interacts_with DB09068?
Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . Involvement of retinoic acid receptor alpha in the stimulation of tissue-type plasminogen-activator gene expression in human endothelial cells . Retinoids stimulate tissue-type plasminogen-activator ( t-PA ) gene expression in human endothelial cells , and are likely to do so by binding to one or more nuclear retinoid receptors . The present study was initiated to identify the retinoid receptor(s) involved in this process . Expression and regulation of retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) were analyzed by Northern-blot analysis of total or poly(A)-rich RNA prepared from cultured human umbilical vein endothelial cells ( HUVEC ) . Prior to any exposure to retinoids , HUVEC express two transcripts for P10276 ( 3.6 kb and 2.8 kb ) , and low levels of transcripts for P10826 ( 3.4 kb and 3.2 kb ) and P13631 ( 3.3 kb and 3.1 kb ) . Two RXR subtypes were identified , RXR-alpha ( 4.8 kb ) and , at a much lower concentration , RXR-beta ( 2.4 kb ) ; no evidence for the presence of RXR-gamma was found . Furthermore , HUVEC express cellular retinol-binding protein I ( P09455 ) and cellular retinoic-acid-binding protein I ( P29762 ) mRNA . Exposure of HUVEC to 1 microM retinoic acid or the DB04942 , Ch55 , led to the induction of the two P10826 mRNAs , RXR-alpha mRNA and P09455 mRNA , whereas the expression of the other receptor and P29762 transcripts did not change appreciably . Using retinoid analogues that bind preferentially to one of the RAR or RXR subtypes , we found evidence that P10276 is involved in the retinoid-induced t-PA expression in HUVEC . This conclusion was strengthened by experiments in which blocking of P10276 with a specific P10276 antagonist , Ro 41-5253 , was demonstrated to suppress the induction of t-PA by retinoids . SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective O60674 ( O60674 ) inhibitors . We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective O60674 inhibitors . High throughput screening of our in-house compound library led to the identification of hit 1 , from which optimization resulted in the discovery of highly potent and selective O60674 inhibitors . Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model . Based upon the desirable profile of 10d ( DB05243 ) it was advanced into clinical trials . Array-comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array-CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array-based comparative genomic hybridization ( array-CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid-binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . A conserved mechanism for gating in an ionotropic glutamate receptor . Ionotropic glutamate receptor ( iGluR ) channels control synaptic activity . The crystallographic structure of P42262 , the prototypical iGluR , reveals a clamshell-like ligand-binding domain ( LBD ) that closes in the presence of glutamate to open a gate on the pore lining α-helix . How LBD closure leads to gate opening remains unclear . Here , we show that bending the pore helix at a highly conserved alanine residue ( Ala-621 ) below the gate is responsible for channel opening . Substituting Ala-621 with the smaller more flexible glycine resulted in a basally active , nondesensitizing channel with ∼39-fold increase in glutamate potency without affecting surface expression or binding . On P42262 (A621G) , the partial agonist kainate showed efficacy similar to a full agonist , and competitive antagonists CNQX and DB03759 acted as a partial agonists . DB00134 -629 in P42262 sits above the gate and is critical in transmitting LBD closure to the gate . Substituting DB00134 -629 with the flexible glycine resulted in reduced channel activity and glutamate potency . The pore regions in potassium channels are structurally similar to iGluRs . Whereas potassium channels typically use glycines as a hinge for gating , iGluRs use the less flexible alanine as a hinge at a similar position to maintain low basal activity allowing for ligand-mediated gating . Inhibition of noradrenaline release via presynaptic P28222 receptors of the rat vena cava . In the rat inferior vena cava preincubated with 3H-noradrenaline , the effects of nine serotonin ( 5-HT ) receptor agonists and of eight antagonists ( including two beta-adrenoceptor blocking agents ) on the electrically evoked 3H overflow were determined . 1 . 5-HT , 5-carboxamido-tryptamine , 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole ( RU 24969 ) , 5-methoxytryptamine , N,N-dimethyl-5HT , tryptamine and 5-aminotryptamine inhibited the evoked 3H overflow . The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for P28222 binding sites , but not with their affinities for P08908 , P28335 or 5-HT2 binding sites . 8-Hydroxy-2-(di-n-propylamino)tetralin ( 8-OH-DPAT ) , a P08908 receptor agonist , and ipsapirone , a partial agonist at these receptors , did not inhibit overflow . 2 . Cyanopindolol facilitated the evoked 3H overflow , an effect which was abolished by propranolol . The maximum inhibition of overflow obtainable with 5-HT was diminished by cyanopindolol . 