and targeting mechanisms.Methods:The radioligand binding inhibition test and[35S]-GTPγS binding assay were used to evaluate the binding affinity of YL-0919 to 5-HT6 receptor in rat striatum,transient CHO cell line and stable Hela cell lines.Novel object recognition(NOR),Morris water maze(MWM)and step-down test(SD)were used to evaluate the cognition-enhancing activity of YL-0919,and the selective 5-HT6 receptor antagonist SB271046 was used to evaluate the relationship between behavioral improvement caused by YL-0919 and 5-HT6 receptor activation.To study the 5-HT6 receptor related mechanisms of YL-0919,the competitive immunofluorescence assay were used to examine the cAMP level in h5-HT6 receptor-expressed in the Hela cells Results:①Radioligand competitive binding experiments showed that YL-0919 had high binding affinity with 5-HT6 receptors in the rat striatum,the CHO cells transiently expressed the h5-HT6 receptor and the Hela cells stably expressed the h5-HT6 receptor,with Ki of 10.72,14.76 and 28.12 nM respectively;[35S]-GTPγS showed full agonist characteristics of YL-0919 in striatum and cells,with EC50 of 71.23,64.73 and 52.92 nM respectively,and the maximum efficiency(Emax)reached 100%which is the same to the 5-HT6 receptor agonist WAY208466,suggesting that YL-0919 is a full 5-HT6 receptor agonist.②Cognitive-related behavioral tests showed that subchronic oral administration of YL-0919(1.25~2.5 mg·kg-1)could significantly increase the recognition index in NOR,the entries and duration in the target quadrant,the entries crossing the platform in WMW,shortened the first time crossing the platform in MWM and the step-down latency in SD,suggesting the cognitionenhancing effects of YL-0919;compared with Vilazodone,the partial agonist of 5-HT1A receptor and 5-HT reuptake inhibitor,which of no such functions;Further study showed that 5-HT6 receptor antagonist SB271046(10 mg·kg-1)completely blocked the cognition-enhancing effects of YL-0919 without affecting the cognitive activity itself,suggesting that 5-HT6 receptor activation might be its underlying mechanisms;③Mechanism study found that YL-0919 could significantly increase cAMP levels in the Hela cells stably-expressed the h5-HT6 receptor,which could be dose-dependent blocked by SB271046.Conclusion:YL-0919 is a full agonist of 5-HT6 receptor.YL-0919 showed significant cognition-enhancing effects in various kinds of animal models,and its underlying important mechanism might be activating 5-HT6 receptor.In addition,enhancing downstream cAMP-CREB signaling pathway of 5-HT6 receptor might at least partially mediate the above process.Moreover,5-HT6 receptor activation might also be one of the mechanisms of antidepressant-and anxiolytic-like effects of YL-0919.In conclusion,this study confirmed the 5-HT6 receptor-related mechanisms of YL-0919,the 1.1 types of antidepressants,laying the experimental foundation for developing novel antidepressants with cognition-enhancing effects.

Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System

Opioid use disorder(OUD)has become a considerable global public health challenge;however,potential medications for the management of OUD that are effective,safe,and nonaddictive are not available.Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor(D3R)have effects on addiction in different animal models.We have previously reported that YQA14,a D3R antagonist,exhibits very high affinity and selectivity for D3Rs over D2Rs,and is able to inhibit cocaine-or methamphetamine-induced reinforcement and reinstatement in self-administration tests.In the present study,our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats,also attenuated heroin-induced reinstatement of drug-seeking behavior.On the other hand,YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice.Moreover,we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system.These findings suggest that D3R might play a very important role in opioid addiction,and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.

Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity

Background:Posttraumatic stress disorder(PTSD)and depression are highly comorbid.Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity.Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD.We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.Methods:First,we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning(FC)and fear extinction paradigm in mice.Psilocybin was administered 30 min before extinction training.Fear extinction testing was performed on the first day;fear extinction retrieval and fear renewal were tested on the sixth and seventh days,respectively.Furthermore,we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density,Western blotting for the protein levels of brain derived neurotrophic factor(BDNF)and mechanistic target of rapamycin(mTOR),and immunofluorescence staining for the numbers of doublecortin(DCX)-and bromodeoxyuridine(BrdU)-positive cells.Results:A single dose of psilocybin(2.5 mg/kg,i.p.)reduced the increase in the percentage of freezing time induced by FC at 24 h,6th day and 7th day after administration.In terms of structural neuroplasticity,psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC;in terms of neuroplasticity related proteins,psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC;in terms of neurogenesis,psilocybin rescued the decrease in the numbers of DCX-and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.Conclusions:A single dose of psilocybin facilitated rapid and sustained fear extinction;this effect might be partially mediated by the promotion of hippocampal neuroplasticity.This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characterized by failure of fear extinction.

Is tax evasion macho?Testosterone,personality traits and evasion

This paper examines the potential effects of testosterone and personality traits on the decision to evade taxes.In a series of experiments,subjects completed behavioural tasks and made a one-shot tax evasion decision.We estimate a negative weakly significant treatment effect,which suggests that an exogenous increase in the testosterone level may inhibit the decision to evade taxes.Our results also suggest that higher dominance and independent self-construal,as well as lower self-control,are associated with a greater likelihood of tax evasion.We discuss the mechanisms potentially linking testosterone to tax evasion.These findings support the inclusion of biological factors in the analysis of tax evasion behaviour.