interacts_with DB01151?
Menstrual cycle-dependent febrile episode mediated by sequence-specific repression of poly(ADP-ribose) polymerase-1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33-year-old woman with rare menstrual cycle-dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen-related P08908 deficiency . We identified an adenine deletion 480-bases upstream of the translation start site ( i.e. , -480delA ) of P08908 in this patient . To determine the underlying mechanism of -480delA-mediated P08908 deficiency , we first showed that P08908 -480 region can be bound by multiple nuclear protein(s) . We then identified poly(ADP-ribose) polymerase ( P09874 ) as one of the proteins that binds to P08908 -480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 -480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β-estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen-induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 -mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle-dependent febrile episodes , and implies that similar " febrile episode " cases may also result from the dysfunction of serotonin transmission . Phenotypic rescue of a Drosophila model of mitochondrial P12235 disease . A point mutation in the Drosophila gene that codes for the major adult isoform of adenine nuclear translocase ( ANT ) represents a model for human diseases that are associated with ANT insufficiency [ stress-sensitive B(1) ( sesB(1) ) ] . We characterized the organismal , bioenergetic and molecular phenotype of sesB(1) flies then tested strategies to compensate the mutant phenotype . In addition to developmental delay and mechanical-stress-induced seizures , sesB(1) flies have an impaired response to sound , defective male courtship , female sterility and curtailed lifespan . These phenotypes , excluding the latter two , are shared with the mitoribosomal protein P28222 mutant , tko(25t) . Mitochondria from sesB(1) adults showed a decreased respiratory control ratio and downregulation of cytochrome oxidase . sesB(1) adults exhibited DB00171 depletion , lactate accumulation and changes in gene expression that were consistent with a metabolic shift towards glycolysis , characterized by activation of lactate dehydrogenase and anaplerotic pathways . Females also showed downregulation of many genes that are required for oogenesis , and their eggs , although fertilized , failed to develop to the larval stages . The sesB(1) phenotypes of developmental delay and mechanical-stress-induced seizures were alleviated by an altered mitochondrial DNA background . Female sterility was substantially rescued by somatic expression of alternative oxidase ( Q15067 ) from the sea squirt Ciona intestinalis , whereas Q15067 did not alleviate developmental delay . Our findings illustrate the potential of different therapeutic strategies for ANT-linked diseases , based on alleviating metabolic stress . 1-(3-Trifluoromethylphenyl) piperazine ( TFMPP ) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats : possible role of serotonin receptors . 1-(3-Trifluoromethylphenyl)piperazine ( TFMPP ) , a serotonin1 ( 5-HT1 ) receptor agonist , injected i.p. in doses of 0.1 and 0.6 mg/kg , did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg/kg per day desipramine ( DB01151 ) . A similar effect was found on infusing 1 and 5 micrograms/microliters TFMPP bilaterally into the ventral tegmental area ( VTA ) . Infusion of 5 micrograms/microliters TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of DB01151 . The effect of 5 micrograms TFMPP infused into the VTA was prevented by the i.p. administration of 5 mg/kg metergoline , a non-selective serotonin receptor antagonist . Infusion of 5 micrograms/microliters 8-hydroxy-2-(di-n-propylamino)tetralin , a specific P08908 receptor agonist , into the VTA did not modify the effect of DB01151 . Besides acting as a P28222 receptor agonist , TFMPP may also act on other 5-HT receptor types , but available evidence suggests that its former action is more important . It thus appears that 5-HT1 receptors in the VTA , presumably of the P28222 type , act by preventing the anti-immobility effect of DB01151 . The role of VTA dopamine and non-dopamine cells in the effect of TFMPP is discussed . Alterations in receptors for thyrotropin-releasing hormone , serotonin , and acetylcholine in amyotrophic lateral sclerosis . We utilized quantitative autoradiography to examine thyrotropin-releasing hormone ( TRH ) receptors , serotonin type 1A ( P08908 ) receptors , muscarinic cholinergic receptors , choline uptake sites , beta-adrenergic receptors , and norepinephrine uptake sites in discrete laminae of spinal cord from patients with amyotrophic lateral sclerosis ( P35858 ) and non-neurologic controls . We found decreases of over 50 % in the concentration of TRH receptors in lamina IX of cervical , thoracic , and lumbar spinal cord from P35858 patients . Similar reductions were noted in concentrations of muscarinic cholinergic receptors in lamina IX of spinal cords from P35858 patients . Significant increases of up to 140 % in P08908 receptor densities were noted in lamina IX of spinal cords from P35858 patients . No differences were noted between the concentrations of beta-adrenergic receptors or norepinephrine uptake sites in patients with P35858 and controls . These findings suggest that TRH and 5-HT may be involved in the pathophysiology of P35858 , and act in a comodulatory role in the normal spinal cord . Agonist-promoted down-regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO- P04264 cells . WT , Ser22 , and Val28 displayed similar high-affinity binding to [ 3H ] -8-OH-DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist-promoted down-regulation was tested by exposure to 100 mumol/L 8-OH-DPAT . After 24-h exposure , WT and Val28 underwent 59.3 +/- 3.9 % and 59.5 +/- 1.4 % reduction in receptor density respectively , whereas the degree of down-regulation was significantly lower for Ser22 ( 21.4 +/- 4.2 % ) . Cell treatment for 24 h with 100 mumol/L 8-OH-DPAT reduced the 5-HT-induced inhibition of DB02527 accumulation by 24.9 +/- 5.1 % for WT and 16.4 +/- 0.8 % for Val28 , but only by 4.8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist-mediated receptor down-regulation and desensitization . Long-term fluoxetine , but not desipramine , inhibits the DB01285 and oxytocin responses to the P08908 agonist , 8-OH-DPAT , in male rats . The present studies determined whether serotonin P08908 receptor-mediated function is modified by chronic exposure to antidepressants . Hormone responses to the P08908 agonist , 8-OH-DPAT , were evaluated after long-term exposure to two antidepressants , the 5-HT uptake blocker , fluoxetine , and the norepinephrine uptake blocker , desipramine ( DB01151 ) . In addition , the density and affinity of P08908 receptors in the hypothalamus and cerebral cortex were measured . Male rats received fluoxetine ( 10 mg/kg i.p. ) , DB01151 ( 5 mg/kg i.p. ) or saline injections once daily for 21 days . 8-OH-DPAT ( 0-500 micrograms/kg s.c. ) was administered 18 h after the final antidepressant injection and 15 min before sacrifice . 8-OH-DPAT significantly increased plasma DB01285 , corticosterone , oxytocin and prolactin , but not renin or vasopressin concentrations . Chronic injections of fluoxetine inhibited the DB01285 , corticosterone and oxytocin responses to 8-OH-DPAT , suggesting reduced P08908 receptor function . In contrast , chronic DB01151 did not alter the hormone responses to 8-OH-DPAT . The density and affinity of P08908 receptors in the frontal cortex or hypothalamus were not altered by either fluoxetine or DB01151 . To verify that the observed effects require prolonged exposure to fluoxetine , rats received a single injection of fluoxetine ( 10 mg/kg , i.p. ) , 3 h before 8-OH-DPAT ( 0-500 micrograms/kg s.c. ) . Acute fluoxetine did not reduce any of the hormone responses to 8-OH-DPAT . In conclusion , the results suggest that chronic , but not acute , exposure to fluoxetine decreases P08908 receptor function . This effect is not seen in rats chronically exposed to DB01151 . ( ABSTRACT TRUNCATED AT 250 WORDS ) 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 . Modulation of a number of genes on personality traits in a sample of healthy subjects . A large number of studies investigated the genetic modulation of personality with mixed results . As a confirmatory analysis of previous findings , we firstly examined the association between several previously examined single nucleotide polymorphisms ( SNPs ) and personality traits in a sample of 158 healthy subjects . As a secondary aim , we tested the potential modulation of additional never previously investigated genes on personality . A blood sample was collected and the