3 . The concentration-response curve for 5-HT was shifted to the right by metitepine , metergoline , quipazine , 6-chloro-2-(1-piperazinyl)pyrazine ( MK 212 ) and propranolol which , given alone , did not affect 3H overflow . The apparent pA2 values of these antagonists tended to be correlated with their affinities for P28222 ( but not P08908 , P28335 or 5-HT2 ) binding sites . Ketanserin , a 5-HT2 receptor antagonist , and spiperone , which blocks 5-HT2 and P08908 but not P28222 or P28335 receptors , failed to antagonize the effect of 5-HT. ( ABSTRACT TRUNCATED AT 250 WORDS ) Immunohistochemical localization of adherens junction components in blood-brain barrier microvessels of the rat . The morphology and molecular composition of intercellular adherens junctions have most frequently been described in epithelial cells and the fascia adhaerens of the intercalated disc . A group of cytoplasmic molecules is known to be associated with adherens junctions . The intercellular bond is mediated by cadherins which bridge the cells by homophilic binding . Recently , endothelial cells have also been shown to form intercellular junctions of the adherens-type . However , they are morphologically less distinct and little is known about their molecular components . In this study we report the localization of some adherens junction components in intact microvessels of the blood-brain barrier in the rat . We used antibodies raised against alpha-actinin , vinculin , zyxin , cadherin ( antipan-cadherin antibody ) and A- P62158 ( P19022 ) in immunohistochemical experiments at light and electron microscopical levels . Microvessel walls reacted positively for all antigens throughout postnatal development . All antigens were localised , though not necessarily exclusively , to interendothelial junctions . At the ultrastructural level , pan-cadherin reactivity was present throughout the entire length of the cleft . These results could mean that in blood-brain barrier endothelial cells the complex tight junction is embedded in an adherens junction which occupies the entire length of the cleft . P10275 inducing bladder cancer progression by promoting an epithelial-mesenchymal transition . The study investigated the role of androgen receptor ( AR ) as a potential target for the treatment of bladder cancer in regulating epithelial-mesenchymal transition or transformation ( EMT ) . Cell proliferation , and migration capacity were determined in bladder cancer T24 cells treated with small interfering RNA directed against AR , and expression levels of P12830 , β-catenin and N- cadherin were assessed using quantitative reverse transcription PCR ( qRT-PCR ) . Tumour cell growth was evaluated in vivo in T24 tumour-bearing nude mice receiving electroporation-assisted administration of anti-AR small interfering RNA . It was found that low AR expression decreased proliferation and migration of bladder cancer cells . In vivo experiments showed that silencing AR expression significantly suppressed AR-positive bladder tumour growth with decreased cell proliferation . Low AR level of T24 bladder cancer cells treated with DB01541 ( DB02901 ) decreased expression of P12830 , β-catenin and P19022 expression , indicating a strong sensitivity to the EMT and In cells with low AR content , TGF-β induced down-regulation of P12830 and β-catenin . It is concluded that suppression of AR expression decreased the production of TGF-β , inhibiting EMT and bladder cancer cell growth in vitro and in vivo , implying that its use might be a potential therapeutic target for the treatment of bladder cancer . Anticonvulsant effects of agomelatine in mice . DB06594 is a potent MT1 and P02795 melatonin receptor agonist and a P28335 serotonin receptor antagonist . We analyzed whether agomelatine has anticonvulsant properties . The anticonvulsant activity of agomelatine ( 25 , 50 or 75 mg/kg , i.p. ) was evaluated in mouse models of pentylenetetrazole ( PTZ-85 mg/kg , i.p. ) , pilocarpine ( 400mg/kg , i.p. ) , picrotoxin ( 7 mg/kg , i.p. ) , strychnine ( 75 mg/kg , i.p. ) or electroshock-induced convulsions . In the PTZ-induced seizure model , agomelatine ( at 25 or 50mg/kg ) showed a significant increase in latency to convulsion , and agomelatine ( at 50 or 75 mg/kg ) also increased significantly time until death . In the pilocarpine-induced seizure model , only agomelatine in high doses ( 75 mg/kg ) showed a significant increase in latency to convulsions and in time until death . In the strychnine- , electroshock- and picrotoxin-induced seizure models , agomelatine caused no significant alterations in latency to convulsions and in time until death when compared to controls . Our results suggest that agomelatine has anticonvulsant activity shown in PTZ- or pilocarpine-induced seizure models . P50579 is required for P19526 initiation and proliferation . In a chemical screening , we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos . DB02640 is known to target methionine aminopeptidase II ( MetAP2 ) , an enzyme whose function in hematopoiesis is unknown . We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models . Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region , the caudal hematopoietic tissue , and pronephric duct . metap2 was inhibited by morpholino and fumagillin treatment , resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization . It also disrupted intersegmental vessels in Tg(fli1:gfp) embryos without affecting development of major axial vasculatures . Inhibition of MetAP2 in CB P28906 (+) cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice . metap2 knock-down in zebrafish and inhibition by fumagillin in zebrafish and human CB P28906 (+) cells inhibited P62158 Kinase II activity and induced P29323 phosphorylation . This study demonstrated a hitherto-undescribed role of MetAP2 in definitive hematopoiesis and a possible link to noncanonical Wnt and P29323 signaling . Acute kidney injury and inflammatory immune reconstitution syndrome in mixed genotype ( A/E ) hepatitis B virus co-infection in HIV-associated lymphoma . We report a first case of HIV-associated lymphoma ( P42357 ) presenting with acute kidney injury ( AKI ) and inflammatory immune reconstitution syndrome ( IRIS ) . A 39-year-old male , treated with nonsteroidal anti-inflammatory drugs ( NSAIDs ) for one month prior to admission , developed AKI , left testicular tumor , and recurrent swelling of the right parotid gland . A resected testicular tumor exhibited features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma . Renal biopsy showed hydro-degeneration of renal tubules , interstitial inflammatory cells , and a small number of lymphoma cells in the sub-capsule , compatible with acute interstitial nephritis . DB00117 renal dysfunction rapidly recovered following chemotherapy and combination antiretroviral therapy ( cART ) . He developed pneumonia concomitantly with a decrease in HIV-RNA level and an increase in P01730 + cells after the first cycle of chemotherapy , which spontaneously resolved after the second cycle of chemotherapy without additional anti-infection drugs ; thus , his pneumonia fulfilled the diagnostic criteria for IRIS . We suggest that IRIS may frequently develop during chemotherapy for P42357 , but may be overlooked . He was coinfected with hepatitis B virus ( HBV ) , which genotypes known as is associated with liver-related mortality and response to antiviral therapy ; recently , an intimate interplay between HIV and HBV in the onset of lymphoma has been reported . Therefore , we addressed the HBV genotype in the patient . The analysis revealed that he exhibited a mixed genotype ( A/E ) not native to Japan and primarily found in Europe and North America or West Africa . These findings suggest that universal vaccination for juveniles against HBV is warranted in Japan . [ Effects of chronic fluoxetine treatment on catalepsy and immune response in mice genetically predisposed to freezing reaction : the role of P08908 and 5- Q13049 receptors and tph2 and P31645 genes ] . ASC/Icg ( Antidepressant Sensitive Catalepsy ) mouse strain selected for high predisposition to pinch-induced catalepsy is characterized by depressive-like behavior and impaired immune response . Chronic treatment with SSRI fluoxetine attenuated catalepsy manifestation and normalized a decreased number of rosette-forming cells ( P41440 ) in spleen in ASC mice . Chronic fluoxetine administration had no effect on catalepsy and P41440 number in mice of parental cataleptic CBA/Lac strain . DB00472 failed to alter P08908 receptor functional activity in mice of both strains and diminished 5- Q13049 receptor functional activity in CBA but not in ASC mice . No effect on cortical P08908 and 5- Q13049 receptor mRNA levels and on P08908 receptor , tph2 ( tryptophan hydroxylase-2 ) and P31645 ( serotonin transporter ) mesencephalic gene expression was observed in ASC mice . Other possible serotonergic mechanisms of fluoxetine effect on catalepsy and immune response in mice with depressive-like state are discussed . P23560 activation of P62158 -kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of P42261 -containing calcium-permeable AMPA receptors . Glutamatergic synapses in early postnatal development transiently express calcium-permeable AMPA receptors ( CP-AMPARs ) . Although these P42262 -lacking receptors are essential and are elevated in response to brain-derived neurotrophic factor ( P23560 ) , little is known regarding molecular mechanisms that govern their expression and synaptic insertion . Here we show that P23560 -induced P42261 translation in rat primary hippocampal neurons requires the activation of mammalian target of rapamycin ( P42345 ) via calcium calmodulin-dependent protein kinase kinase ( CaMKK ) . Specifically , P23560 -mediated phosphorylation of threonine 308 ( T308 ) in AKT , a known substrate of CaMKK and an upstream activator of P42345 -dependent translation , was prevented by ( 1 ) pharmacological inhibition of CaMKK with STO-609 , ( 2 ) overexpression of a dominant-negative CaMKK , or ( 3 ) short hairpin-mediated knockdown of CaMKK . P42261 surface expression induced by P23560 , as assessed by immunocytochemistry using an extracellular N-terminal P42261 antibody or by surface biotinylation , was impaired following knockdown of CaMKK or treatment with STO-609 . Activation of CaMKK by P23560 requires transient receptor potential canonical ( TRPC ) channels as SKF-96365 , but not the DB01221 receptor antagonist d-APV , prevented P23560 -induced P42261 surface expression as well as phosphorylation of CaMKI , AKT(T308) , and P42345 . Using siRNA we confirmed the involvement of Q9UL62 and Q9Y210 subunits in P23560 -induced AKT(T308) phosphorylation . The P23560 -induced increase in mEPSC was blocked by IEM-1460 , a selected antagonist of CP-AMPARs , as well as by the specific repression of acute P42261 translation via siRNA to P42261 but not P42262 . Together these data support the conclusion that newly synthesized P42261 subunits , induced by P23560 , are readily incorporated into synapses where they enhance the expression of CP-AMPARs and synaptic strength . Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 -immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed . Molecular basis for the immunostimulatory activity of guanine nucleoside analogs : activation of Q9NYK1 . Certain Q99618 -substituted and N7 , Q99618 -disubstituted guanine ribonucleosides comprise a class of small molecules with immunostimulatory activity . In a variety of animal models , these agents stimulate both humoral and cellular immune responses . The antiviral actions of these guanosine analogs have been attributed to their ability to induce type I IFNs . However , the molecular mechanisms by which the guanosine analogs potentiate immune responses are not known . Here , we report that several guanosine analogs activate Q9NYK1 ( Q9NYK1 ) . DB04860 , 7-deazaguanosine , and related guanosine analogs activated mouse immune cells in a manner analogous to known TLR ligands , inducing cytokine production in mouse splenocytes ( P05231 and IL-12 , type I and II IFNs ) , bone marrow-derived macrophages ( P05231 and IL-12 ) , and in human peripheral blood leukocytes ( type I IFNs , tumor necrosis factor alpha and IL-12 ) . The guanosine congeners also up-regulated costimulatory molecules and MHC I/II in dendritic cells . Genetic complementation studies in human embryonic kidney 293 cells confirmed that the guanosine analogs activate cells exclusively via Q9NYK1 . The stimulation of Q9NYK1 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB . However , Q9NR97 activation by R-848 and O60603 activation by [ S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-R- DB00151 -S- DB00133 -Lys4-OH , trihydrochloride ) ] were not inhibited by chloroquine , whereas Q9NR96 activation by CpG oligodeoxynucleotides was abolished . In summary , we present evidence that guanosine analogs activate immune cells via Q9NYK1 by a pathway that requires endosomal maturation . Thus , the B cell-stimulating and antiviral activities of the guanosine analogs may be explained by their Q9NYK1 -activating capacity . DB09068 ( Lu AA21004 ) , a novel multimodal antidepressant , enhances memory in rats . The serotonergic system plays an important role in cognitive functions via various 5-HT receptors . DB09068 ( Lu AA21004 ) in development as a novel multimodal antidepressant is a 5- Q9H205 , P34969 and P28221 receptor antagonist , a P28222 receptor partial agonist , a P08908 receptor agonist and a 5-HT transporter ( 5-HTT ) inhibitor in vitro . Preclinical studies suggest that 5- Q9H205 and P34969 receptor antagonism as well as P08908 receptor agonism may have a positive impact on cognitive functions including memory . Thus vortioxetine may potentially enhance memory . We investigated preclinical effects of vortioxetine ( 1-10mg/kg administered subcutaneously [ s.c. ] ) on memory in behavioral tests , and on cortical neurotransmitter levels considered important in rat memory function . Contextual fear conditioning and novel object recognition tests were applied to assess memory in rats . Microdialysis studies were conducted to measure extracellular neurotransmitter levels in the rat medial prefrontal cortex . DB09068 administered 1h before or immediately after acquisition of contextual fear conditioning led to an increase in freezing time during the retention test . This mnemonic effect was not related to changes in pain sensitivity as measured in the hotplate test . Rats treated with vortioxetine 1h before training spent more time exploring the novel object in the novel object recognition test . In microdialysis studies of the rat medial prefrontal cortex , vortioxetine increased extracellular levels of acetylcholine and histamine . In conclusion , vortioxetine enhanced contextual and episodic memory in rat behavioral models . Further demonstration of its potential effect on memory functions in clinical settings is warranted . Involvement of 5-HT₇ receptors in vortioxetine 's modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5-HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . DB09068 is a multimodal antidepressant that inhibits P28221 , 5- Q9H205 , P34969 receptor activity , 5-HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 ::LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 ::LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 ::LUC mice with 0.1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine ( 10 mg/kg , s.c. ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2.5 mg/kg , s.c. ) or the P34969 receptor antagonist SB269970 ( 30 mg/kg , s.c. ) , just prior to activity onset revealed significant delays in wheel-running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg/kg , i.p. ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg/kg , i.p. ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .