interacts_with DB00486?
P36888 ligand impedes the efficacy of P36888 inhibitors in vitro and in vivo . We examined in vivo P36888 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the P36888 inhibitor lestaurtinib , comparing newly diagnosed acute myeloid leukemia patients with relapsed patients . Because we noted that in vivo P36888 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients , we investigated whether plasma P36888 ligand ( FL ) levels could influence the efficacy of P36888 inhibition in these patients . After intensive chemotherapy , FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients , whereas they rose to a mean of 1148 pg/mL in the relapsed patients . FL levels rose even higher with successive courses of chemotherapy , to a mean of 3251 pg/mL after the fourth course . In vitro , exogenous FL at concentrations similar to those observed in patients mitigated P36888 inhibition and cytotoxicity for each of 5 different P36888 inhibitors ( lestaurtinib , midostaurin , sorafenib , KW-2449 , and DB05213 ) . The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting P36888 in this clinical setting . These findings could have important implications regarding the design and outcome of trials of P36888 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy . Insights into antifolate resistance from malarial P00374 -TS structures . Plasmodium falciparum dihydrofolate reductase-thymidylate synthase ( PfDHFR-TS ) is an important target of antimalarial drugs . The efficacy of this class of P00374 -inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity . The crystal structures of PfDHFR-TS from the wild type ( TM4/8.2 ) and the quadruple drug-resistant mutant ( V1/S ) strains , in complex with a potent inhibitor WR99210 , as well as the resistant double mutant ( P04264 P21554 ) with the antimalarial pyrimethamine , reveal features for overcoming resistance . In contrast to pyrimethamine , the flexible side chain of WR99210 can adopt a conformation that fits well in the active site , thereby contributing to binding . The single-chain bifunctional PfDHFR-TS has a helical insert between the P00374 and TS domains that is involved in dimerization and domain organization . Moreover , positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to P00374 active sites . These features provide possible approaches for the design of new drugs to overcome antifolate resistance . Anandamide regulates the expression of GnRH1 , GnRH2 , and DB00644 -Rs in frog testis . DB00644 ( either GnRH1 or GnRH2 ) exerts a local activity in vertebrate testis , including human testis . Relationships between endocannabinoid ( eCB ) and DB00644 systems in gonads have never been elucidated in any species so far . To reveal a cross-talk between eCBs and DB00644 at testicular level , we characterized the expression of DB00644 ( GnRH1 and GnRH2 ) as well as P30968 ( DB00644 - Q96GN5 , -R2 , and -R3 ) mRNA in the testis of the anuran amphibian Rana esculenta during the annual sexual cycle ; furthermore , the corresponding transcripts were localized inside the testis by in situ hybridization . The possible endogenous production of the eCB , anandamide ( AEA ) , was investigated in testis by analyzing the expression of its biosynthetic enzyme , Nape-pld . Incubations of testis pieces with AEA were carried out in the postreproductive period ( June ) and in February , when a new spermatogenetic wave takes place . In June , AEA treatment significantly decreased GnRH1 and DB00644 -R2 mRNA , stimulated the transcription of GnRH2 and DB00644 - Q96GN5 , and did not affect DB00644 -R3 expression . In February , AEA treatment upregulated GnRH2 and DB00644 -R3 mRNA , downregulated DB00644 -R2 , and did not affect GnRH1 and DB00644 - Q96GN5 expression . These effects were mediated by type 1 cannabinoid receptor ( P21554 ) since they were fully counteracted by SR141716A ( DB06155 ) , a selective P21554 antagonist . In conclusion , eCB system modulates DB00644 activity in frog testis during the annual sexual cycle in a stage-dependent fashion . Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer . PURPOSE : Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent . DB04845 achieves comparable pathologic complete response ( pCR ) rates to other active drugs in the neoadjuvant setting . This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent . EXPERIMENTAL DESIGN : Women with untreated , histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide , followed by 1:1 randomization to ixabepilone ( n = 148 ) or paclitaxel ( n = 147 ) . Rates of pCR were compared between treatment arms based on predefined biomarker sets : Q13509 , Q9Y6A5 , and CAPG gene expression , a 20- and 26-gene expression model , P08183 protein expression , and other potential markers of sensitivity . βIII-tubulin protein expression is reported separately but is referred to here for completeness . All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy . Gene expression profiling data were used for molecular subtyping . RESULTS : There