Temperament and Character Inventory ( TCI ) has been administered to all participants . Multivariate analysis of covariance , controlling for sex and age , was used to test SNP influence on TCI scores . Examination of previously studied gene variants showed an effect of adrenergic alpha 2B receptor ( P18089 ) on Cooperativeness and of serotonin receptor P28223 on Self Directedness . Examination of new variants revealed that sex hormone binding protein ( P04278 ) was associated with reward dependence . Moreover , several additional variants showed a tendency towards association with some TCI traits , confirming previous results . This study suggests that P18089 , P28223 and P04278 genes may be involved in the modulation of personality in healthy subjects . The major limitation of this study was the small sample size . P07550 -mediated effects on sinus rate and atrial and ventricular contractility on isolated , blood-perfused dog heart preparations . Changes in the sinus rate , right atrial contractile force and left ventricular contractile force in response to isoproterenol , epinephrine , dobutamine , salbutamol and procaterol were studied in isolated , blood-perfused right atrial or left ventricular cardiac preparations of the dog . Each substance elicited dose-dependent increases in the three parameters and the ranking of the potency ( ED50 ) for each effect was isoproterenol greater than epinephrine greater than dobutamine greater than or equal to salbutamol greater than or equal to procaterol . The ED50 of procaterol for changing sinus rate was lower than for altering atrial and ventricular contractile force , whereas the ED50 of dobutamine for changing sinus rate was higher . Ranking on the basis of the ratio of increase in sinus rate to increase in atrial tension induced by the agonists gave the following order : procaterol greater than or equal to salbutamol greater than epinephrine greater than or equal to isoproterenol greater than dobutamine . DB01366 -induced increases in sinus rate and atrial contractile force were dose-dependently inhibited by the beta-2 adrenoceptor antagonist , ICI 118,551 , but only attenuated slightly by the beta-1 antagonist , atenolol . On the other hand , the positive chrono- and inotropic effects on the right atrium induced by dobutamine and isoproterenol were blocked completely by atenolol . The epinephrine- or salbutamol-induced positive chrono- and inotropic responses in the right atrium were inhibited moderately by both antagonists , but ICI 118,551 inhibited sinus rate increases more effectively than the atrial tension increases. ( ABSTRACT TRUNCATED AT 250 WORDS ) Decreasing Poly(ADP- DB01936 ) Polymerase Activity Restores ΔF508 P13569 Trafficking . Most cystic fibrosis is caused by mutations in P13569 that prevent its trafficking from the ER to the plasma membrane and is associated with exaggerated inflammation , altered metabolism , and diminished responses to oxidative stress . P09874 is activated by oxidative stress and causes energy depletion and cell dysfunction . Inhibition of this enzyme protects against excessive inflammation and recent studies have also implicated it in intracellular protein trafficking . We hypothesized that P09874 activity is altered in CF and affects trafficking and function of the most common CF mutant ΔF508 P13569 . Indeed , P09874 activity was 2.9-fold higher in CF ( ΔF508/ΔF508 ) human bronchial epithelial primary cells than in non-CF cells , and similar results were obtained by comparing CF vs. non-CF bronchial epithelial cell lines ( 2.5-fold higher in CFBE41o(-) vs. 16HBE14o(-) , P < 0.002 ) . A P09874 inhibitor ( ABT-888 , DB07232 ) partially restored P13569 channel activity in CFBE41o(-) cells overexpressing ΔF508 P13569 . Similarly , reducing P09874 activity by 85 % in ileum from transgenic CF mice ( Cftr(tm1)Eur ) partially rescued ΔF508 P13569 activity to 7 % of wild type mouse levels , and similar correction ( 7.8 % ) was observed in vivo by measuring salivary secretion . Inhibiting P09874 with ABT-888 or siRNA partially restored ΔF508 P13569 trafficking in cell lines , and most ΔF508 P13569 was complex glycosylated when heterologously expressed in P09874 (-/-) mouse embryonic fibroblasts . Finally , levels of the mature glycoform of P13569 were reduced by peroxynitrite , a strong activator of P09874 . These results demonstrate that P09874 activity is increased in CF , and identify a novel pathway that could be targeted by proteostatic correctors of P13569 trafficking . 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 . Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3.4 nM ) , in addition to P28221 , 5-HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose-dependently slowed raphe unit activity ( ED50 = 300 micrograms/kg i.v. ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms/kg i.v. ) and olanzapine ( ED50 = 1000 micrograms/kg i.v. ) . Pretreatment with the P08908 antagonist WAY-100,635 ( 10 micrograms/kg i.v. ) prevented the ziprasidone-induced inhibition ; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( DB01151 ) , a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . DB01151 ( 5 mg/kg i.v. ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions . The glutamate/neutral amino acid transporter family Q99705 : molecular , physiological and pharmacological aspects . The solute carrier family 1 ( Q99705 ) includes five high-affinity glutamate transporters , P43005 , GLT-1 , P43003 , P48664 and O00341 ( P43005 , P43004 , P43003 , P48664 , and O00341 , respectively ) as well as the two neutral amino acid transporters , P43007 and Q15758 ( P43007 and ALC1A5 , respectively ) . Although each of these transporters have similar predicted structures , they exhibit distinct functional properties which are variations of a common transport mechanism . The high-affinity glutamate transporters mediate transport of l- DB00142 , l- DB00128 and d- DB00128 , accompanied by the cotransport of 3 Na(+) and 1 H(+) , and the countertransport of 1 K(+) , whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala , DB00133 , DB00151 and DB00156 . The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient . This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system . During pathological conditions , such as brain ischemia ( e.g. after a stroke ) , however , glutamate exit can occur due to " reversed glutamate transport " , which is caused by a reversal of the electrochemical gradients of the coupling ions . Selective inhibition of the neuronal glutamate transporter P43005 ( P43005 ) may be of therapeutic interest to block glutamate release from neurons during ischemia . On the other hand , upregulation of the glial glutamate transporter P43004 ( P43004 ) may help protect motor neurons in patients with amyotrophic lateral sclerosis ( P35858 ) , since loss of function of P43004 has been associated with the pathogenesis of certain forms of P35858 . Distorted antigen-presenting function of Langerhans cells induced by tumor necrosis factor alpha via a mechanism that appears different from that induced by ultraviolet B radiation . P01375 alpha ( P01375 alpha ) has been shown to mimic 2 effects of ultraviolet B ( UVB ) radiation in mice : morphologic damage to epidermal Langerhans cells ( LC ) and the inability to mount a normal contact hypersensitivity ( CH ) response . Our previous studies have shown LC to be the target of the immune tolerance evoked by UVB radiation , both during induction of CH in vivo and during presentation of protein antigen to P01730 + Th1 cells ( Th1 ) in vitro . To determine whether these influences of P01375 alpha and of UVB radiation on LC are related , 2 sets of experiments were performed . We first examined the effect of recombinant P01375 alpha on the capacity of epidermal cells enriched for LC ( IEC ) to present DB05299 ( KLH ) to KLH-specific and Iad-restricted Th1 . Addition of P01375 alpha to co-cultures of IEC and Th1 significantly reduced proliferation in a dose-dependent manner . This inhibition was specific since it was reversed by neutralizing Ab against P01375 alpha . That P01375 alpha blocked Th1 proliferation by acting directly on LC is supported by 2 findings : 1 ) selective treatment of IEC prior to co-culturing also led to failure to present KLH ; and 2 ) P01375 alpha did not reduce Th1 proliferation stimulated by phorbol myristate acetate plus ionomycin , or by P60568 . We next examined the capacity of anti- P01375 alpha Ab to protect LC from loss of antigen-presenting cell ( P25054 ) function induced by a single dose of 200 J/m2 UVB . Anti- P01375 alpha Ab tested over a broad dose range did not prevent or restore the ability of UVB-irradiated IEC to present KLH to Th1. ( ABSTRACT TRUNCATED AT 250 WORDS ) Arsenic decreases antinociceptive activity