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Sample records for 5-ht1a receptor binding

  1. Involvement of the 5-HT(1A) receptor in the anti-immobility effects of fluvoxamine in the forced swimming test and mouse strain differences in 5-HT(1A) receptor binding.

    Science.gov (United States)

    Sugimoto, Yumi; Furutani, Sachiko; Kajiwara, Yoshinobu; Hirano, Kazufumi; Yamada, Shizuo; Tagawa, Noriko; Kobayashi, Yoshiharu; Hotta, Yoshihiro; Yamada, Jun

    2010-03-10

    We previously demonstrated the presence of strain differences in baseline immobility time and sensitivity to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in five strains of mice (ICR, ddY, C57BL, DBA/2 and BALB/c mice). Furthermore, variations in serotonin (5-HT) transporter binding in the brain were strongly related to strain differences in baseline immobility and sensitivity to fluvoxamine. In the present study, we examined the involvement of the 5-HT(1A) receptor in anti-immobility effects in DBA/2 mice, which show high sensitivity to fluvoxamine. The anti-immobility effects of fluvoxamine in DBA/2 mice were inhibited by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT(1B) receptor antagonist 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide (GR55562), the 5-HT(2) receptor antagonist 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT(3) receptor antagonist ondansetron and the 5-HT(4) receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not influence the anti-immobility effects of fluvoxamine in DBA/2 mice. These results suggest that fluvoxamine-induced antidepressant-like effects in DBA/2 mice are mediated by the 5-HT(1A) receptor. We analyzed 5-HT(1A) receptor binding in the brains of five strains of mice. Strain differences in 5-HT(1A) receptor binding were observed. 5-HT(1A) receptor binding in brain was not correlated with baseline immobility time in the five strains of mice examined. These results suggest that, although the anti-immobility effects of fluvoxamine in DBA/2 mice are mediated by the 5-HT(1A) receptor, strain differences in 5-HT(1A) receptor binding are not related to variation in immobility time and responses to fluvoxamine.

  2. Increased binding of 5-HT1A receptors in a dissociative amnesic patient after the recovery process.

    Science.gov (United States)

    Kitamura, Soichiro; Yasuno, Fumihiko; Inoue, Makoto; Kosaka, Jun; Kiuchi, Kuniaki; Matsuoka, Kiwamu; Kishimoto, Toshifumi; Suhara, Tetsuya

    2014-10-30

    Dissociative amnesia is characterized by an inability to retrieve information already saved in memories. 5-HT has some role in neural regulatory control and may be related to the recovery from dissociative amnesia. To examine the role of 5-HT1A receptors in the recovery from dissociative amnesia, we performed two positron emission tomography (PET) scans on a 30-year-old patient of dissociative amnesia using [(11)C]WAY-100635, the first at amnesic state, and the second at the time he had recovered. Exploratory voxel-based analysis (VBA) was performed using SPM software. 5-HT1A BPND images were compared between the patient at amnesic and recovery states and healthy subjects (14 males, mean age 29.8 ± 6.45) with Jack-knife analysis. 5-HT1A receptor bindings of the patient at the recovery state were significantly higher than those of healthy subjects in the right superior and middle frontal cortex, left inferior frontal and orbitofrontal cortex and bilateral inferior temporal cortex. The increase in BPND values of recovery state was beyond 10% of those of amnesia state in these regions except in the right superior frontal cortex. We considered that neural regulatory control by the increase of 5-HT1A receptors in cortical regions played a role in the recovery from dissociative amnesia.

  3. 5-HT(1A) receptors and memory.

    Science.gov (United States)

    Meneses, Alfredo; Perez-Garcia, Georgina

    2007-01-01

    The study of 5-hydroxytryptamine (5-HT) systems has benefited from the identification, classification and cloning of multiple 5-HT receptors (5-HT(1)-5-HT(7)). Increasing evidence suggests that 5-HT pathways, reuptake site/transporter complex and 5-HT receptors represent a strategic distribution for learning and memory. A key question still remaining is whether 5-HT markers (e.g., receptors) are directly or indirectly contributing to the physiological and pharmacological basis of memory and its pathogenesis or, rather, if they represent protective or adaptable mechanisms (at least in initial stages). In the current paper, the major aim is to revise recent advances regarding mammalian 5-HT(1A) receptors in light of their physiological, pathophysiological and therapeutic implications in memory. An attempt is made to identify and discuss sources of discrepancies by employing an analytic approach to examine the nature and degree of difficulty of behavioral tasks used, as well as implicating other factors (for example, brain areas, training time or duration, and drug administration) which might offer new insights into the understanding and interpretation of these data. In this context, 8-OH-DPAT deserves special attention since for many years it has been the more selective 5-HT drug and, hence, more frequently used. As 5-HT(1A) receptors are key components of serotonergic signaling, investigation of their memory mechanisms and action sites and the conditions under which they might operate, could yield valuable insights. Moreover, selective drugs with agonists, neutral antagonists or inverse agonist properties for 5-HT(1A) (and 5-HT(7)) receptors may constitute a new therapeutic opportunity for learning and memory disorders.

  4. 5-HT(1A) receptor and 5-HTT binding during the menstrual cycle in healthy women examined with [(11)C] WAY100635 and [(11)C] MADAM PET.

    Science.gov (United States)

    Jovanovic, Hristina; Karlsson, Per; Cerin, Asta; Halldin, Christer; Nordström, Anna-Lena

    2009-04-30

    The aim of the present study was to explore the effects of the menstrual cycle phases on 5-HT(1A) receptor and 5-HTT binding potentials (BPs) in healthy women by using positron emission tomography (PET). Women were investigated in the follicular and luteal phase of the menstrual cycle with radioligands [(11)C]WAY10035 (n=13) and [(11)C]MADAM (n=8) to study 5-HT(1A) and 5-HTT BPs. The BPs values were quantified using the simplified reference tissue model. The phases of the menstrual cycle were characterized by transvaginal ultrasound (TSV) and plasma levels of hormones estradiol (E(2)), progesterone (P(4)), follicle stimulating hormone (FSH) and luteinizing hormone (LH).The 5-HT(1A) receptor and 5-HTT BPs did not significantly differ between follicular and luteal phases in any of the investigated regions. There were no significant correlations between the change in E(2) or P(4) values with the change in 5-HT(1A) receptor or 5-HTT BPs. The results provide principally a new in vivo finding in human female biology, suggesting the absence of influence of menstrual cycle phase on 5-HT(1A) receptors or 5-HTT. The finding however does not preclude that gonadal hormones differentially influence central serotonin system inwomen and men, which might contribute to gender differences in serotonin-associated disorders.

  5. Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635.

    Science.gov (United States)

    Bailer, Ursula F; Frank, Guido K; Henry, Shannan E; Price, Julie C; Meltzer, Carolyn C; Weissfeld, Lisa; Mathis, Chester A; Drevets, Wayne C; Wagner, Angela; Hoge, Jessica; Ziolko, Scott K; McConaha, Claire W; Kaye, Walter H

    2005-09-01

    Previous studies have shown that women with anorexia nervosa (AN), when ill and after recovery, have alterations of serotonin (5-HT) neuronal activity and core eating disorder symptoms, such as anxiety. To further characterize the 5-HT system in AN, we investigated 5-HT1A receptor activity using positron emission tomography imaging because this receptor is implicated in anxiety and feeding behavior. To avoid the confounding effects of malnutrition, we studied 13 women who had recovered from restricting-type AN (mean age, 23.3 +/- 5.2 years) and 12 women who had recovered from bulimia-type AN (mean age, 28.6 +/- 7.3 years) (>1 year normal weight, regular menstrual cycles, no bingeing or purging). These subjects were compared with 18 healthy control women (mean age, 25.1 +/- 5.8 years). Intervention The 5-HT1A receptor binding was measured using positron emission tomography imaging and a specific 5-HT1A receptor antagonist, [carbonyl-11C]WAY-100635. Specific 5-HT1A receptor binding was assessed using the binding potential measure. Binding potential values were derived using both the Logan graphical method and compartmental modeling. The binding potential in a region of interest was calculated with the formula: binding potential = distribution volume of the region of interest minus distribution volume of the cerebellum. Women recovered from bulimia-type AN had significantly (P<.05) increased [11C]WAY-100635 binding potential in cingulate, lateral and mesial temporal, lateral and medial orbital frontal, parietal, and prefrontal cortical regions and in the dorsal raphe compared with control women. No differences were found for women recovered from restricting-type AN relative to controls. For women recovered from restricting-type AN, the 5-HT1A postsynaptic receptor binding in mesial temporal and subgenual cingulate regions was positively correlated with harm avoidance. We observed increased 5-HT1A receptor binding in women who had recovered from bulimia-type AN but not

  6. Neuroticism and serotonin 5-HT1A receptors in healthy subjects

    DEFF Research Database (Denmark)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell

    2015-01-01

    Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy...... and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals...... with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may...

  7. Influences of housing conditions and ethanol intake on binding characteristics of D2, 5-HT1A, and benzodiazepine receptors of rats.

    Science.gov (United States)

    Rilke, O; May, T; Oehler, J; Wolffgramm, J

    1995-09-01

    The effects of different housing conditions and ethanol treatment (6 vol % in the drinking water) on the in vitro binding characteristics of striatal dopaminergic D2 ([3H]spiperone), hippocampal serotonergic 5-HT1A ([3H]8-OH-DPAT), and cortical benzodiazepine ([3H]flunitrazepam) receptors have been examined. Social deprivation due to contact caging, short- (1 day) and long-term isolation (5 weeks) yielded a significant decrease of striatal D2 receptor density with the greatest decrease after long-term isolation (-21% Bmax) without changes of Kd in comparison to group animals. The effect of ethanol on striatal D2 receptor density depended on the housing conditions. Whereas ethanol treatment reduced receptor density of group animals (down to 88%), chronic exposure to ethanol under long-term isolation elicited no significant alteration of D2 receptor density compared with group animals. Different housing and ethanol treatment had no effect on 5-HT1A receptor affinity and density. Alterations of benzodiazepine receptor density were not found, but social deprivation as well as ethanol treatment of group animals caused an increased affinity of [3H]flunitrazepam (reduced Kd value). These results indicate that different housing conditions of adult rats evoked significant alterations in D2 and benzodiazepine receptor binding assays, which were modified by ethanol treatment in the case of striatal D2 receptor density.

  8. Measurement of 5-HT(1A) receptor density and in-vivo binding parameters of [(18)F]mefway in the nonhuman primate.

    Science.gov (United States)

    Wooten, Dustin W; Hillmer, Ansel T; Moirano, Jeffrey M; Ahlers, Elizabeth O; Slesarev, Maxim; Barnhart, Todd E; Mukherjee, Jogeshwar; Schneider, Mary L; Christian, Bradley T

    2012-08-01

    The goal of this work was to characterize the in-vivo behavior of [(18)F]mefway as a suitable positron emission tomography (PET) radiotracer for the assay of 5-hydroxytryptamine(1A) (5-HT(1A)) receptor density (B(max)). Six rhesus monkeys were studied using a multiple-injection (M-I) protocol consisting of three sequential bolus injections of [(18)F]mefway. Injection times and amounts of unlabeled mefway were optimized for the precise measurement of B(max) and specific binding parameters k(off) and k(on) for estimation of apparent K(D). The PET time series were acquired for 180 minutes with arterial sampling performed throughout. Compartmental analysis using the arterial input function was performed to obtain estimates for K(1), k(2), k(off), B(max), and K(Dapp) in the cerebral cortex and raphe nuclei (RN) using a model that accounted for nontracer doses of mefway. Averaged over subjects, highest binding was seen in the mesial temporal and dorsal anterior cingulate cortices with B(max) values of 42±8 and 36±8 pmol/mL, respectively, and lower values in the superior temporal cortex, RN, and parietal cortex of 24±4, 19±4, and 13±2 pmol/mL, respectively. The K(Dapp) of mefway for the 5-HT(1A) receptor sites was 4.3±1.3 nmol/L. In conclusion, these results show that M-I [(18)F]mefway PET experiments can be used for the in-vivo measurement of 5-HT(1A) receptor density.

  9. Neuroticism and serotonin 5-HT1A receptors in healthy subjects.

    Science.gov (United States)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell; Hietala, Jarmo

    2015-10-30

    Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy subjects is unclear. We measured brain serotonin 5-HT1A receptor in 34 healthy subjects in vivo using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635. Binding potential (BPP) was determined using the golden standard of kinetic compartmental modeling using arterial blood samples and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may be a trait-like phenomenon and partly explained by higher neuroticism in patients with affective disorders. The link between personality traits and 5-HT1A receptors should be studied in patients with major depression.

  10. Synthesis and preliminary evaluation of aminoalkanol derivatives of selected azatricycloundecane system for binding with beta-adrenergic and 5HT1A and 5HT2A receptors.

    Science.gov (United States)

    Kossakowski, Jerzy; Kuran, Bozena

    2007-01-01

    A series of aminoalkanol derivatives of 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)] undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione was prepared. The pharmacological profile of selected compounds was evaluated for affinity to beta-adrenoreceptors and serotoninergic receptors (5HT1A and 5HT2A).

  11. Compositions and methods related to serotonin 5-HT1A receptors

    Science.gov (United States)

    Mukherjee, Jogeshwar; Saigal, Neil

    2010-06-08

    Contemplated substituted arylpiperazinyl compounds, and most preferably 18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with 18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

  12. Serotonin 5HT1A receptor availability and pathological crying after stroke

    DEFF Research Database (Denmark)

    Møller, Mette; Andersen, G; Gjedde, A

    2007-01-01

    OBJECTIVES: Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (p(B)) of the 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635, which is reversible...

  13. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S;

    2010-01-01

    specific for the serotonin 2A receptor (5-HT(2A)R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT(2A)Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered...... by BDNF depletion. 5-HT(2A) ([(3)H]-MDL100907) and 5-HT(1A) ([(3)H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT(2A) receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT(1A) receptor binding...... was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT(2A) and 5-HT(1A) mRNA expression but normal 5-HT(2C) content in these brain regions in BDNF(2L/2LCk-cre) mice. We investigated whether the reduction in frontal 5-HT(2A...

  14. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S;

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairment...... by BDNF depletion. 5-HT(2A) ([(3)H]-MDL100907) and 5-HT(1A) ([(3)H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT(2A) receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT(1A) receptor binding...... was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT(2A) and 5-HT(1A) mRNA expression but normal 5-HT(2C) content in these brain regions in BDNF(2L/2LCk-cre) mice. We investigated whether the reduction in frontal 5-HT(2A...

  15. Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands.

    Science.gov (United States)

    Ofori, Edward; Zhu, Xue Y; Etukala, Jagan R; Peprah, Kwakye; Jordan, Kamanski R; Adkins, Adia A; Bricker, Barbara A; Kang, Hye J; Huang, Xi-Ping; Roth, Bryan L; Ablordeppey, Seth Y

    2016-08-15

    5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

  16. Introduction of a new complex imide system into the structure of LCAPs. The synthesis and a 5-HT1A, 5-HT2A and D2 receptor binding study.

    Science.gov (United States)

    Kossakowski, Jerzy; Raszkiewicz, Aldona; Bugno, Ryszard; Bojarski, Andrzej J

    2004-01-01

    A series of 17 long-chain arylpiperazines containing bulky, complex imide systems (5,8-dimethyl-3b,9-epoxy-(3a,4,5,6,7,8,9,9a)-octahydro-1H-benzo[e]isoindole-1,3(2H)-dione or 4,9-diphenyl-4,9-epoxy-3a,4,9,9a-tetra-hydro-1H-benzo[f]isoindole-1,3(2H)-dione) was synthesized and evaluated for their affinity for serotonin 5-HT1A, 5-HT2A and dopamine D2 receptors. Most of the new compounds showed moderate activity at 5-HT1A binding sites (Ki = 100-492 nM), and two derivatives were found to have marked affinity for the 5-HT2A receptor subtype. None of the tested compounds displayed appreciable binding to dopamine D2 receptors Structure-activity relationships were discussed in respect to an arylpiperazine fragment, whereas the comparison of different imide terminals enabled determination of the size of a hydrophobic pocket (approximately 300 A3) within the 5-HT1A receptor.

  17. Synthesis and dual D2 and 5-HT1A receptor binding affinities of 5-piperidinyl and 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones.

    Science.gov (United States)

    Ullah, Nisar

    2014-04-01

    A series of new 5-piperidinyl and 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones have been synthesized and evaluated for dual D2 and 5-HT1A receptor binding affinities. The synthesized ligands are structurally related to bifeprunox, a potential atypical antipsychotic, having potent D2 receptor antagonist and 5-HT1A receptor agonist properties. The Suzuki-Miyaura reaction of cyclic vinyl boronate with appropriate aryl halide yielded arylpiperidine, which was eventually transformed to piperidinyl-1H-benzo[d]imidazol-2(3H)-one. The reductive amination of the latter with appropriate biarylaldehdyes rendered the synthesis of 5-piperidinyl-1H-benzo[d]imidazol-2(3H)-ones. Likewise, the Buchwald-Hartwig coupling reactions of 1-boc-piperazine with appropriate aryl halide and subsequent removal of the boc group rendered arylpiperazine. The reductive amination of the latter with appropriate biarylaldehdyes accomplished the synthesis of 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones. The structure-activity relationship studies showed that cyclopentenylpyridine and cyclopentenylbenzyl groups contribute significantly to the dual D2 and 5-HT1A receptor binding affinities of these compounds.

  18. Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1.

    Science.gov (United States)

    Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R

    2014-11-01

    The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA's but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression.

  19. The 5-HT1A Receptor and the Stimulus Effects of LSD in the Rat

    Science.gov (United States)

    Reissig, C.J.; Eckler, J.R.; Rabin, R.A.; Winter, J.C.

    2005-01-01

    Rationale It has been suggested that the 5-HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD). Objectives The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD. Methods 12 Male F-344 rats were trained in a two-lever, fixed ratio10, food reinforced task with LSD (0.1 mg/kg; IP; 15 min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT1A agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT1A ligands were also tested in the presence of the selective 5-HT1A receptor antagonist, WAY-100,635 (0.3 mg/kg; SC; 30 min. pretreatment). Results In combination tests stimulus control by LSD was increased by all 5-HT1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT1A receptor was abolished by administration of WAY-100,635. Conclusions These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT1A receptor has a significant modulatory role in the stimulus effects of LSD. PMID:16025319

  20. Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

    Directory of Open Access Journals (Sweden)

    Paul R Albert

    2010-06-01

    Full Text Available Major depression is the most common form of mental illness, and is treated with antidepressant compounds that increase serotonin (5-HT neurotransmission. Increased 5-HT1A autoreceptor levels in the raphe nuclei act as a “brake” to inhibit the 5-HT system, leading to depression and resistance to antidepressants. Several 5-HT1A receptor agonists (buspirone, flesinoxan, ipsapirone that preferentially desensitize 5-HT1A autoreceptors have been tested for augmentation of antidepressant drugs with mixed results. One explanation could be the presence of the C(-1019G 5-HT1A promoter polymorphism that prevents gene repression of the 5-HT1A autoreceptor. Furthermore, down-regulation of 5-HT1A autoreceptor expression, not simply desensitization of receptor signaling, appears to be required to enhance and accelerate antidepressant action. The current review focuses on the transcriptional regulators of 5-HT1A autoreceptor expression, their roles in permitting response to 5-HT1A-targeted treatments and their potential as targets for new antidepressant compounds for treatment-resistant depression.

  1. Classification of 5-HT(1A) receptor ligands on the basis of their binding affinities by using PSO-Adaboost-SVM.

    Science.gov (United States)

    Cheng, Zhengjun; Zhang, Yuntao; Zhou, Changhong; Zhang, Wenjun; Gao, Shibo

    2009-07-29

    In the present work, the support vector machine (SVM) and Adaboost-SVM have been used to develop a classification model as a potential screening mechanism for a novel series of 5-HT(1A) selective ligands. Each compound is represented by calculated structural descriptors that encode topological features. The particle swarm optimization (PSO) and the stepwise multiple linear regression (Stepwise-MLR) methods have been used to search descriptor space and select the descriptors which are responsible for the inhibitory activity of these compounds. The model containing seven descriptors found by Adaboost-SVM, has showed better predictive capability than the other models. The total accuracy in prediction for the training and test set is 100.0% and 95.0% for PSO-Adaboost-SVM, 99.1% and 92.5% for PSO-SVM, 99.1% and 82.5% for Stepwise-MLR-Adaboost-SVM, 99.1% and 77.5% for Stepwise-MLR-SVM, respectively. The results indicate that Adaboost-SVM can be used as a useful modeling tool for QSAR studies.

