Food-derived protein hydrolysates and peptides:anxiolytic and antidepressant activities,characteristics,and mechanisms

Globally,the prevalence of anxiety and depression has reached epidemic proportions.Food-derived protein hydrolysates and peptides delivered through dietary supplementation can avoid the negative risks associated with traditional pharmaceuticals while delivering superior anxiolytic and antidepressant effects.This review summarizes current research on food-derived anxiolytic and antidepressant protein hydrolysates and peptides,and subsequently analyses their physicochemical characteristics and elaborates on their mechanisms.The aim of this work is to contribute to the in-depth study and provide a theoretical foundation for the development of related products to better serve patients with anxiety and depression.

Association between 5-HTR1A gene C-1019G polymorphism and antidepressant response in patients with major depressive disorder:A meta-analysis

BACKGROUND Major depressive disorder(MDD)is a substantial global health concern,and its treatment is complicated by the variability in individual response to antide-pressants.AIM To consolidate research and clarify the impact of genetic variation on MDD treatment outcomes.METHODS Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,a systematic search across PubMed,EMBASE,Web of Science,and the Cochrane Library was conducted without date restrictions,utilizing key terms related to MDD,serotonin 1A receptor polymorphism(5-HTR1A),C-1019G polymorphism,and antidepressant response.Studies meeting inclusion criteria were thoroughly screened,and quality assessed using the Newcastle-Ottawa Scale.Statistical analyses,includingχ2 and I²values,were used to evaluate heterogeneity and fixed-effect or random-effect models were applied accordingly.RESULTS The initial search yielded 1216 articles,with 11 studies meeting criteria for inclusion.Analysis of various genetic models showed no significant association between the 5-HTR1A C-1019G polymorphism and antidepressant efficacy.The heterogeneity was low to moderate,and no publication bias was detected through funnel plot symmetry and Egger's and Begg's tests.CONCLUSION This meta-analysis does not support a significant association between the 5-HTR1A C-1019G polymorphism and the efficacy of antidepressant treatment in MDD.The findings call for further research with larger cohorts to substantiate these results and enhance the understanding of antidepressant pharmacogenetics.

Fasting produces antidepressant-like effects via activating mammalian target of rapamycin complex 1 signaling pathway in ovariectomized mice

Recent studies have shown that a 9-hour fast in mice reduces the amount of time spent immobile in the forced swimming test.Howeve r,whether 9-hour fasting has therapeutic effects in female mice with depressive symptoms has not been established.Therefore,in this study,we simulated perimenopausal depression via an ovariectomy in mice,and subjected them to a single 9-hour fasting 7 days later.We found that the ovariectomy increased the time spent immobile in the forced swimming test,inhibited expression of the mammalian target of rapamycin complex 1 signaling pathway in the hippocampus and prefro ntal cortex,and decreased the density of dendritic spines in the hippocampus.The 9-hour acute fasting alleviated the above-mentioned phenomena.Furthermore,all of the antidepressant-like effects of 9-hour fasting were reve rsed by an inhibitor of the mammalian to rget of rapamycin complex 1.Electrophysiology data showed a remarkable increase in long-term potentiation in the hippocampal CA1 of the ovariectomized mice subjected to fasting compared with the findings in the ovariectomized mice not subjected to fasting.These findings show that the antidepressant-like effects of 9-hour fasting may be related to the activation of the mammalian target of the rapamycin complex 1 signaling pathway and synaptic plasticity in the mammalian hippocampus.Thus,fasting may be a potential treatment for depression.

Integrating UHPLC-MS/MS quantitative analysis and exogenous purine supplementation to elucidate the antidepressant mechanism of Chaigui granules by regulating purine metabolism

Chaigui granules(CG)are a compound composed of six herbal medicines with significant antidepressant effects.However,the antidepressant mechanism of CG remains unclear.In the present study,we attempted to elucidate the antidepressant mechanism of CG by regulating purine metabolism and purinergic signaling.First,the regulatory effect of CG on purine metabolites in the prefrontal cortex(PFC)of chronic unpredictable mild stress(CUMS)rats was analyzed by ultra high-performance liquid chromatography tandem mass spectrometry(UHPLC-MS/MS)targeted quantitative analysis.Meanwhile,purinergic receptors(P2X7 receptor(P2X7R),A1 receptor(A1R)and A2A receptor(A2AR))and signaling pathways(nod-like receptor protein 3(NLRP3)inflammasome pathway and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)pathway)associated with purine metabolism were analyzed by western blotting and enzyme-linked immunosorbent assay(ELISA).Besides,antidepressant mechanism of CG by modulating purine metabolites to activate purinergic receptors and related signaling pathways was dissected by exogenous supplementation of purine metabolites and antagonism of purinergic receptors in vitro.An in vivo study showed that the decrease in xanthine and the increase in four purine nucleosides were closely related to the antidepressant effects of CG.Additionally,purinergic receptors(P2X7R,A1R and A2AR)and related signaling pathways(NLRP3 inflammasome pathway and cAMP-PKA pathway)were also significantly regulated by CG.The results of exogenous supplementation of purine metabolites and antagonism of purinergic receptors showed that excessive accumulation of xanthine led to activation of the P2X7R-NLRP3 inflammasome pathway,and the reduction of adenosine and inosine inhibited the A1R-cAMP-PKA pathway,which was significantly ameliorated by CG.Overall,CG could promote neuroprotection and ultimately play an antidepressant role by inhibiting the xanthine-P2X7R-NLRP3 inflammasome pathway and activating the adenosine/inosine-A1R-cAMP-PKA pathway.

Gastrointestinal Microbiome and related metabolites in Depression and Antidepressants - a comprehensive review

Depression,a prevalent mood disorder,has emerged as a significant health concern in society.While the exact cause of depression remains incompletely understood,there is substantial evidence linking the gastrointestinal microbiome and its metabolites to this condition.Through combined multi-omics analysis,it has been observed that the composition of the gastrointestinal microbiome,including Firmicutes,Bacteroidetes,and Actinobacteria,undergoes significant alterations in depressed individuals.Moreover,the production of short-chain fatty acids,tryptophan,and bile acids by these gut microbes is also found to be modified in depression.Furthermore,studies have demonstrated that antidepressant medications exert their therapeutic effects by interacting with the gastrointestinal microbiome and their metabolites.This review provides an overview of the association between the gastrointestinal microbiome,related metabolites,and depression.It highlights the potential of these factors to serve as mechanisms of action for antidepressant medications.Additionally,the review summarizes the commonly used technical tools in depression research.

A Case Study of Severe QT Interval Prolongation Caused by Antidepressants

QT interval prolongation can be categorized into primary and secondary types according to its etiology.In this paper,we report a case of severe asymptomatic QT interval prolongation secondary to antidepressants.Regular follow-up and electrocardiogram monitoring is crucial when applying antidepressants,especially for patients without cardiac symptoms.This article presents case studies and examines existing literature on long QT syndrome to enhance the diagnosis and management of QT interval prolongation.This is especially relevant for non-psychiatric healthcare professionals who need to be attentive to the side effects of antidepressants to prevent potential adverse consequences resulting from oversight.

Effi cacy of tricyclic antidepressants in irritable bowel syndrome:A meta-analysis

We aimed to evaluate the efficacy of tricyclic antidepressants(TCAs) as a therapeutic option for irritable bowel syndrome(IBS) through meta-analysis of randomized controlled trials.For the years 1966 until September 2008,PubMed,Scopus,Web of Science,and Cochrane Central Register of Controlled Trials were searched for double-blind,placebo-controlled trials investigating the effi cacy of TCAs in the management of IBS.Seven randomized,placebo-controlled clinical trials met our criteria and were included in the metaanalysis.TCAs used in the treatment arm of these trials included amitriptyline,imipramine,desipramine,doxepin and trimipramine.The pooled relative risk for clinical improvement with TCA therapy was 1.93(95% CI:1.44 to 2.6,P<0.0001).Effect size of TCAs versus placebo for mean change in abdominal pain score among the two studies was -44.15(95% CI:-53.27 to -35.04,P<0.0001).It is concluded that low dose TCAs exhibit clinically and statistically signifi cant control of IBS symptoms.

Network Pharmacology-based Research of Active Components of Albiziae Flos and Mechanisms of Its Antidepressant Effect

Albiziae Flos(AF)has been experimentally proven to have an antidepressant effect.However,due to the complexity of botanical ingredients,the exact pharmacological mechanism of action of AF in depression has not been completely deciphered.This study used the network pharmacology method to construct a component-target-pathway network to explore the active components and potential mechanisms of action of AF.The methods included collection and screening of chemical components,prediction of depression-associated targets of the active components,gene enrichment,and network construction and analysis.Quercetin and 4 other active components were found to exert an tidepressant effects mainly via monoaminergic neurotransmitters and cAMP signaling and neuroactive ligand・wceptor interaction pathways.DRD2,HTR1 A,and SLC6A4 were identified as important targets of the studied bioactive components of AF.This network pharmacology analysis provides guidance for further study of the antidepressant mechanism of AF.

Neuroplasticity and major depression, the role of modern antidepressant drugs

The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, Psyc Lit, and Psyc Info search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells(both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants(ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders.

Antidepressants can treat inflammatory bowel disease through regulation of the nuclear factor-κB/nitric oxide pathway and inhibition of cytokine production:A hypothesis

Inflammatory bowel disease (IBD) is a group of inflammatory disorders mainly affecting the colon and small intestine. The main types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). UC is restricted to the large intestine whereas CD can affect any part of the gastrointestinal tract. Treating this disorder depends on the form and level of severity. Common treatment involves an anti-inflammatory drug, such as mesalazine, and an immunosuppressant, such as prednisone. Several signaling pathways, including nuclear factor (NF)-κB and nitric oxide (NO), and genetic and environmental factors are believed to play an important role in IBD. Amitriptyline is a commonly used antidepressant with known anti-inflammatory activities. Amitriptyline also acts on the NF-κB/NO pathway or cytokine production. Therefore, we hypothesize that antidepressants like amitriptyline can be pioneered and considered effective as an innovative and effective therapeutic in the treatment and attenuation of development of IBD in adjusted doses.

Antidepressants for bipolar disorder A meta-analysis of randomized, double-blind, controlled trials

OBJECTIVE： To examine the efficacy and safety of short-term and long-term use of antidepres- sants in the treatment of bipolar disorder. DATA SOURCES： A literature search of randomized, double-blind, controlled trials published until December 2012 was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central Register of Controlled Trials databases. The keywords ＂bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia, mixed mania and depression, rapid cycling and bipolar disorder＂, AND ＂antidepressant agent, antidepressive agents second- generation, antidepressive agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake in- hibitor, serotonin uptake inhibitor, and tricyclic antidepressant agent＂ were used. The studies that were listed in the reference list of the published papers but were not retrieved in the above-mentioned databases were supplemented. STUDY SELECTION： Studies selected were double-blind randomized controlled trials assessing the efficacy and safety of antidepressants in patients with bipolar disorder. All participants were aged 18 years or older, and were diagnosed as having primary bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers were used in experimental interventions. Placebos, mood stabilizers, antipsychotics and other antide pressants were used in the control interventions. Studies that were quasi-randomized studies, or used antidepressants in combination with antipsy- chotics in the experimental group were excluded. All analyses were conducted using Review Man- ager 5.1 provided by the Cochrane Collaboration.

Brain functional changes in facial expression recognition in patients with major depressive disorder before and after antidepressant treatment A functional magnetic resonance imaging study

Functional magnetic resonance imaging was used during emotion recognition to identify changes in functional brain activation in 21 first-episode, treatment-naive major depressive disorder patients before and after antidepressant treatment. Following escitalopram oxalate treatment, patients exhibited decreased activation in bilateral precentral gyrus, bilateral middle frontal gyrus, left middle temporal gyrus, bilateral postcentral gyrus, left cingulate and right parahippocampal gyrus, and increased activation in right superior frontal gyrus, bilateral superior parietal Iobule and left occipital gyrus during sad facial expression recognition. After antidepressant treatment, patients also exhibited decreased activation in the bilateral middle frontal gyrus, bilateral cingulate and right parahippocampal gyrus, and increased activation in the right inferior frontal gyrus, left fusiform gyrus and right precuneus during happy facial expression recognition. Our experimental findings indicate that the limbic-cortical network might be a key target region for antidepressant treatment in major depressive disorder.

Montmorillonite/Poly(L-Lactide)microcomposite spheres as reservoirs of antidepressant drugs and their controlled release property

This work evaluates intercalation of Nortriptyline(NT)and Venlafaxine(VFX)in an interlayer gallery of Na^(+)-MMT(Montmorillonite),which was further compounded with Poly(LLactide)(PLLA)to form microcomposite spheres(MPs)for oral controlled drug delivery.The XRD patterns,thermal and spectroscopic analyses indicated intercalation of drugs into the MMT interlayer that was stabilized by electrostatic interaction.No significant changes in structural and functional properties of drugs were found in the MMT layers.In vitro drug release studies showed controlled release pattern.

Evaluation of antidepressant activity of methanolic and hydroalcoholic extracts of Acorus calamus L.rhizome through tail suspension test and forced swimming test of mice

Objective:Acorus calamus(AC)L.(Araceae)is an annual semi-aquatic and aromatic plant found in Europe,North America and Asia.Its rhizomes are often used by Native Americans,Americans,and Chinese as well as by other cultures.Ethnobotanical studies and documents have shown their use in various disease treatments,such as insomnia,mental disorders,diabetes mellitus,epilepsy,inflammation,asthma,neuropathic pain,and diarrhea.In this study,the antidepressant activity of methanolic and hydroalcoholic extracts of the AC rhizome part in mice was investigated.Methods:Three doses of methanolic extract of AC rhizome(MEACR)(25,50 and 100 mg/kg b.wt),three doses of hydroalcoholic extract of AC rhizome(HAACR)(100,200 and 400 mg/kg b.wt),and standards(imipramine,15 mg/kg b.wt and fluoxetine,20 mg/kg b.wt)was daily oral administration to the mice for consecutive 14 days.The extract effect on the immobility time was monitored by a tail suspension test(TST)and a forced swimming test(FST).Monoamine oxidase(MAO)levels were also analyzed using standard methods.Results:The optimum antidepressant activity was viewed at 100 mg/kg b.wt of MEACR extract and400 mg/kg b.wt of HAACR extract with 23.82%and 20.59%immobility period reduction,respectively.Besides,the extracts weakened the FST-induced elevation of MAO activity significantly and returned to near-normal levels of neurotransmitters in the brain.100 mg/kg b.wt or above of MEACR extract significantly prevented the MAO-A and MAO-B activities in mice brain at a dose-dependent fashion.But,just 400 mg/kg b.wt of HAACR extract prevented the activity of MAO-A and MAO-B.Fluoxetine and imipramine showed a tendency to prevent the activity of MAO-A and MAO-B.Conclusion:This study suggests that AC rhizome extract mediated antidepressant activity by modulating the central neurochemical and hypothalamic-pituitary-adrenal(HPA)axis in response to FST and TSTinduced stress.Therefore,AC rhizome extract can be used as a valuable plant supplement to treat depressive disorders.

Antidepressant Prescribing Patterns for Depressive and Anxiety Disorders in a Singapore Hospital

Objective: Although antidepressants are the recommended first-line pharmacological treatments for depressive and anxiety disorders, their prescribing patterns have not been studied in Singapore. We investigate antidepressant prescription patterns for outpatients with depressive and anxiety disorders in a general hospital in Singapore. We hypothesize that intolerance to side effects and lack of efficacy may contribute to medication switching, and that initiation of antidepressant therapy is not easily tolerated. Methods: A retrospective review of the casenotes of outpatients was carried out between January 2013 and December 2013. A total of 206 patients were randomly selected. The study was approved by the hospital’s institutional review board. Data analysis was carried out using SPSS version 18. Results: There were more females than males (ratio 1.7:1) with a mean age of 50.6 ± 15.2 years. Depressive disorder, comprising 50% of the sample, was the most frequent diagnosis followed by anxiety disorder (27.2%), mixed anxiety-depression (16%) and adjustment disorder (5.8%). Almost all patients (97.1%) were prescribed antidepressants, the most common being selective serotonin reuptake inhibitors (SSRI) (75.5%), followed by the noradrenaline and specific serotonin antidepressant (NaSSA) (13.5%) and tricyclic antidepressants (TCA) (8.5%). Patients prescribed SSRIs tended to be younger and better educated (p = 0.0005). More than half of the patients (52.1%) required antidepressant switching mainly due to lack of efficacy and intolerance of side effects. Combination therapy was prescribed for 17% of patients with SSRI-NaSSA, the most preferred combination. Nearly a quarter (23.8%) patients required augmentation therapy with atypical antipsychotics. Combination (p = 0.024) and augmentation (p = 0.033) were utilized more often for depression than for anxiety disorders. Conclusion: Antidepressant medications are commonly prescribed for depression and anxiety disorders. The main reasons for switching antidepressants were intolerance and lack of efficacy. That about half of the patients reported side effects necessitating medication change confirmed our hypothesis that antidepressant therapy was not easy to initiate. This has important implications for treatment adherence and outcome.

Synthesis, Crystal Structure and Antidepressant Activity of 5-[4-(Benzyloxy)phenyl]-9-(n-propyl)-4,6-dioxa-1-azabicyclo[3.3.1]nonane Hydrochloride 0.5Hydrate

The title compound 2（C22H28N＋O3）·H2O·2Cl-was synthesized by the reaction of 2-bromo-1-[4-（benzyloxy）phenyl]-1-pentone with 2,2＇-azanediyldiethanol. The crystal determined by X-ray diffraction analysis belongs to the monoclinic system, space group Pc with a = 18.312（3）, b = 14.838（3）, c = 7.6227（14） , β = 97.981（4）°, Z = 2, Mr = 797.82, V = 2051.1（6） 3, Dc = 1.292 g/cm3, S = 0.956, μ = 0.21 mm-1, F（000） = 852, the final R = 0.0625 and wR = 0.1428 for 5683 observed reflections （Ⅰ 〉 2σ（Ⅰ））. Flack parameter is 0.10（9）. The title compound is composed by four non-coplanar ring systems, two benzenes and two morpholines. One morpholine ring （C（3）-C（4）-N（1）-C（1）-C（2）-O（1）） forms a chair conformation, while the other （C（4）-C（3）-O（2）-C（6）-C（5）-N（1）） assumes a boat conformation. X-ray crystal structure displays extensive N-H…Cl and O-H…Cl intermolecular hydrogen bonds. The preliminary antidepressant activity test indicates that the inhibition ratio of SERT （5-HT Transporter） was 35.9% at the dosage of 10.0 mg/L.

Agmatine as a novel candidate for rapid-onset antidepressant response

Major depressive disorder(MDD)is a disabling and highly prevalent mood disorder as well as a common cause of suicide.Chronic stress,inflammation,and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD.Although conventional antidepressants are widely used in the clinic,they can take weeks to months to produce therapeutic effects.The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD.However,the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use.Therefore,agmatine,an endogenous glutamatergic modulator,has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway,similar to ketamine.However,recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota,which have been shown to play a crucial role in the pathophysiology of MDD,may also participate in the antidepressant-like effects of both ketamine and agmatine.This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies.Considering the anti-inflammatory properties of agmatine,it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state.Moreover,the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.

Novel antidepressants targeting TREK1 channel

OBJECTIVE To find that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.METHODS Molecular biology and cell transfection,electrophysiology,molecular docking,molecular dynamics simulations,virtual screening for TREK1,and depressive-related behavior tests.RESULTS Extracellular domain of TREK1 channel existed a dynamic cavity in the extracellular domain by the method of computations,mutagenesis and electrophysiology.Molecular dynamics simulations suggested that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway.Using virtual screening approach,we identified other inhibitors targeting the extracellular allosteric ligand-binding site of these channels.Overall,our results suggested that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins.The TREK1 inhibitor TKDC had significantly faster onset than that of fluoxetine in chronic administration trials,and the study confirms that TREK1 was an important target for the development of rapid antidepressants.CONCLUSION The study is a significant step forward for understanding the function of TREK and for identifying specific inhibitors,which should be of interest to others in the field.