of paracetamol : possible involvement of serotonergic and endocannabinoid receptors . We assessed whether repeated arsenic exposure can decrease paracetamol-mediated antinociception by modulating serotonergic and endocannabinoid pathways . Rats were preexposed to elemental arsenic ( 4ppm ) as sodium arsenite through drinking water for 28 days . Next day paracetamol 's ( 400mg/kg , oral ) antinociceptive activity was assessed through formalin-induced nociception . Serotonin content and gene expression of P08908 , 5- Q13049 and P21554 receptors were evaluated in brainstem and frontal cortex . Arsenic decreased paracetamol-mediated analgesia . DB00316 , but not arsenic , increased serotonin content in these regions . Arsenic attenuated paracetamol-mediated increase in serotonin level . DB00316 did not alter P08908 expression , but caused down-regulation of 5- Q13049 and up-regulation of P21554 receptors . Arsenic down-regulated these receptors . However , paracetamol-mediated down-regulation of 5- Q13049 was more pronounced . Arsenic did not modify paracetamol 's effect on P08908 expression , but reduced paracetamol-mediated down-regulation of 5- Q13049 and reversed up-regulation of P21554 receptors . Results suggest arsenic reduced paracetamol-induced analgesia possibly by interfering with pronociceptive 5- Q13049 and antinociceptive P21554 receptors . P18089 genotype differentially modulates stress-induced neural activity in the amygdala and hippocampus during emotional memory retrieval . RATIONALE : DB00368 interacts with stress hormones in the amygdala and hippocampus to enhance emotional memory consolidation , but the noradrenergic-glucocorticoid interaction at retrieval , where stress impairs memory , is less understood . OBJECTIVES : We used a genetic neuroimaging approach to investigate whether a genetic variation of the noradrenergic system impacts stress-induced neural activity in amygdala and hippocampus during recognition of emotional memory . METHODS : This study is based on genotype-dependent reanalysis of data from our previous publication ( Li et al. Brain Imaging Behav 2014 ) . Twenty-two healthy male volunteers were genotyped for the P18089 gene encoding the α2B-adrenergic receptor . Ten deletion carriers and 12 noncarriers performed an emotional face recognition task , while their brain activity was measured with fMRI . During encoding , 50 fearful and 50 neutral faces were presented . One hour later , they underwent either an acute stress ( Trier Social Stress Test ) or a control procedure which was followed immediately by the retrieval session , where participants had to discriminate between 100 old and 50 new faces . RESULTS : A genotype-dependent modulation of neural activity at retrieval was found in the bilateral amygdala and right hippocampus . Deletion carriers showed decreased neural activity in the amygdala when recognizing emotional faces in control condition and increased amygdala activity under stress . Noncarriers showed no differences in emotional modulated amygdala activation under stress or control . Instead , stress-induced increases during recognition of emotional faces were present in the right hippocampus . CONCLUSION : The genotype-dependent effects of acute stress on neural activity in amygdala and hippocampus provide evidence for noradrenergic-glucocorticoid interaction in emotional memory retrieval . Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder . A time-to-onset analysis for family-based samples was performed on the genomewide association ( GWAS ) data for attention deficit hyperactivity disorder ( ADHD ) to determine if associations exist with the age at onset of ADHD . The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array . After data cleaning procedures , 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest . No SNP achieved genome-wide significance , and the lowest P-values had a magnitude of 10(-7) . Several SNPs among a pre-specified list of candidate genes had nominal associations including Q8IVB4 , P21728 , P07550 , Q01959 , Q16649 , P08588 , P21579 , P28223 , P32121 , and P43681 . Of these findings Q8IVB4 stood out as a promising candidate , with nominally significant SNPs in six distinct regions of the gene . Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( -241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 -SNP1 [ rs3803300 ] and P31749 -SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients . DB00952 . The new P28222 /1D agonist naratriptan , introduced in many countries in 1997 and 1998 for the acute treatment of migraine , was designed to complement the sumatriptan portfolio of offerings ( including the injection , the tablets , the nasal spray , and in some countries , the suppository ) by offering patients excellent tolerability and a sustained duration of action . Clinical studies on naratriptan , including more than 4000 patients treating more than 15,000 migraine attacks , show that naratriptan tablets 2.5 mg are distinguished from other P28222 /1D agonists for migraine on the basis of their excellent tolerability profile , which does not differ from that of placebo . In addition to its tolerability , naratriptan tablets 2.5 mg possess a long duration of action with a low incidence of headache recurrence ( 17-28 % in phase II and III clinical trials ) . With its tolerability profile and long duration of action , naratriptan tablets 2.5 mg may be particularly appropriate as a single-dose alternative to NSAIDs and analgesics , which often are not effective in migraine but are used because of tolerability considerations . Neuronal specific increase of phosphatidylserine by docosahexaenoic acid . DB00144 ( PS ) , the major acidic phospholipid class in eukaryotic biomembranes , plays an important role in various signaling pathways . We have previously demonstrated that docosahexaenoic acid ( DB01708 , 22:6n-3 ) positively modulates PS biosynthesis and accumulation in neuronal cells , promoting survival . In this paper , we demonstrate that the increase of PS levels upon DB01708 enrichment is not a universal mechanism , but specific to neuronal cells . When cells were enriched with 20 muM DB01708 , 18:0 , 22:6-PS increased in both neuronal ( Neuro 2A ) and non-neuronal cells ( Chinese hamster ovary P04264 cells , NIH-3T3 , and human embryonic kidney cells ) . However , the increase of the total PS level was observed only in Neuro 2A cells because of the fact that other PS species , such as 18:0 , 18:1-PS and 18:1 , 18:1-PS decreased significantly in non-neuronal cells , compensating for the increase of 18:0 , 22:6-PS . DB01708 enrichment did not affect the messenger RNA levels of PS synthase 1 ( PSS1 ) and Q9BVG9 . Over-expression of genes encoding PSS1 or Q9BVG9 altered neither the PS level nor the effect of DB01708 on PS increase in both neuronal and non-neuronal cells . From these results , it is concluded that the PS increase by DB01708 , specifically observed in neuronal cells , may represent a unique mechanism for expanding the PS pool so far known in mammalian cells . DB02426 effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms P12235 and P05141 may be responsible for basal and fatty-acid-induced uncoupling respectively . In brown-fat mitochondria , fatty acids induce thermogenic uncoupling through activation of P25874 ( uncoupling protein 1 ) . However , even in brown-fat mitochondria from P25874 -/- mice , fatty-acid-induced uncoupling exists . In the present investigation , we used the inhibitor CAtr ( carboxyatractyloside ) to examine the involvement of the ANT ( adenine nucleotide translocator ) in the mediation of this P25874 -independent fatty-acid-induced uncoupling in brown-fat mitochondria . We found that the contribution of ANT to fatty-acid-induced uncoupling in P25874 -/- brown-fat mitochondria was minimal ( whereas it was responsible for nearly half the fatty-acid-induced uncoupling in liver mitochondria ) . As compared with liver mitochondria , brown-fat mitochondria exhibit a relatively high ( P25874 -independent ) basal respiration ( ' proton leak ' ) . Unexpectedly , a large fraction of this high basal respiration was sensitive to CAtr , whereas in liver mitochondria , basal respiration was CAtr-insensitive . Total ANT protein levels were similar in brown-fat mitochondria from wild-type mice and in liver mitochondria , but the level was increased in brown-fat mitochondria from P25874 -/- mice . However , in liver , only Ant2 mRNA was found , whereas in brown adipose tissue , Ant1 and Ant2 mRNA levels were equal . The data are therefore compatible with a tentative model in which the P05141 isoform mediates fatty-acid-induced uncoupling , whereas the P12235 isoform may mediate a significant part of the high basal proton leak in brown-fat mitochondria .