  2. Classification of 5-HT1A Receptor Ligands on the Basis of Their Binding Affinities by Using PSO-Adaboost-SVM

    Directory of Open Access Journals (Sweden)

    Wenjun Zhang

    2009-07-01

    Full Text Available In the present work, the support vector machine (SVM and Adaboost-SVM have been used to develop a classification model as a potential screening mechanism for a novel series of 5-HT1A selective ligands. Each compound is represented by calculated structural descriptors that encode topological features. The particle swarm optimization (PSO and the stepwise multiple linear regression (Stepwise-MLR methods have been used to search descriptor space and select the descriptors which are responsible for the inhibitory activity of these compounds. The model containing seven descriptors found by Adaboost-SVM, has showed better predictive capability than the other models. The total accuracy in prediction for the training and test set is 100.0% and 95.0% for PSO-Adaboost-SVM, 99.1% and 92.5% for PSO-SVM, 99.1% and 82.5% for Stepwise-MLR-Adaboost-SVM, 99.1% and 77.5% for Stepwise-MLR-SVM, respectively. The results indicate that Adaboost-SVM can be used as a useful modeling tool for QSAR studies.

  3. Targeted to medication-induced dyskinesia and tardive dyskinesia: A role of 5-HT1A receptor

    Institute of Scientific and Technical Information of China (English)

    ZHEN Xue-chu

    2008-01-01

    Objective To outline the recent progress in drug discovery for medication-induced dyskinesia (Parkinson disease, PD) and tardive diskinesia (schizophrenia) with emphasizing the role of 5-HT1A receptor. Methods Development of extrapyramidal syndrome (EPS) followed either chronic L-DOPA administration in PD (L-DOPA-induced dyskinesia, LID) or antipsychotic treatment in schizophrenia (Tardive dyskinesia, TD) remains a challenge in the clinical practice and drug discovery. In addition to the abnormal dopamine activity in the nigrostrial area that contributes to the LID or TD, recent information indicates that 5-HT1A receptor also plays an important role which is merging as promising target in treatment of LID or TD. Results l-Stepholidine (l-SPD), isolated from the Chinese herb Stephania, is known as a dual dopamine receptor agent (D1 receptor agonistic and D2 antagonistic activity). In addition, we further demonstrated that l-SPD binds to 5-HT1A receptor and exhibits a partial agonistic activity. In LID rat model, l-SPD not only attenuated the development of L-DOPA-induced dyskinesia (LID), but also relived the established LID. The effect of l-SPD on LID was completely blocked by pretreatment of 5-HT1A receptor antagonist, indicating the role of 5-HT1A receptor. Furthermore, we designed and synthesis a dual dopamine/5-HT1A receptor agonist MCL-135, which also exhibits a significant relief on LID while elicits its antiparkinsonian action. Conclusions 5-HT1A receptor plys an important role in the development of LID, targeted to dual dopamine/5-HT receptor may represent a promising strategy for drug design and discovery in LID and TD treatment.

  4. [On the role of selective silencer Freud-1 in the regulation of the brain 5-HT(1A) receptor gene expression].

    Science.gov (United States)

    Naumenko, V S; Osipova, D V; Tsybko, A S

    2010-01-01

    Selective 5-HT(1A) receptor silencer (Freud-1) is known to be one of the main factors for transcriptional regulation of brain serotonin 5-HT(1A) receptor. However, there is a lack of data on implication of Freud-1 in the mechanisms underlying genetically determined and experimentally altered 5-HT(1A) receptor system state in vivo. In the present study we have found a difference in the 5-HT(1A) gene expression in the midbrain of AKR and CBA inbred mouse strains. At the same time no distinction in Freud-1 expression was observed. We have revealed 90.3% of homology between mouse and rat 5-HT(1A) receptor DRE-element, whereas there was no difference in DRE-element sequence between AKR and CBA mice. This indicates the absence of differences in Freud-1 binding site in these mouse strains. In the model of 5-HT(1A) receptor desensitization produced by chronic 5-HT(1A) receptor agonist administration, a significant reduction of 5-HT(1A) receptor gene expression together with considerable increase of Freud-1 expression were found. These data allow us to conclude that the selective silencer of 5-HT(1A) receptor, Freud-1, is involved in the compensatory mechanisms that modulate the functional state of brain serotonin system, although it is not the only factor for 5-HT(1A) receptor transcriptional regulation.

  5. Memory time-course: mRNA 5-HT1A and 5-HT7 receptors.

    Science.gov (United States)

    Perez-Garcia, Georgina; Meneses, Alfredo

    2009-08-24

    In an attempt to clarify conflicting results about serotonin (5-hydroxytryptamine, 5-HT) 5-HT(1A) and 5-HT(7) receptors in memory formation, their mRNA expression was determined by RT-PCR in key brain areas for explicit and implicit memory. The time-course (0-120 h) of autoshaped responses was progressive and mRNA 5-HT(1A) or 5-HT(7) receptors expression monotonically augmented or declined in prefrontal cortex, hippocampus and raphe nuclei, respectively. At 24-48 h acutely 8-OH-DPAT (0.062 mg/kg) administration enhanced memory and attenuated mRNA 5-HT(1A)memory; however both combinations suppressed or up-regulated mRNA expression 5-HT(1A) or 5-HT(7) receptors. In contrast, AS19 (5.0 mg/kg) facilitated memory consolidation, decreased or increased hippocampal 5-HT(7) and 5-HT(1A) receptors expression. Together these data revealed that, when both 5-HT(1A) and 5-HT(7) receptors were stimulated by 8-OHDPAT under memory consolidation, subtle changes emerged, not evident at behavioral level though detectable at genes expression. Notably, high levels of efficient memory were maintained even when serotonergic tone, via either 5-HT(1A) or 5-HT(7) receptor, was down- or up-regulated. Nevertheless, WAY100635 plus SB-269970 impaired memory consolidation and suppressed their expression. Considering that serotonergic changes are prominent in AD patients with an earlier onset of disease the present approach might be useful in the identification of functional changes associated to memory formation, memory deficits and reversing or even preventing these deficits.

  6. Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans.

    Science.gov (United States)

    Lesch, K P; Poten, B; Söhnle, K; Schulte, H M

    1990-01-01

    The selective 5-HT1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT1/2 receptor antagonist metergoline and was completely antagonized by the nonselective beta-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT1A receptor. The selective beta 1-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs.

  7. The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain.

    Science.gov (United States)

    Aznar, Susana; Qian, Zhaoxia; Shah, Reshma; Rahbek, Birgitte; Knudsen, Gitte M

    2003-01-03

    The 5-HT(1A) receptor is a well-characterized serotonin receptor playing a role in many central nervous functions and known to be involved in depression and other mental disorders. In situ hybridization, immunocytochemical, and binding studies have shown that the 5-HT(1A) receptor is widely distributed in the rat brain, with a particularly high density in the limbic system. The receptor's localization in the different neuronal subtypes, which may be of importance for understanding its role in neuronal circuitries, is, however, unknown. In this study we show by immunocytochemical double-labeling techniques, that the 5-HT(1A) receptor is present on both pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define two different subtypes of interneurons. Moreover, semiquantitative analysis showed that the receptor's distribution in the different neuronal types varies between brain areas. In cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both principal cells and calbindin- and parvalbumin-containing neurons. In septum and thalamus, the receptor was mostly present on calbindin- and parvalbumin-containing cells. Especially in the medial septum and thalamic reticular nucleus, the receptor highly colocalized with parvalbumin-positive neurons. These results suggest a diverse function of the 5-HT(1A) receptor in modulating neuronal circuitry in different brain areas, that may depend on the type of neuron the receptor is predominantly located on.

  8. Verbal memory and 5-HT1A receptors in healthy volunteers--A PET study with [carbonyl-(11)C]WAY-100635.

    Science.gov (United States)

    Penttilä, Jani; Hirvonen, Jussi; Tuominen, Lauri; Lumme, Ville; Ilonen, Tuula; Någren, Kjell; Hietala, Jarmo

    2016-03-01

    The serotonin 5-HT1A receptor is a putative drug development target in disorders with cognitive and in particular memory deficits. However, previous human positron emission tomography (PET) studies on 5-HT1A receptor binding and memory functions have yielded discrepant results. We explored the association between verbal memory and 5-HT1A receptor binding in 24 healthy subjects (14 male, 10 female, aged 18-41 years). The cognitive tests included the Wechsler Memory Scale-Revised (WMS-R), Wechsler Adult Intelligence Scale-Revised (WAIS-R) and Wisconsin Card Sorting Test (WCST). 5-HT1A receptor binding was measured with PET and the radioligand [carbonyl-(11)C]WAY-100635, which was quantified with the gold standard method based on kinetic modeling using arterial blood samples. We found that global 5-HT1A receptor binding was positively correlated with measures of verbal memory, such that subjects who had higher receptor binding tended to have better verbal memory than subjects who had lower receptor binding. Regional analyses suggested significant correlations in multiple neocortical brain regions and the raphe nuclei. We did not find significant correlations between 5-HT1A receptor binding and executive functions as measured with WCST. We conclude that neocortical as well as raphe 5-HT1A receptors are involved in verbal memory function in man.

  9. 5-HT1A and 5-HT7 receptors contribute to lurasidone-induced dopamine efflux.

    Science.gov (United States)

    Huang, Mei; Horiguchi, Masakuni; Felix, Anna R; Meltzer, Herbert Y

    2012-05-09

    Lurasidone is a novel, atypical antipsychotic drug with serotonin [5-hydroxytryptamine (5-HT)]2A, 5-HT7, dopamine (DA) D2 antagonist, and 5-HT1A receptor partial agonist properties. The ability of lurasidone to reverse the effects of subchronic administration phencyclidine, to impair novel object recognition in rats, an animal model of cognitive impairment in schizophrenia, is dependent, in part, on its 5-HT1A agonist and 5-HT7 receptor antagonist properties. We tested whether 5-HT1A partial agonism or 5-HT7 antagonism, or both, contributed to the ability of lurasidone to enhance cortical and hippocampal DA efflux, which may be related to its ability to improve cognition. Here, we report that lurasidone, 0.25 and 0.5, but not 0.1 mg/kg, subcutaneously, significantly increased DA efflux in the prefrontal cortex and hippocampus in a dose-dependent manner. Lurasidone, 0.5 mg/kg, also produced a smaller increase in DA efflux in the nucleus accumbens. Pretreatment with the 5-HT1A receptor antagonist, WAY100635 (0.2 mg/kg, subcutaneously), partially blocked the lurasidone-induced cortical and hippocampal DA efflux. Further, subeffective doses of the 5-HT1A receptor agonist, tandospirone (0.2 mg/kg), or the 5-HT7 antagonist, SB269970 (0.3 mg/kg), potentiated the ability of a subeffective dose of lurasidone (0.1 mg/kg) to increase DA efflux in the prefrontal cortex. These findings suggest that the effects of lurasidone on the prefrontal cortex and hippocampus, DA efflux are dependent, at least partially, on its 5-HT1A agonist and 5-HT7 antagonist properties and may contribute to its efficacy to reverse the effects of subchronic phencyclidine treatment and improve schizophrenia.

  10. [5-HT1A/5-HT7 receptor interplay: Chronic activation of 5-HT7 receptors decreases the functional activity of 5-HT1A receptor and its сontent in the mouse brain].

    Science.gov (United States)

    Kondaurova, E M; Bazovkina, D V; Naumenko, V S

    2017-01-01

    Serotonin receptors 5-HT1A and 5-HT7 are involved in the development of various psychopathologies. Some data indicate that there is an interplay between 5-HT1A 5-HT7 receptors that could be implicated in the regulation of their function. This work analyzed the effects of chronic 5-HT7 activation on the functional activity of 5-HT7 and 5-HT1A receptors, on the corresponding protein levels, and on the expression of genes encoding 5-HT7 and 5-HT1A receptors in the mouse brain. Chronic administration of the 5-HT7 selective agonist LP44 (20.5 nmol, i.c.v., 14 days) produced considerable desensitization of both 5-HT7 and 5-HT1A receptors. In LP44-treated mice, the hypothermic responses mediated by both 5-HT7 and 5-HT1A receptors were attenuated. Moreover, the levels of 5-HT1A receptor protein in the midbrain and the frontal cortex of LP44-treated mice were significantly decreased. However, the brain levels of 5-HT7 receptor protein did not differ between LP44-treated and control mice. Chronic LP44 treatment did not alter the expression of the 5-HT7 and 5-HT1A receptor genes in all investigated brain structure. These data suggest that 5-HT7 receptors participate in the posttranscriptional regulation of the 5-HT1A receptors functioning.

  11. 5-HT1A receptors modulate small-conductance Ca2+-activated K+ channels

    DEFF Research Database (Denmark)

    Grunnet, Morten; Jespersen, Thomas; Perrier, Jean-François

    2004-01-01

    Small-conductance calcium-activated potassium channels (SK) are responsible for the medium afterhyperpolarisation (mAHP) following action potentials in neurons. Here we tested the ability of serotonin (5-HT) to modulate the activity of SK channels by coexpressing 5-HT1A receptors with different...

  12. N-Oxide analogs of WAY-100635 : new high affinity 5-HT (1A) receptor antagonists

    NARCIS (Netherlands)

    Oberwinkler - Marchais, Sandrine; Nowicki, B; Pike, VW; Halldin, C; Sandell, J; Chou, YH; Gulyas, B; Brennum, LT; Farde, L; Wikstrom, H V

    2005-01-01

    WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective radiol

  13. N-Oxide analogs of WAY-100635 : new high affinity 5-HT1A receptor antagonists

    NARCIS (Netherlands)

    Marchais-Oberwinkler, S; Nowicki, B; Pike, VW; Halldin, C; Sandell, J; Chou, YH; Gulyas, B; Brennum, LT; Farde, L; Wikstrom, HV

    2005-01-01

    WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective radiol

  14. Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.

    NARCIS (Netherlands)

    Pattij, T.; Groenink, L.; Hijzen, T.H.; Oosting, R.S.; Maes, R.A.A.; Gugten, J. van der; Olivier, B.

    2002-01-01

    5-HT(1A) receptor knockout (KO) mice have been described as more anxious in various anxiety paradigms. Because anxiety is often associated with autonomic changes like elevated body temperature and tachycardia, radiotelemetry was used to study these parameters in wild type (WT) and KO mice in stress-

  15. Classification of 5-HT1A receptor agonists and antagonists using GA-SVM method

    Institute of Scientific and Technical Information of China (English)

    Xue-lian ZHU; Hai-yan CAI; Zhi-jian XU; Yong WANG; He-yao WANG; Ao ZHANG; Wei-liang ZHU

    2011-01-01

    Aim:To construct a reliable computational model for the classification of agonists and antagonists of 5-HT1A receptor.Methods:Support vector machine (SVM),a well-known machine learning method,was employed to build a prediction model,and genetic algorithm (GA) was used to select the most relevant descriptors and to optimize two important parameters,C and r of the SVM model.The overall dataset used in this study comprised 284 ligands of the 5-HT1A receptor with diverse structures reported in the literatures.Results:A SVM model was successfully developed that could be used to predict the probability of a ligand being an agonist or antagonist of the 5-HT1A receptor.The predictive accuracy for training and test sets was 0.942 and 0.865,respectively.For compounds with probability estimate higher than 0.7,the predictive accuracy of the model for training and test sets was 0.954 and 0.927,respectively.To further validate our model,the receiver operating characteristic (ROC) curve was plotted,and the Area-Under-the-ROC-Curve (AUC) value was calculated to be 0.883 for training set and 0.906 for test set.Conclusion:A reliable SVM model was successfully developed that could effectively distinguish agonists and antagonists among the ligands of the 5-HT1A receptor.To our knowledge,this is the first effort for the classification of 5-HT1A receptor agonists and antagonists based on a diverse dataset.This method may be used to classify the ligands of other members of the GPCR family.

  16. Systematic Screening of the Serotonin Receptor 1A (5-HT1A) Gene in Chronic Tinnitus

    Institute of Scientific and Technical Information of China (English)

    Kleinjung T; Langguth B; Fischer B; Hajak G; Eichhammer P; Sand PG

    2006-01-01

    Objective Chronic tinnitus is a highly prevalent condition and has been hypothesized to result from an innate disturbance in central nervous serotonergic transmission. Given the frequent comorbidity with major depression and anxiety, we argue that candidate genes for these disorders are likely to overlap. The present study addresses the gene encoding for the 5-HT1A receptor as a putative risk factor for tinnitus. Methods In 88 subjects with a diagnosis of chronic subjective tinnitus who underwent a detailed neurootological examination, the entire 5-HT1A gene was amplified using overlapping PCR products. Amplicons were custom sequenced bidirectionally and were screened for variants in multiple alignments against the human genome reference. Results We identified a synonymous C > T exchange at residue 184 (Pro) in 7/88 subjects, but detected no missense variants in the population under study. Specifically, the following residues were fully conserved: 16 (Pro), 22 (Gly), 28 (Ile), 98 (Val), 220(Arg), 267 (Val), 273 (Gly), and 418 (Asn). Discussion The present data count against the causation of chronic tinnitus by a change in the 5-HT1A receptor's amino acid sequence. However, the allele frequency for the 184Pro minor allele (0.04) reached twice the frequency reported in control cohorts from the same ethnicity.Additional investigations are invited to clarify the role of the 5-HT1A polymorphism in larger samples, and to control for comorbid affective disorders.

  17. Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders.

    Science.gov (United States)

    Naumenko, Vladimir S; Popova, Nina K; Lacivita, Enza; Leopoldo, Marcello; Ponimaskin, Evgeni G

    2014-07-01

    Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. Besides the important role of 5-HT receptors in the pathogenesis of depressive disorders and in their clinical medications, underlying mechanisms are far from being completely understood. This review focuses on possible cross talk between two serotonin receptors, 5-HT1A and the 5-HT7 . Although these receptors are highly co-expressed in brain regions implicated in depression, and most agonists developed for the 5-HT1A or 5-HT7 receptors have cross-reactivity, their functional interaction has not been yet established. It has been recently shown that 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo. From the functional point of view, heterodimerization has been shown to play an important role in regulation of receptor-mediated signaling and internalization, suggesting the implication of heterodimerization in the development and maintenance of depression. Interaction between these receptors is also of clinical interest, because both receptors represent an important pharmacological target for the treatment of depression and anxiety.

  18. 5-HT1A receptors modulate the consolidation of learning in normal and cognitively impaired rats.

    Science.gov (United States)

    Meneses, A; Hong, E

    1999-03-01

    Attempts were made to further analyze the role of 5-HT1A receptors in consolidation of learning by evaluating the role of these receptors in cognitively normal and impaired animals. The effects of post-training administration of 8-OH-DPAT and 5-HT1A receptor antagonists, WAY 100135, WAY 100635, and S-UH-301, plus the cholinergic and glutamatergic antagonists, scopolamine and dizolcipine, respectively, were determined using an autoshaping learning task. The results showed that 8-OH-DPAT increased the number of conditioned responses, whereas WAY100135, WAY100635, and S-UH-301, and the 5-HT depleter, p-chloroamphetamine (PCA), had no effect. PCA did not change the silent properties of the 5-HT1A receptor antagonists. PCA, WAY100635, and S-UH-301, but not GR127935 (a 5-HT1B/1D-receptor antagonist) or MDL100907 (a 5-HT2A receptor antagonist), reversed the effect to 8-OH-DPAT. Ketanserin (a 5-HT2A/2C receptor antagonist) and ondansetron (a 5-HT3 receptor antagonist), at a dose that increased the conditioned responses by itself, reversed the effect of 8-OH-DPAT. Moreover, 8-OH-DPAT or S-UH-301 reversed the learning deficit induced by scopolamine and dizocilpine whereas WAY100635 reversed the effect of scopolamine only. These data confirm a role for presynaptic 5-HT1A receptors during the consolidation of learning and support the hypothesis that serotonergic, cholinergic, and glutamatergic systems interact in cognitively impaired animals.

  19. Synthesis and in vitro binding studies of piperazine-alkyl-naphthamides: impact of homology and sulphonamide/carboxamide bioisosteric replacement on the affinity for 5-HT1A, alpha2A, D4.2, D3 and D2L receptors.

    Science.gov (United States)

    Résimont, Mélissa; Liégeois, Jean-François

    2010-09-01

    A series of carboxamide and sulphonamide alkyl(ethyl to hexyl)piperazine analogues were prepared and tested for their affinity to bind to a range of receptors potentially involved in psychiatric disorders. These chemical modifications led us to explore the impact of homology and bioisosteric replacement of the amide group. All of these compounds possessed a high affinity for 5-HT(1A) receptors, irrespective of the size of the linker, the carboxamide derivative with a pentyl linker had the highest affinity for alpha(2A) receptor sites and also a high affinity for 5-HT(1A) and D3 receptors. The sulphonamide analogue with a hexyl linker possessed a high affinity for 5-HT(1A), D4.2 and D3 receptors.

  20. Effects of 5-HT1A receptor agonists and L-5-HTP in Montgomery's conflict test.

    Science.gov (United States)

    Söderpalm, B; Hjorth, S; Engel, J A

    1989-01-01

    The effects of the pyrimidinyl-piperazines buspirone, gepirone, ipsapirone and their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP) as well as of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and L-5-hydroxytryptophan (L-5-HTP) were investigated in Montgomery's conflict test--an animal anxiety model based on the animal's inborn urge to explore a new environment and its simultaneous fear of elevated, open spaces. Subcutaneous buspirone (32-128 nmol/kg), gepirone (32-128 nmol/kg), ipsapirone (32-512 nmol/kg) and 8-OH-DPAT (50-200 nmol/kg), as well as intraperitoneal L-5-HTP (56 mumol/kg) produced anxiolytic-like effects. However, at higher doses the magnitude of these effects decreased and overall the dose-response curves displayed inverted U-shapes. The highest doses (2048 nmol/kg) of buspirone and of gepirone even decreased responding below control levels, possibly in part due to concomitant sedation/motor impairment. After L-5-HTP (448 mumol/kg) and PmP (512 nmol/kg) anxiogenic-like effects were observed. The results indicate that anxiolytic- and anxiogenic-like effects of drugs affecting central serotonergic neurotransmission can be obtained in a sensitive rat anxiety model which neither involves consummatory behavior nor punishment. The anxiolytic-like effects of these compounds may be due to their 5-HT1A agonistic properties. Moreover, the present data may provide support for a possible reciprocal association of presynaptic 5-HT1A receptors vs. postsynaptic 5-HT1A as well as 5-HT2 receptors with regard to anxiety.

  1. Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens.

    Science.gov (United States)

    Clotfelter, Ethan D; O'Hare, Erin P; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2007-01-01

    The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT and with the 5-HT1A receptor agonist 8-OH-DPAT both decreased aggressive behavior; however, treatment with the 5-HT1A receptor antagonist WAY-100635 did not increase aggression. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine caused no significant changes in aggressive behavior and a significant decline in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Treatment with the serotonin synthesis inhibitor p-chlorophenylalanine resulted in no change in aggression, yet serotonergic activity decreased significantly. Finally, a diet supplemented with L-tryptophan (Trp), the precursor to 5-HT, showed no consistent effects on aggressive behavior or brain monoamine concentrations. These results suggest a complex role for serotonin in the expression of aggression in teleost fishes, and that B. splendens may be a useful model organism in pharmacological and toxicological studies.

  2. CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors

    Science.gov (United States)

    Zhang, Jing; Cai, Cheng-Yun; Wu, Hai-Yin; Zhu, Li-Juan; Luo, Chun-Xia; Zhu, Dong-Ya

    2016-01-01

    Serotonin 1a-receptor (5-HT1aR) has been specifically implicated in the pathogenesis of anxiety. However, the mechanism underlying the role of 5-HT1aR in anxiety remains poorly understood. Here we show in mice that the transcription factor cAMP response element binding protein (CREB) in the hippocampus functions as an effector of 5-HT1aR in modulating anxiety-related behaviors. We generated recombinant lentivirus LV-CREB133-GFP expressing a dominant negative CREB which could not be phosphorylated at Ser133 to specifically reduce CREB activity, and LV-VP16-CREB-GFP expressing a constitutively active fusion protein VP16-CREB which could be phosphorylated by itself to specifically enhance CREB activity. LV-CREB133-GFP neutralized 5-HT1aR agonist-induced up-regulation of synapse density, spine density, dendrite complexity, neurogenesis, and the expression of synapsin and spinophilin, two well-characterized synaptic proteins, and abolished the anxiolytic effect of 5-HT1aR agonist; whereas LV-VP16-CREB-GFP rescued the 5-HT1aR antagonist-induced down-regulation of synapse density, spine density, dendrite complexity, neurogenesis and synapsin and spinophilin expression, and reversed the anxiogenic effect of 5-HT1aR antagonist. The deletion of neurogenesis by irradiation or the diminution of synaptogenesis by knockdown of synapsin expression abolished the anxiolytic effects of both CREB and 5-HT1aR activation. These findings suggest that CREB-mediated hippoacampus structural plasticity is crucial for the role of 5-HT1aR in modulating anxiety-related behaviors. PMID:27404655

  3. Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder.

    Science.gov (United States)

    Szewczyk, Bernadeta; Albert, Paul R; Burns, Ariel M; Czesak, Margaret; Overholser, James C; Jurjus, George J; Meltzer, Herbert Y; Konick, Lisa C; Dieter, Lesa; Herbst, Nicole; May, Warren; Rajkowska, Grazyna; Stockmeier, Craig A; Austin, Mark C

    2009-03-01

    A variety of studies have documented alterations in 5-HT1A receptor binding sites in the brain of subjects with major depressive disorder (MDD). The recently identified transcription factor, nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) has been shown to function as a transcriptional modulator of the human 5-HT1A receptor gene. The present study was undertaken to document the regional and cellular localization of NUDR in the human prefrontal cortex and to examine the levels of NUDR and 5-HT1A receptor protein in prefrontal cortex of female and male depressed and control subjects. NUDR immunoreactivity was present in neurons and glia across cortical layers and was co-localized with 5-HT1A receptor immunoreactive neurons. NUDR immunoreactivity as measured by Western blot was significantly decreased in the prefrontal cortex of female depressed subjects (42%, p=0.02) and unchanged in male depressed subjects relative to gender-matched control subjects. Similarly, 5-HT1A receptor protein level was significantly reduced in the prefrontal cortex of female depressed subjects (46%, p=0.03) and unchanged in male depressed subjects compared to gender-matched control subjects. Reduced protein expression of NUDR in the prefrontal cortex of female subjects with MDD may reflect a functional alteration in this transcription factor, which may contribute to the decrease in 5-HT1A receptors observed in the same female subjects with MDD. In addition, the gender-specific alterations in cortical NUDR and 5-HT1A receptor proteins could represent an underlying biological mechanism associated with the higher incidence of depression in women.

  4. Alterations of 5-HT1A receptor-induced G-protein functional activation and relationship to memory deficits in patients with pharmacoresistant temporal lobe epilepsy.

    Science.gov (United States)

    Cuellar-Herrera, Manola; Velasco, Ana Luisa; Velasco, Francisco; Trejo, David; Alonso-Vanegas, Mario; Nuche-Bricaire, Avril; Vázquez-Barrón, Daruni; Guevara-Guzmán, Rosalinda; Rocha, Luisa

    2014-12-01

    The 5-hydroxytryptamine-1A (5-HT1A) receptors are known to be involved in the inhibition of seizures in epilepsy. Moreover, studies propose a role for the 5-HT1A receptor in memory function; it is believed that the higher density of this receptor in the hippocampus plays an important role in its regulation. Positron emission tomography (PET) studies in patients with mesial temporal lobe epilepsy (mTLE) have demonstrated that a decrease in 5-HT1A receptor binding in temporal regions may play a role in memory impairment. The evidences lead us to speculate whether this decrease in receptor binding is associated with a reduced receptor number or if the functionality of the 5-HT1A receptor-induced G-protein activation and/or the second messenger cascade is modified. The purpose of the present study is to determine 5-HT1A receptor-induced G-protein functional activation by 8-OH-DPAT-stimulated [(35)S]GTPγS binding assay in hippocampal tissue of surgical patients with mTLE. We correlate functional activity with epilepsy history and neuropsychological assessment of memory. We found that maximum functional activation stimulation values (Emax) of [(35)S]GTPγS binding were significantly increased in mTLE group when compared to autopsy samples. Furthermore, significant correlations were found: (1) positive coefficients between the Emax with the age of patient and frequency of seizures; (2) negative coefficients between the Emax and working memory, immediate recall and delayed recall memory tasks. Our data suggest that the epileptic hippocampus of patients with mTLE presents an increase in 5-HT1A receptor-induced G-protein functional activation, and that this altered activity is related to age and seizure frequency, as well as to memory consolidation deficit.

  5. GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background.

    NARCIS (Netherlands)

    Pattij, T.; Groenink, L.; Oosting, R.S.; Gugten, J. van der; Maes, R.A.A.; Olivier, B.

    2002-01-01

    Previous studies in 5-HT(1A) receptor knockout (1AKO) mice on a mixed Swiss Websterx129/Sv (SWx129/Sv) and a pure 129/Sv genetic background suggest a differential gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor complex sensitivity in both strains, independent from the anxious phenotype. To

  6. What do we really know about 5-HT1A receptor signaling in neuronal cells?

    Directory of Open Access Journals (Sweden)

    JENNY LUCY FIEDLER

    2016-11-01

    Full Text Available Serotonin (5-HT is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of serotonin receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT1A receptor (5-HT1AR, specially contrasting with those findings obtained in neuronal cells. The 5-HT1AR is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT1AR differs from other serotonin receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by Gα isoforms and some cascades involve βγ signaling. The activity of 5-HT1AR usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca2+, levels which may be linked to specific types of behavior and cognition. Furthermore, evidence indicates that 5-HT1AR induces neuritogesis and synapse formation, probably by modulation of the neuronal cytoskeleton through MAPK and PI3K-Akt signaling pathways. Advances in understanding the actions of 5-HT1AR and its association with different signaling pathways in the central nervous system will reveal their pivotal role in health and disease.

  7. What Do We Really Know About 5-HT1A Receptor Signaling in Neuronal Cells?

    Science.gov (United States)

    Rojas, Paulina S.; Fiedler, Jenny L.

    2016-01-01

    Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of 5-HT receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT1A receptor (5-HT1AR), specially contrasting with those findings obtained in neuronal cells. The 5-HT1AR is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT1AR differs from other 5-HT receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by Gα isoforms and some cascades involve βγ signaling. The activity of 5-HT1AR usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca2+, levels which may be linked to specific types of behavior and cognition. Furthermore, evidence indicates that 5-HT1AR induces neuritogesis and synapse formation, probably by modulation of the neuronal cytoskeleton through MAPK and phosphoinositide-3-kinase (PI3K)-Akt signaling pathways. Advances in understanding the actions of 5-HT1AR and its association with different signaling pathways in the central nervous system will reveal their pivotal role in health and disease. PMID:27932955

  8. Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

    Science.gov (United States)

    Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa

    2013-11-29

    Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

  9. 5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission.

    Science.gov (United States)

    Costa, L; Trovato, C; Musumeci, S A; Catania, M V; Ciranna, L

    2012-04-01

    We have studied the effects of 5-HT(1A) and 5-HT(7) serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT(1A)/5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT(1A) and 5-HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the

  10. The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats.

    Science.gov (United States)

    Horiguchi, M; Meltzer, H Y

    2012-05-01

    Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin (5-HT)(1A) agonists, and tandospirone, a 5-HT(1A) partial agonist, have been reported to improve cognition in schizophrenia. We tested the effect of 5-HT(1A) agonism, alone, and in combination with other psychotropic agents, including the atypical APD, lurasidone, in reversing the deficit in novel object recognition (NOR) induced by subchronic treatment with the non-competitive NMDA receptor antagonist, phencyclidine (PCP) (2 mg/kg, b.i.d., for 7 days). Subchronic treatment with PCP induced a persistent NOR deficit. Lurasidone (0.1 mg/kg), a potent 5-HT(1A) partial agonist, 5-HT(2A) antagonist, and weaker D(2) antagonist, tandospirone (0.6 mg/kg), and the selective post-synaptic 5-HT(1A) agonist, F15599 (0.16 mg/kg), ameliorated the subchronic PCP-induced-NOR deficit. The 5-HT(1A) antagonist, WAY100635 (0.6 mg/kg), blocked the ameliorating effects of tandospirone and lurasidone. The combination of sub-effective doses of tandospirone (0.2 mg/kg) and lurasidone (0.03 mg/kg) also reversed the PCP-induced NOR-deficit. Buspirone, a less potent partial 5-HT(1A) agonist than tandospirone, was less effective. Co-administration of tandospirone (0.2 mg/kg) and pimavanserin (3 mg/kg), a relatively selective 5-HT(2A) receptor inverse agonist, did not reverse the effect of sub-chronic PCP on NOR. The D(2) antagonist, haloperidol, blocked the ameliorating effect of tandospirone on the PCP-induced deficit in NOR. These results indicate that 5-HT(1A) agonism is adequate to ameliorate the PCP-induced impairment in NOR and suggest further study of utilizing the combination of a 5-HT(1A) agonist and an atypical APD to ameliorate some types of cognitive impairment in schizophrenia.

  11. Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors.

    Science.gov (United States)

    Morrison, Kathleen E; Swallows, Cody L; Cooper, Matthew A

    2011-08-01

    Past experience can alter how individuals respond to stressful events. The brain serotonin system is a key factor modulating stress-related behavior and may contribute to individual variation in coping styles. In this study we investigated whether dominant and subordinate hamsters respond differently to social defeat and whether their behavioral responses are associated with changes in 5-HT1A and 5-HT2A receptor immunoreactivity in several limbic brain regions. We paired weight-matched hamsters in daily aggressive encounters for two weeks so that they formed a stable dominance relationship. We also included controls that were exposed to an empty cage each day for two weeks. Twenty-four hours after the final pairing or empty cage exposure, subjects were socially defeated in 3, 5-min encounters with a more aggressive hamster. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains following conditioned defeat testing and performed immunohistochemistry for 5-HT1A and 5-HT2A receptors. We found that dominants showed less submissive and defensive behavior at conditioned defeat testing compared to both subordinates and controls. Additionally, both dominants and subordinates had an increased number of 5-HT1A immunopositive cells in the basolateral amygdala compared to controls. Subordinates also had more 5-HT1A immunopositive cells in the dorsal medial amygdala than did controls. Finally, dominants had fewer 5-HT1A immunopositive cells in the paraventricular nucleus of the hypothalamus compared to controls. Our results indicate that dominant social status results in a blunted conditioned defeat response and a distinct pattern of 5-HT1A receptor expression, which may contribute to resistance to conditioned defeat.

  12. Rethinking 5-HT1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior.

    Science.gov (United States)

    Altieri, Stefanie C; Garcia-Garcia, Alvaro L; Leonardo, E David; Andrews, Anne M

    2013-01-16

    The complexities of the involvement of the serotonin transmitter system in numerous biological processes and psychiatric disorders is, to a substantial degree, attributable to the large number of serotonin receptor families and subtypes that have been identified and characterized for over four decades. Of these, the 5-HT(1A) receptor subtype, which was the first to be cloned and characterized, has received considerable attention based on its purported role in the etiology and treatment of mood and anxiety disorders. 5-HT(1A) receptors function both at presynaptic (autoreceptor) and postsynaptic (heteroreceptor) sites. Recent research has implicated distinct roles for these two populations of receptors in mediating emotion-related behavior. New concepts as to how 5-HT(1A) receptors function to control serotonergic tone throughout life were highlights of the proceedings of the 2012 Serotonin Club Meeting in Montpellier, France. Here, we review recent findings and current perspectives on functional aspects of 5-HT(1A) auto- and heteroreceptors with particular regard to their involvement in altered anxiety and mood states.

  13. Synthesis of Conformationally Constrained Aryl- or Heteroarylpiperazinyl Derivatives of Selected Imides as 5-HT1A Receptor Ligands

    Directory of Open Access Journals (Sweden)

    Bożena Kuran

    2006-08-01

    Full Text Available The preparation of a number of cyclic imide 5-HT1A receptor ligandderivatives has been described. Their structures were conformationally constrained byintroducing rigid linkers containing unsaturated bonds or aromatic benzene rings. Thesecompounds are expected to possess anxiolytic and antidepressant activity.

  14. Synthesis of conformationally constrained aryl- or heteroarylpiperazinyl derivatives of selected imides as 5-HT1A receptor ligands.

    Science.gov (United States)

    Kossakowski, Jerzy; Krawiecka, Mariola; Kuran, Bozena

    2006-08-23

    The preparation of a number of cyclic imide 5-HT(1A) receptor ligand derivatives has been described. Their structures were conformationally constrained by introducing rigid linkers containing unsaturated bonds or aromatic benzene rings. These compounds are expected to possess anxiolytic and antidepressant activity.

  15. Potential anxiolytic properties of R-(+)-8-OSO2CF3-PAT, a 5-HT1A receptor agonist

    NARCIS (Netherlands)

    Barf, T; Korte, SM; KorteBouws, G; Sonesson, C; Damsma, G; Bohus, B; Wikstrom, H

    1996-01-01

    The anxiolytic property of R-(+)-8-OSO3CF3-PAT (R-(+)-8-[[(trifluoromethyl)sulfonyl]oxy]-2-(n-propyl-amino)tetralin), a 5-HT1A receptor agonist, was evaluated in Wistar rats by means of animal models of anxiety, the conditioned defensive burying model and the conditioned stress-induced freezing resp

  16. Adrenaline release by the 5-HT1A receptor agonist 8-OH-DPAT is partly responsible for pituitary activation

    NARCIS (Netherlands)

    Korte, S.M; Buwalda, B; Bohus, B.G J; de Kloet, E.R

    1996-01-01

    In male Wistar rats the effect of adrenalectomy on pituitary activation by the 5-HT1A receptor agonist. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), was studied. Rats were injected intravenously with 8-OH-DPAT (0.10 mg/kg) in their home cages. Blood samples were withdrawn from freely moving c

  17. Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: Involvement of 5-HT1A receptors.

    Science.gov (United States)

    Kumar, Jigna Rajesh; Rajkumar, Ramamoorthy; Lee, Liying Corinne; Dawe, Gavin S

    2016-11-01

    The nucleus incertus (NI), a brainstem structure with diverse anatomical connections, is implicated in anxiety, arousal, hippocampal theta modulation, and stress responses. It expresses a variety of neurotransmitters, neuropeptides and receptors such as 5-HT1A, D2 and CRF1 receptors. We hypothesized that the NI may play a role in the neuropharmacology of buspirone, a clinical anxiolytic which is a 5-HT1A receptor partial agonist and a D2 receptor antagonist. Several preclinical studies have reported a biphasic anxiety-modulating effect of buspirone but the precise mechanism and structures underlying this effect are not well-understood. The present study implicates the NI in the anxiogenic effects of a high dose of buspirone. Systemic buspirone (3 mg/kg) induced anxiogenic effects in elevated plus maze, light-dark box and open field exploration paradigms in rats and strongly activated the NI, as reflected by c-Fos expression. This anxiogenic effect was reproduced by direct infusion of buspirone (5 μg) into the NI, but was abolished in NI-CRF-saporin-lesioned rats, indicating that the NI is present in neural circuits driving anxiogenic behaviour. Pharmacological studies with NAD 299, a selective 5-HT1A antagonist, or quinpirole, a D2/D3 agonist, were conducted to examine the receptor system in the NI involved in this anxiogenic effect. Opposing the 5-HT1A agonism but not the D2 antagonism of buspirone in the NI attenuated the anxiogenic effects of systemic buspirone. In conclusion, 5-HT1A receptors in the NI contribute to the anxiogenic effect of an acute high dose of buspirone in rats and may be functionally relevant to physiological anxiety.

  18. Drug evaluation: PRX-00023, a selective 5-HT1A receptor agonist for depression.

    Science.gov (United States)

    de Paulis, Tomas

    2007-01-01

    EPIX Pharmaceuticals Inc (formerly Predix Pharmaceuticals Inc) is developing PRX-00023, an oral aryl piperazine 5-HT1A agonist, for the potential treatment of depression. While initially in development for generalized anxiety disorder, EPIX is now only focusing on the development of PRX-00023 for depression. In November 2006, EPIX reported that it planned to initiate a phase II trial in patients with depression in the first half of 2007.

  19. Distribution and localization of 5-HT(1A) receptors in the rat lumbar spinal cord after transection and deafferentation.

    Science.gov (United States)

    Otoshi, Chad K; Walwyn, Wendy M; Tillakaratne, Niranjala J K; Zhong, Hui; Roy, Roland R; Edgerton, V Reggie

    2009-04-01

    The serotonergic system is highly plastic, capable of adapting to changing afferent information in diverse mammalian systems. We hypothesized that removing supraspinal and/or peripheral input would play an important role in defining the distribution of one of the most prevalent serotonergic receptors, the 5-HT(1A) receptor (R), in the spinal cord. We investigated the distribution of this receptor in response to a complete thoracic (T7-T8) spinal cord transection (eliminating supraspinal input), or to spinal cord isolation (eliminating both supraspinal and peripheral input) in adult rats. Using two antibodies raised against either the second extracellular region (ECL(2)) or the third intracellular region (ICL(3)) of the 5-HT(1A)R, we compared the 5-HT(1A)R levels and distributions in specific laminae of the L3-L5 segments among the control, spinal cord-transected, and spinal cord-isolated groups. Each antibody labeled different populations of 5-HT(1A)R: ECL(2) labeled receptors in the axon hillock, whereas ICL(3) labeled receptors predominantly throughout the soma and proximal dendrites. Spinal cord transection increased the number of ECL(2)-positive cells in the medial region of laminae III-IV and lamina VII, and the mean length of the labeled axon hillocks in lamina IX. The number of ICL(3)-labeled cells was higher in lamina VII and in both the medial and lateral regions of lamina IX in the spinal cord-transected compared to the control group. In contrast, the length and number of ECL(2)-immunolabeled processes and ICL(3)-immunolabeled cells were similar in the spinal cord-isolated and control groups. Combined, these data demonstrate that the upregulation in 5-HT(1A)R that occurs with spinal cord transection alone is dependent on the presence of sensory input.

  20. 5-HT1A receptor activation reduces fear-related behavior following social defeat in Syrian hamsters.

    Science.gov (United States)

    Bader, Lauren R; Carboni, Joseph D; Burleson, Cody A; Cooper, Matthew A

    2014-07-01

    Social defeat leads to selective avoidance of familiar opponents as well as general avoidance of novel, non-threatening intruders. Avoidance of familiar opponents represents a fear-related memory whereas generalized social avoidance indicates anxiety-like behavior. We have previously shown that serotonin signaling alters responses to social defeat in Syrian hamsters, although it is unclear whether serotonin modulates defeat-induced fear, anxiety, or both. In this study we focus on 5-HT1A receptors, in part, because their activation had been linked to the acquisition of conditioned fear. We hypothesized that pharmacological activation of 5-HT1A receptors prior to social defeat would reduce avoidance of familiar opponents and impair Arc expression in the basolateral amygdala (BLA), but not alter anxiety-like behavior. We administered 8-OH-DPAT, a 5-HT1A receptor agonist, prior to 3, 5-minute social defeats and 24h later exposed hamsters to a social interaction test to measure the conditioned defeat response immediately followed by either a Y-maze test or an open field test. In a separate experiment, we administered 8-OH-DPAT prior to 3, 5-minute social defeats and later removed the brains for Arc immunohistochemistry. Social defeat increased the number of Arc immunopositive cells in the central amygdala (CeA), prelimbic cortex (PL), and BLA, and 8-OH-DPAT treatment reduced Arc immunoreactivity in the PL. These results suggest that 5-HT1A receptor activation impairs the fear memory associated with social defeat, but does not alter defeat-induced anxiety. Overall, 5-HT1A receptor activation may impair Arc expression in select brain regions such as the PL and thereby disrupt the development of a fear memory essential for the conditioned defeat response.

  1. 5-HT1A/7 receptor agonist excites cardiac vagal neurons via inhibition of both GABAergic and glycinergic inputs

    Institute of Scientific and Technical Information of China (English)

    Yong-hua CHEN; Li-li HOU; Ji-jiang WANG

    2008-01-01

    Aim: To study the synaptic mechanisms involved in the 5-hydroxytryptaminel AF/7 (5-HT1A/7) receptor-mediated reflex control of cardiac vagal preganglionic neurons (CVPN). Methods: CVPN were retrogradely labeled and identified in brain stem slices of newborn rats, and their synaptic activity was examined using whole-cell patch-clamp. Results: 8-Hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), an agonist of 5-HT1A/7 receptors, had no effect on the glutamatergic inputs of CVPN. In contrast, it significantly decreased the frequency and the amplitude of both the GABAergic and the glycinergic spontaneous inhibitory postsynaptic currents (slPSC). 8-OH-DPAT also caused significant amplitude decrease of the GABAergic currents evoked by stimulation of the nucleus tractus solitarius. Both the fre-quency inhibition and the amplitude inhibition of the GABAergic and the glycinergic sIPSC by 8-OH-DPAT had dose-dependent tendencies and could be reversed by WAY-100635, an antagonist of 5-HT1A/7 receptors. In the pre-exist-ence of tetrodotoxin, 8-OH-DPAT had no effect on the GABAergic or the glycinergic miniature inhibitory postsynaptic currents, and had no effect on the GABAergic or the glycinergic currents evoked by exogenous GABA or glycine. Conclusion:The 5-HT1A/7 receptor agonist excites CVPN indirectly via the inhibition of both the GABAergic and glycinergic inputs. These findings have at least in part re-vealed the synaptic mechanisms involved in the 5-HT1A/7 receptor-mediated reflex control of cardiac vagal nerves in intact animals.

  2. Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons.

    Science.gov (United States)

    Rojas, Paulina S; Neira, David; Muñoz, Mauricio; Lavandero, Sergio; Fiedler, Jenny L

    2014-08-01

    Serotonin (5-HT) production and expression of 5-HT receptors (5-HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5-HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5-HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G-protein-coupled 5-HT1A R and 5-HT7 R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5-HT promotes neurite outgrowth through 5-HT1A R and 5-HT7 R. The involvement of 5-HT1A R and 5-HT7 R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5-HT and specific antagonists for 5-HT1A R and 5-HT7 R (WAY-100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5-HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT7 R was blocked, the addition of 5-HT increased the number of primary neurites, suggesting that 5HT7 R could inhibit neuritogenesis. In contrast, 5-HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY-100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5-HT1A R and 5-HT7 R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth.

  3. Effect of 5-HT1A-receptor functional polymorphism on Theory of Mind performances in schizophrenia.

    Science.gov (United States)

    Bosia, Marta; Anselmetti, Simona; Bechi, Margherita; Lorenzi, Cristina; Pirovano, Adele; Cocchi, Federica; Buonocore, Mariachiara; Bramanti, Placido; Smeraldi, Enrico; Cavallaro, Roberto

    2011-07-30

    Theory of Mind (ToM) abilities are known to be impaired in schizophrenia and data from functional brain imaging studies showed that ToM deficit is correlated to prefrontal cortex (PFC) dysfunction. Moreover, several lines of evidence suggest a critical role for dopaminergic-serotoninergic interactions at the PFC level. In this view, we aimed to analyse the specific effect of the -1019C/G functional polymorphism of the serotonin 1A receptor (5-HT1A-R), involved in both serotonin and dopamine transmission regulation. A total of 118 clinically stabilised schizophrenia patients was assessed with a neuropsychological battery, including evaluation of IQ, verbal memory, attention and executive function and a ToM task; they also underwent 5-HT1A-R genotyping. We observed a significant effect of the 5-HT1A-R genotype on ToM performances, with the CC genotype performing significantly better. The finding suggests an effect of the 5-HT1A-R polymorphism on ToM cognitive performance in schizophrenia patients, probably through complex interactions between dopaminergic and serotoninergic systems, involved in mentalising. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.

    Science.gov (United States)

    Pytka, Karolina; Kazek, Grzegorz; Siwek, Agata; Mordyl, Barbara; Głuch-Lutwin, Monika; Rapacz, Anna; Olczyk, Adrian; Gałuszka, Adam; Waszkielewicz, Anna; Marona, Henryk; Sapa, Jacek; Filipek, Barbara; Zygmunt, Małgorzata

    2016-01-01

    Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active

  5. COMT and 5-HT1A-receptor genotypes potentially affect executive functions improvement after cognitive remediation in schizophrenia

    Science.gov (United States)

    Bosia, Marta; Bechi, Margherita; Pirovano, Adele; Buonocore, Mariachiara; Lorenzi, Cristina; Cocchi, Federica; Bramanti, Placido; Smeraldi, Enrico; Cavallaro, Roberto

    2014-01-01

    Cognitive remediation therapy (CRT) has been proved to improve cognitive deficits in schizophrenia and to enhance functional outcomes of classical rehabilitation. However, CRT outcomes are heterogeneous and predictors of response are still unknown. Genetic variability, especially in the dopaminergic system, has been hypothesized to affect CRT. We previously reported that rs4680 of the catechol-O-methyltrasferase (COMT) influences improvements in executive functions in patients treated with CRT, but this result was not confirmed by other studies. Such inconsistent findings may depend, other than on clinical variables, also on other genes involved in cognition. Recent studies proved that serotonin 1A receptor (5-HT1A-R) regulates dopamine in the prefrontal cortex (PFC), and clinical works suggested a 5-HT1A-R role in cognition. We then analysed possible effects of COMT rs4680 and 5-HT1A-R rs6295 on CRT outcomes, taking into account also clinical and demographic factors. Eighty-six clinically stabilized schizophrenia patients treated with three months CRT were assessed with the Wisconsin Card Sorting Test, as a measure of executive functions, at enrolment and after CRT treatment, and underwent COMT and 5-HT1A-R genotyping. We found a significant main effect of COMT genotype and an interaction with 5-HT1A-R on executive function improvement after CRT. The results suggest that these two polymorphisms may have an additive effect on individual capacity to recover from cognitive deficit, probably through their role on PFC dopaminergic transmission modulation, known to be critical for modulating cognitive functions. PMID:25750798

  6. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors.