was no significant difference in the rate of pCR in both treatment arms in βIII-tubulin-positive patients . Higher pCR rates were observed among βIII-tubulin-positive patients than in βIII-tubulin-negative patients . Furthermore , no correlation was evident between Q13509 , Q9Y6A5 , and CAPG gene expression , P08183 protein expression , multi-gene expression models , and the efficacy of ixabepilone or paclitaxel , even within the estrogen receptor-negative subset . CONCLUSION : These results indicate that βIII-tubulin protein and mRNA expression , P08183 protein expression , Q9Y6A5 and CAPG gene expression , and multigene expression models ( 20- and 26-gene ) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer . A mechanism for the synergistic antimalarial action of atovaquone and proguanil . A combination of atovaquone and proguanil has been found to be quite effective in treating malaria , with little evidence of the emergence of resistance when atovaquone was used as a single agent . We have examined possible mechanisms for the synergy between these two drugs . While proguanil by itself had no effect on electron transport or mitochondrial membrane potential ( DeltaPsim ) , it significantly enhanced the ability of atovaquone to collapse DeltaPsim when used in combination . This enhancement was observed at pharmacologically achievable doses . DB01131 acted as a biguanide rather than as its metabolite cycloguanil ( a parasite dihydrofolate reductase [ P00374 ] inhibitor ) to enhance the atovaquone effect ; another P00374 inhibitor , pyrimethamine , also had no enhancing effect . DB01131 -mediated enhancement was specific for atovaquone , since the effects of other mitochondrial electron transport inhibitors , such as myxothiazole and antimycin , were not altered by inclusion of proguanil . Surprisingly , proguanil did not enhance the ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites . These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses DeltaPsim in malaria parasites . This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance . The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner . The effects of rimonabant on brown adipose tissue in rat : implications for energy expenditure . The cannabinoid P21554 receptor antagonist rimonabant ( SR 141716 ) produces a sustained decrease in body weight on a background of a transient reduction in food intake . An increase in energy expenditure has been implicated , possibly mediated via peripheral endocannabinoid system ; however , the role of the central endocannabinoid system is unclear . The present study investigates this role . DB06155 ( 10 mg/kg IP ) was administered for 21 days to rats surgically implanted with biotelemetry devices to measure temperature in the interscapular brown adipose tissue ( Q14032 ) . Q14032 temperature as a putative measure of thermogenesis in the Q14032 , physical activity , body weight , food intake , as well as changes in P25874 messenger RNA ( mRNA ) and protein were measured . In addition , role of the CNS in mediating these actions of rimonabant was determined in rats where the Q14032 was sympathetically denervated . As expected , chronic administration of rimonabant significantly reduced body weight for the entire treatment period despite only a transient decrease in food intake . There was a profound increase in Q14032 temperature , particularly during the dark phase of each circadian cycle throughout the treatment period . A corresponding increase in uncoupling protein ( P25874 ) was also observed following chronic rimonabant treatment . The rimonabant-induced elevation in Q14032 temperature and decrease in body weight were significantly attenuated following denervation , indicating an involvement of the CNS . These findings suggest that the long-term weight loss associated with rimonabant treatment is due at least in part to an elevation in energy expenditure , represented here by elevated temperature recorded in the Q14032 , which is mediated primarily by the central endocannabinoid system . Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs . The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors ( P21554 and CB2 ) . To study the stereochemical requirements of the side chain , we synthesized a series of cannabinoids in which rotation around the C1'- P06681 ' bond is blocked . The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone , the TMSOTf-mediated formation of the dihydropyran ring , and the stereospecific introduction of the beta-11-hydroxymethyl group . All the analogs tested showed nanomolar affinity for the receptors , the cis-hept-1-ene side chain having the highest affinity for P21554 ( Ki = 0.89 nM ) and showing the widest separation between P21554 and CB2 affinities . The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to P21554 ( Ki = 8.9 nM ) and had the lowest selectivity between P21554 and CB2 . Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors . We have recently shown that the mu-opioid receptor [ P35372 , also termed mu-opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid-specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co-expressing P35372 and O14939 , treatment with ( D-Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C-terminal splice variant of the mu-opioid receptor ( MOR1D , also termed MOP(1D) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist-independent ( constitutive ) O14939 -activation facilitating agonist-induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over-expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta-opioid receptor [ Q8IXH6 , also termed delta-opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 -dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor ( GPCR ) endocytosis . Q07973 as a potential target for cancer therapy . Increasing evidence has accumulated to suggest that vitamin D may reduce the risk of cancer through its biologically active metabolite , DB00136 , which inhibits proliferation and angiogenesis , induces differentiation and apoptosis , and regulates many other cellular functions . Thus , it is plausible to assume that rapid clearance of DB00136 by highly expressed Q07973 could interrupt the normal physiology of cells and might be one cause of cancer initiation and progression . In fact , enhancement of Q07973 expression has been reported in literature for many cancers . Based on these findings , Q07973 -specific inhibitors and vitamin D analogs which are resistant to Q07973 -dependent catabolism might be useful for cancer treatment . Q07973 -specific inhibitor VID400 , which is an azole compound , markedly enhanced and prolonged the antiproliferative activity of DB00136 in the human keratinocytes . Likewise , Q07973 -resistant analogs such as 2α-(3-hydroxypropoxy)- DB00136 ( O2C3 ) and its P06681 -epimer ED-71 ( DB05295 ) , and 19nor- 2α-(3-hydroxypropyl)- DB00136 ( MART-10 ) showed potent biological effects . Our in vivo studies using rats revealed that MART-10 had a low calcemic effect , which is a suitable property as an anticancer drug . Much lower affinity of MART-10 for vitamin D binding protein ( DBP ) as compared with DB00136 may be related to its more potent cellular activities . Based on these results , we conclude that ( 1 ) high affinity for P11473 , ( 2 ) resistance to Q07973 -dependent catabolism , ( 3 ) low affinity for DBP , and ( 4 ) low calcemic effect may be required for designing potent vitamin D analogs for cancer treatment . Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the P36888 receptor . Activating mutations of P36888 have been detected in patients with acute myeloid leukemia ( AML ) . Two distinct types of P36888 mutations are most common : internal tandem duplication ( ITD ) of sequences coding for the juxtamembrane domain and point mutations at codon 835 ( Asp835 ) within the kinase domain . Both types of mutations constitutively activate the tyrosine kinase activity of P36888 in experimental systems and result in factor-independent proliferation of Ba/ P13726 and 32D cells . Recently , novel mutations within the activation loop were identified in patients with AML : deletion of isoleucine 836 ( Ile836del ) and an exchange of isoleucine 836 to methionine plus an arginine insertion ( Ile836Met+ DB00125 ) . To examine whether the Ile836 mutations result in constitutive activation of the P36888 receptor , we introduced both mutant P36888 cDNAs transiently into P29320 293 cells . Both mutant P36888 receptors were constitutively autophosphorylated in the absence of ligand and kinase activity led to constitutive activation of downstream signaling cascades as determined by activation of the P42229 ( signal transducer and activator of transcription 5 ) pathway . When stably expressed in the growth factor-dependent cell lines Ba/ P13726 and 32D , both deletion and insertion mutants led to factor-independent proliferation , indicating that both mutants have transforming capabilities . We then examined the sensitivity of the P36888 ITD , P36888 Asp835Tyr , and the novel P36888 receptor mutants toward the kinase inhibitors AG1296 , PKC412 , and SU5614 . We show that these P36888 kinase inhibitors have distinct inhibitory potencies against different activating P36888 receptor mutants . These results suggest that it may be useful to determine the exact kind of P36888 mutation when applying receptor kinase inhibitors in clinical trials . Expression profiles of mitochondrial genes in the frontal cortex and the caudate nucleus of developing humans and mice selectively bred for high and low fear . A growing body of evidence suggests that mitochondrial function may be important in brain development and psychiatric disorders . However , detailed expression profiles of those genes in human brain development and fear-related behavior remain unclear . Using microarray data available from the public domain and the Gene Ontology analysis , we identified the genes and the functional categories associated with chronological age in the prefrontal cortex ( P27918 ) and the caudate nucleus ( CN ) of psychiatrically normal humans ranging in age from birth to 50 years . Among those , we found that a substantial number of genes in the P27918 ( 115 ) and the CN ( 117 ) are associated with the GO term : mitochondrion ( FDR qv < 0.05 ) . A greater number of the genes in the P27918 ( 91 % ) than the genes in the CN ( 62 % ) showed a linear increase in expression during postnatal development . Using quantitative PCR , we validated the developmental expression pattern of four genes including monoamine oxidase B ( P27338 ) , DB00157 dehydrogenase flavoprotein ( P49821 ) , mitochondrial uncoupling protein 5 ( O95258 ) and tubulin beta-3 chain ( Q13509 ) . In mice , overall developmental expression pattern of P27338 , O95258 and Q13509 in the P27918 were comparable to the pattern observed in humans ( p < 0.05 ) . However , mice selectively bred for high fear did not exhibit normal developmental changes of P27338 and Q13509 . These findings suggest that the genes associated with mitochondrial function in the P27918 play a significant role in brain development and fear-related behavior . Searching for a marker for Alzheimer 's disease- P02649 . The authors present their study of 10 patients affected by Alzheimer 's disease and 10 patients with multinfarctual dementia , who are already part of a P21554 study , senile dementia project , longitudinal study . The method adopted was that of DNA crossbreeding and amplification , so as to have a precise individualisation of alleles APo-E , Apo E-3 , Apo E-4 and of their various phenotype combinations . These isoforms are evaluated and compared with the disease studied , in order to help to identify a timely-marker for senile dementia . On the results obtained we hypothesised an association between Apo E-4 and the disease of about 40 % for Alzheimer 's disease , which leads us to increase our number of cases , regarding associations between demential diseases either Alzheimer or vascular and the presence of Apo E-4 . DB02709 protects against peripheral deficits in a mouse model of Huntington 's disease . Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription , cell survival and metabolism . Activation of Q96EB6 , a mammalian sirtuin , extends longevity and increases neuronal survival . An important substrate of Q96EB6 is peroxisome proliferator-activated receptor gamma co-activator-1alpha ( P20142 -1alpha ) , a principal regulator of energy metabolism , whose function is significantly impaired in Huntington 's disease ( HD ) . We studied the effects of a pharmacological preparation of the Q96EB6 activator resveratrol ( DB05073 -M ) , in the N171-82Q transgenic mouse model of HD . We analyzed motor performance , survival , central and peripheral pathology and levels of P20142 -1alpha expression . Administration of DB05073 -M increased expression of P20142 -1alpha , as well as its downstream targets , nuclear respiratory factor-1 ( Q16656 ) and uncoupling protein-1 ( P25874 -1 ) in brown adipose tissue ( Q14032 ) , but there was no effect on P20142 -1alpha , Q16656 or the mitochondrial transcription factor ( Tfam ) in the striatum . DB05073 -M administration also reduced Q14032 vacuolation and decreased elevated blood glucose levels . However , there was no significant improvement in weight loss , motor performance , survival and striatal atrophy . Activation of the P20142 -1alpha signaling pathway via resveratrol-induced activation of Q96EB6 , therefore , is an effective therapy in Q14032 , but not in the central nervous system of HD transgenic mice . AM2389 , a high-affinity , in vivo potent P21554 -receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 (®) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB(1)R ) HHC-ligand AM2389 [ 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251 , a CB(1)R-selective antagonist/inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg/kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin/water . Generalization/substitution tests were conducted with AM2389 , AM5983 , and Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . RESULTS : Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg/kg ) . AM251 ( 3 and 10 mg/kg ) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025 , 0.0571 , and 0.2635 mg/kg , respectively , in the low-dose condition . The corresponding ED(50) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg/kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation . Possible involvement of endocannabinoids in the increase of morphine consumption in maternally deprived rat . Whether adolescent exposure to chronic DB00470 ( THC ) facilitates progression to opioid consumption is still controversial . In a maternal deprivation model ( 3 h daily from postnatal day 1-14 ) , we previously reported that adolescent exposure to chronic THC blocks morphine dependence in maternally deprived ( D ) rats . Owing to the existence of a functional cross-interaction between the opioid and cannabinoid systems in reward , we evaluated if the vulnerability to opiate reward in D rats , may involve an alteration