Antidepressant and anti-nociceptive effects of Nigella sativa and its main constituent,thymoquinone:A literature review

Medicinal plants and their ingredients have beneficial effects on human health.Nigella sativa is a herbal plant with multiple biological and pharmacological activities.Previous studies demonstrated the anti-inflammatory and antioxidant properties of Nigella sativa and its main constituent thymoquinone significantly contributes to the antidepressant and anti-nociception effects of this plant.It has been reported that thymoquinone may achieve its antidepressant effect by preventing the elimination of brain neurotransmitters affecting depression such as serotonin.The role of brain-derived neurotrophic factors in the antidepressant effects of thymoquinone has also been documented.Additionally,thymoquinone can attenuate pain by upregulation of intracellular signaling pathways related to nitric oxide and K_(ATP)^(+)channels.The present review summarizes the antidepressant and anti-nociceptive activity of Nigella sativa and its main constituent thymoquinone by searching literature on electronic databases such as PubMed,Web of Science,Scopus,and Google Scholar from the beginning of 2010 until the end of August 2022.

Role of PDE4D splice variants in the mediation of antidepressant and cognition-enhancing actions and its mechanisms

OBJECTIVE Phosphodiesterase 4(PDE4),specific for cyclicAMP(cAMP)-hydrolyzing,has four isoforms(PDE4A-D) with at least 25 splice variants. PDE4 inhibitors produce definite antidepressant-like and cognitive-enhancing effects. However,none of PDE4 inhibitors has yet been approved for clinical utility so far due to the concomitant side effects. The present research is to explore the splice variants of PDE4 D responsible for antidepressant-like and cognitive-enhancing effects of PDE4 inhibitors but not side effects. METHODS Long-form PDE4 Ds were silenced by the bilateral microinfusion of lentiviral vector containing mi RNAs(4Dmi R) into the prefrontal cortex(PFC),PDE4D4 or D5 was overexpressed by the bilateral microinfusion of lentiviral vector containing full c DNA into hippocampus. Antidepressant-like behaviors were measured by tail-suspension test(TST),forced swimming test(FST)and chronic unpredictable stress model. Cognitive behaviors were measured by the novel object recognition test(NOR) and Morris water maze test(MWM) in both normal mice and the mice with chronic unpredictable stress-induced memory deficits. The emetic potential was evaluated by the assessment of the anaesthetic reversal effect,a surrogate of the emesis test in non-vomiting species. The expressions of PDE4 isoforms/splice variants and cAMP level were examined by Western-blot and ELISA analysis. The dendritic complexity and spine density were assessed by Golgi staining. RESULTS(1)High and specific expression of EGFP(green,indicator of 4Dmi R expression) in PFC was observed under fluorescence microscopy.(2) 4Dmi R significantly down-regulated PDE4D4/5 splice variants,but not PDE4 A,PDE4 B or PDE4D1/2/3.(3) 4Dmi R treatments significantly increased cAMP signaling and dendritic complexity in PFC.(4) Rolipram and/or 4Dmi R treatments significantly decreased immobility in TST and FST.(5) Rolipram and/or 4Dmi R treatments reversed the depressive-like behaviors in chronically stressed mice,including the reduced sucrose preference,prolonged latency to novelty-suppressed feeding and increased immobility in FST.(6) Rolipram and/or 4Dmi R treatments significantly increased the recognition index in NOR task and both the entries and durations in MWM task.(7) Rolipram and/or 4Dmi R treatments reversed the memory deficits in chronically stressed mice,including the reduced the recognition index in NOR task and the decreased durations in MWM task.(8) Rolipram and/or 4DmiR treatments reversed the decreased cA MP signaling,dendritic complexity and spine density.(9) Rolipram or plus 4Dmi R treatment significantly decreased the duration of anaesthesia in the alpha2 adrenergic receptor-mediated anesthesia,but not 4Dmi R treatment alone.(10)Hippocampal overexpression of PDE4D5,but not PDE4D4,produced depressive-like and cognitive defect behaviors,which were reversed by rolipram.The measurements including cAMP signaling,dendritic complexity and in vivo hippocampal LTP,showed the same changes. CONCLUSION Long-form PDE4 Ds,especially the PDE4D5,are the major isoforms responsible for antidepressant-like and cognitive-enhancing effects with little side effects. The critical roles of long-form PDE4 Ds are mediated by their regulation of cAMP signaling pathway and neuroplasticity.