of the endocannabinoid system . Anandamide and 2-arachidonoylglycerol ( 2-AG ) , were quantified in the striatum and mesencephalon of adolescent and adult D and non-deprived ( animal facility rearing , AFR ) rats by isotope dilution liquid chromatography-mass spectrometry . Oral morphine self-administration behavior was analyzed for 14 weeks , 24 days after chronic injection of the cannabinoid P21554 receptor antagonist/inverse agonist , SR141716A ( 3 mg/kg ) for 2 weeks during adolescence ( P01160 35-48 ) . Adolescent D rats exhibited higher basal levels of anandamide than adolescent AFR rats in the nucleus accumbens ( 38 % ) , the caudate-putamen nucleus ( 62 % ) and the mesencephalon ( 320 % ) , whereas adult D rats showed an increase of anandamide and 2-AG levels in the nucleus accumbens ( 50 % and 24 % , respectively ) and of 2-AG in the caudate-putamen nucleus ( 48 % ) , compared to adult AFR rats . Chronic administration of SR141716A to adolescent D rats blocked the escalation behavior in the morphine consumption test . Our data suggest that altered brain endocannabinoid levels may contribute to the escalation behavior in the morphine consumption test in a maternal deprivation model . Lack of direct action of atriopeptidase inhibitor on cellular pH regulation in rabbit S2 proximal straight tubules . While the in vivo diuretic and antihypertensive effects of the newly-developed drug DB00616 ( UK-79300 ) , a prodrug of a selective atriopeptidase inhibitor UK-73967 ( DB00058 ) are well established , the mechanism of its diuretic action is not yet fully understood due to the lack of information about its direct effects on proximal tubules . To elucidate whether this atriopeptidase inhibitor has any direct effects on proximal tubules , we examined the effect of DB00058 on intracellular pH ( pHi ) of the in vitro microperfused proximal S2 segment of rabbit kidney , using the pH-sensitive fluorescent dye , (2',7')-bis(carboxyethyl)-(5,6)-carboxyfluorescein ( BCECF ) . In the steady-state condition , pHi was 7.13 +/- 0.02 ( n = 19 ) . P08473 inhibitor ( DB00058 ) at 100 microM added to the bath changed pHi by only 0.02 +/- 0.07 unit ( n = 7 , p > 0.05 ) in 10 min . The same concentration of DB00058 in the lumen changed pHi by 0.03 +/- 0.02 unit ( n = 6 , p > 0.05 ) . To test whether the synergistic effects of DB00058 on the luminal and basolateral transport systems prevented the apparent change in pHi , we also examined the effect of DB00058 in the presence of amiloride in the lumen . The inhibition of Na+/H+ antiporter by the addition of 1 mM of amiloride to the lumen caused no change in pHi response to basolateral DB00058 application . DB00058 was without effect on pHi also in the presence of atrial natriuretic polypeptide ( P01160 ) . These results suggest that DB00058 per se has no significant effect on the process of proximal acidification over a short time period . Opioid and neurotransmitter regulation of pituitary gonadotropin-releasing hormone ( DB00644 ) receptors in the ovariectomized estradiol-treated rat : role of altered DB00644 secretion . An acute transient fall in the number of pituitary DB00644 receptors ( P30968 ) is observed before the preovulatory gonadotropin surge in cycling rats and before the afternoon daily gonadotropin surge in ovariectomized estradiol-treated rats . In the latter model , this fall can be reproduced by administration of the opioid antagonist naloxone , whereas the opioid agonist morphine acutely increases P30968 . In this study we investigated the mechanisms of this opioid effect and examined the effects of other neurotransmitter substances on modulation of pituitary P30968 . Administration of the dopaminergic agonists bromocriptine and L-dopa or the alpha-adrenergic receptor blocker phenoxybenzamine elevated P30968 acutely from average basal values of 240 +/- 22 and 254 +/- 21 fmol/mg protein to maximal values of 374 +/- 49 , 441 +/- 67 and 461 +/- 75 fmol/mg , respectively , whereas the alpha-adrenergic agonist clonidine transiently decreased P30968 to 186 +/- 19 fmol/mg . Placement of radiofrequency lesions in the mediobasal hypothalamus or pretreatment with anti- DB00644 serum completely abolished the ability of both morphine and naloxone to modulate the number of P30968 . These data indicate that the opioid-induced modulation of pituitary P30968 requires an intact hypothalamus and that both dopaminergic and alpha-adrenergic neurotransmitter systems may be involved . The final step of this action probably involves acute modulation of DB00644 secretion ( altered frequency and/or amplitude ) , which results in acute transient changes in the number of pituitary P30968 . Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers . Evidence suggests that emotional memory plays a role in the pathophysiology of depression/anxiety disorders . DB00368 crucially modulates emotional memory . Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology . A functional deletion polymorphism in the α-2B adrenoceptor gene ( P18089 ) has been linked to emotional memory and post-traumatic stress disorder . The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals . We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by P18089 genotype . P18089 deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers , consistent with prior studies . DB00234 attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers . This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans . Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex . BACKGROUND : Cannabinoids have deleterious effects on prefrontal cortex ( P27918 ) -mediated functions and multiple evidences link the endogenous cannabinoid ( endocannabinoid ) system , cannabis use and schizophrenia , a disease in which P27918 functions are altered . Nonetheless , the molecular composition and the physiological functions of the endocannabinoid system in the P27918 are unknown . METHODOLOGY/PRINCIPAL FINDINGS : Here , using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the P27918 : presynaptic cannabinoid P21554 receptors ( CB1R ) faced postsynaptic P41594 while diacylglycerol lipase alpha ( Q9Y4D2 ) , the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol ( 2-AG ) was expressed in the same dendritic processes as P41594 . Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents . Prolonged synaptic stimulation at 10Hz induced a profound long-term depression ( LTD ) of layers V/VI excitatory inputs . The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic P41594 , phospholipase C and a rise in postsynaptic Ca(2+) as predicted from the localization of the different components of the endocannabinoid system . Blocking the degradation of 2-AG ( with Q76M96 602 ) but not of anandamide ( with Q76M96 597 ) converted subthreshold tetanus to LTD-inducing ones . Moreover , inhibiting the synthesis of 2-AG with DB01083 , blocked endocannabinoid-mediated LTD . All together , our data show that 2-AG mediates LTD at these synapses . CONCLUSIONS/SIGNIFICANCE : Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the P27918 . Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of P27918 -related pathologies . The deletion variant of α2b-adrenergic receptor is associated with decreased risk in Alzheimer 's disease and mild cognitive impairment . A common genetic polymorphism of the α2b-adrenergic receptor ( P18089 ) resulting in a deletion of three glutamic acids located on the third intracellular loop of the protein , has been associated with memory formation enhanced by emotional events . Additionally , there are several studies documenting the involvement of this polymorphism in other types of cognition , such as episodic memory . The aim of this study was to investigate the possible relationship of this genetic variance with a common memory affecting disease , Alzheimer 's disease . Our study was carried out in a total number of 311 Greek subjects , including 119 sporadic AD patients , 95 D6RGH6 cases and 97 controls . Genomic DNA was extracted from whole blood and the fragments containing the polymorphism were amplified by PCR analysis . A genotypic analysis of the P02649 polymorphism was also carried out . A significant difference in the frequency of the P18089 genetic variation among the three groups was observed . Specifically , the deletion variant is more prevalent in controls than in AD and D6RGH6 patients . Our data demonstrate for the first time an independent contribution of the P18089 genetic polymorphism to memory impairment and we further suggest a possible protective role of the deletion variant against the disease development . Atrial and brain natriuretic peptides : secretion during exercise in patients with essential hypertension and modulation by acute angiotensin-converting enzyme inhibition . 1. This study examined whether brain and atrial natriuretic peptides ( DB04899 , P01160 ) are secreted together through the coronary sinus from the heart , and whether plasma concentrations of DB04899 and P01160 were affected by ergometric exercise in patients with essential hypertension . The effects of temocapril , a potent angiotensin-converting enzyme ( P12821 ) inhibitor , on plasma concentrations of these peptides was also examined . 2 . The plasma concentrations of immunoreactive ( ir ) DB04899 and ir- P01160 in the coronary sinus in seven patients with ischaemic heart disease during cardiac catheterization were far greater than values with plasma obtained at the same time from the femoral artery . 3 . The plasma concentrations of ir- DB04899 and ir- P01160 increased with exercise and were correlated with each other . DB08836 reduced the blood pressure and slightly ( but significantly ) decreased the levels of both peptides at rest and during exercise . 4 . The results suggest that DB04899 and P01160 were secreted together through the coronary sinus from the heart . The secretion was increased by exercise and suppressed by acute P12821 inhibition . The increase in these peptides during exercise may reflect a compensatory mechanism against further elevation of blood pressure .