    Science.gov (United States)

    Pazos, M Ruth; Mohammed, Nagat; Lafuente, Hector; Santos, Martin; Martínez-Pinilla, Eva; Moreno, Estefania; Valdizan, Elsa; Romero, Julián; Pazos, Angel; Franco, Rafael; Hillard, Cecilia J; Alvarez, Francisco J; Martínez-Orgado, Jose

    2013-08-01

    The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB₂ receptor antagonist (AM630) or a serotonin 5HT(1A) receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H(±)-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB₂ and 5HT(1A) receptors. The involvement of CB₂ receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB₂ and 5HT(1A) receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB₂ and 5HT(1A) receptors are implicated in these effects.

  7. Serotonin Transporter Genotype Affects Serotonin 5-HT1A Binding in Primates

    OpenAIRE

    Christian, Bradley T; Wooten, Dustin W; Hillmer, Ansel T.; Tudorascu, Dana L.; Converse, Alexander K.; Moore, Colleen F.; Ahlers, Elizabeth O.; Barnhart, Todd E.; Kalin, Ned H.; Barr, Christina S.; Schneider, Mary L.

    2013-01-01

    Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding using in vivo imaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor bi...

  8. Peripheral 5-HT1A and 5-HT7 Serotonergic Receptors Modulate Parasympathetic Neurotransmission in Long-Term Diabetic Rats

    Science.gov (United States)

    Restrepo, Beatriz; Martín, María Luisa; San Román, Luis; Morán, Asunción

    2010-01-01

    We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT), effect reproduced by 5-carboxamidotryptamine maleate (5-CT), a 5-HT1/7 agonist. The enhancement of the bradycardia at low doses of 5-CT was reproduced by 5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) and abolished by WAY-100,635, 5-HT1A antagonist. Pretreatment with 5-HT1 antagonist methiothepin blocked the stimulatory and inhibitory effect of 5-CT, whereas pimozide, 5-HT7 antagonist, only abolished 5-CT inhibitory action. In conclusion, long-term diabetes elicits changes in the subtype of the 5-HT receptor involved in modulation of vagally induced bradycardia. Activation of the 5-HT1A receptors induces enhancement, whereas attenuation is due to 5-HT7 receptor activation. This 5-HT dual effect occurs at pre- and postjunctional levels. PMID:21403818

  9. Peripheral 5-HT 1A and 5-HT 7 Serotonergic Receptors Modulate Parasympathetic Neurotransmission in Long-Term Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Beatriz Restrepo

    2010-01-01

    Full Text Available We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT, effect reproduced by 5-carboxamidotryptamine maleate (5-CT, a 5-HT1/7 agonist. The enhancement of the bradycardia at low doses of 5-CT was reproduced by 5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT and abolished by WAY-100,635, 5-HT1A antagonist. Pretreatment with 5-HT1 antagonist methiothepin blocked the stimulatory and inhibitory effect of 5-CT, whereas pimozide, 5-HT7 antagonist, only abolished 5-CT inhibitory action. In conclusion, long-term diabetes elicits changes in the subtype of the 5-HT receptor involved in modulation of vagally induced bradycardia. Activation of the 5-HT1A receptors induces enhancement, whereas attenuation is due to 5-HT7 receptor activation. This 5-HT dual effect occurs at pre- and postjunctional levels.

  10. Effects of the 5-HT(1A) Receptor Agonist Tandospirone on ACTH-Induced Sleep Disturbance in Rats.

    Science.gov (United States)

    Tsutsui, Ryuki; Shinomiya, Kazuaki; Sendo, Toshiaki; Kitamura, Yoshihisa; Kamei, Chiaki

    2015-01-01

    The aim of this study was to compare the effect of the serotonin (5-HT)1A receptor agonist tandospirone versus that of the benzodiazepine hypnotic flunitrazepam in a rat model of long-term adrenocorticotropic hormone (ACTH)-induced sleep disturbance. Rats implanted with electrodes for recording electroencephalogram and electromyogram were injected with ACTH once daily at a dose of 100 µg/rat. Administration of ACTH for 10 d caused a significant increase in sleep latency, decrease in non-rapid eye movement (non-REM) sleep time, and increase in wake time. Tandospirone caused a significant decrease in sleep latency and increase in non-REM sleep time in rats treated with ACTH. The effect of tandospirone on sleep patterns was antagonized by the 5-HT1A receptor antagonist WAY-100635. In contrast, flunitrazepam had no significant effect on sleep parameters in ACTH-treated rats. These results clearly indicate that long-term administration of ACTH causes sleep disturbance, and stimulating the 5-HT1A receptor by tandospirone may be efficacious for improving sleep in cases in which benzodiazepine hypnotics are ineffective.

  11. Cartography of 5-HT1A and 5-HT2A Receptor Subtypes in Prefrontal Cortex and Its Projections.

    Science.gov (United States)

    Mengod, Guadalupe; Palacios, José M; Cortés, Roser

    2015-07-15

    Since the development of chemical neuroanatomical tools in the 1960s, a tremendous wealth of information has been generated on the anatomical components of the serotonergic system, at the microscopic level in the brain including the prefrontal cortex (PFC). The PFC receives a widespread distribution of serotonin (5-hydroxytryptamine, 5-HT) terminals from the median and dorsal raphe nuclei. 5-HT receptors were first visualized using radioligand autoradiography in the late 1980s and early 1990s and showed, in contrast to 5-HT innervation, a differential distribution of binding sites associated with different 5-HT receptor subtypes. Due to the cloning of the different 5-HT receptor subtype genes in the late 1980s and early 1990s, it was possible, using in situ hybridization histochemistry, to localize cells expressing mRNA for these receptors. Double in situ hybridization histochemistry and immunohistochemistry allowed for the chemical characterization of the phenotype of cells expressing 5-HT receptors. Tract tracing technology allowed a detailed cartography of the neuronal connections of PFC and other brain areas. Based on these data, maps have been constructed that reflect our current understanding of the different circuits where 5-HT receptors can modulate the electrophysiological, pharmacological, and behavioral functions of the PFC. We will review current knowledge regarding the cellular localization of 5-HT1A and 5-HT2A receptors in mammalian PFC and their possible functions in the neuronal circuits of the PFC. We will discuss data generated in our laboratory as well as in others, focusing on localization in the pyramidal and GABAergic neuronal cell populations in different mammalian species using molecular neuroanatomy and on the connections with other brain regions.

  12. Isoquinoline derivatives isolated from the fruit of Annona muricata as 5-HTergic 5-HT1A receptor agonists in rats: unexploited antidepressive (lead) products.

    Science.gov (United States)

    Hasrat, J A; De Bruyne, T; De Backer, J P; Vauquelin, G; Vlietinck, A J

    1997-11-01

    The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [3H]rauwolscine to 5-HTergic 5-HT1A receptors in calf hippocampus, and three alkaloids, annonaine (1), nornuciferine (2) and asimilobine (3), isolated from the fruit have been shown to have IC50 values of 3 microM, 9 microM and 5 microM, respectively, although in ligand-binding studies it was not possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the results of functional assays of the alkaloids. The inhibition of cAMP accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A receptor from man. None of the alkaloids showed antagonistic properties towards the 5-HT1A receptors because in the antagonistic tests no influence on the forskolin-stimulated increase of cAMP level was detected. Full agonistic properties were measured for all three compounds; the inhibition constants (Ki) for 1, 2 and 3 were Annona muricata possesses anti-depressive effects, possibly induced by compounds 1, 2 and 3, and that in the past potent leads for the development of anti-depressive therapeutics have not been used.

  13. Towards novel 5-HT7versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: design, synthesis, and antidepressant properties. Part II.

    Science.gov (United States)

    Canale, Vittorio; Kurczab, Rafał; Partyka, Anna; Satała, Grzegorz; Witek, Jagna; Jastrzębska-Więsek, Magdalena; Pawłowski, Maciej; Bojarski, Andrzej J; Wesołowska, Anna; Zajdel, Paweł

    2015-03-06

    A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970.

  14. Is the anxiolytic-like effect of acute 8-0H-DPAT mediated by 5-HT1A receptors? O efeito ansiolítico do 8-OH-DPAT é mediado por receptores 5-HT1A?

    Directory of Open Access Journals (Sweden)

    Marcos Alberto Trombelli

    1998-07-01

    Full Text Available Para estudar o papel dos receptores 5-HT1A na ansiedade, realizamos uma curva dose-efeito com o agonista pleno de receptores 5HT1A administrado em ratos expostos ao labirinto em cruz elevado. A dose de 0,5mg/kg (IP de 8-OH-DPAT aumentou significativamente a porcentagem de entradas e de tempo dispendido nos braços abertos. Esses resultados são indicativos de efeito ansiolítico. O número total de entradas nos braços fechados, que é um índice de atividade locomotora, também foi significativamente aumentado. Nenhuma alteração significativa foi verificada com a administração (IP da dose mais baixa (0,25mg/kg ou da dose mais alta (1,0mg/kg do 8-OH-DPAT. Contrastantemente, a administração de 2,0mg/kg (IP de diazepam produziu um efeito ansiolítico similar, mas não afetou a locomoção. O pré-tratamento com 1,0mg/kg do WAY 100135 não antagonizou os efeitos obtidos com a administração de 0,5mg/kg do 8-OH-DPAT sobre os índices de ansiedade e locomoção. Esses resultados demonstram que o 8-OH-DPAT produziu um efeito ansiolítico e estimulante de atividade locomotora no labirinto em cruz elevado. Entretanto, estes efeitos não parecem ser mediados por receptores 5-HT1A.In the study of the role of 5-HT1A receptors in anxiety, dose-effect curve for the full 5-HT1A receptor agonist 8-OH-DPAT was determined in rats exploring the elevated plus-maze. Dose of 0.5mg/kg, IP, of 8-OH-DPAT significantly increased the percentage of open arm entries and of time spent on the open arms, displaying an anxiolytic effect. Total number of entries into the enclosed arms, an index of locomotion, was also significantly increased. A lower (0.25mg/kg and a higher dose (1.0mg/kg of 8-OH-DPAT were ineffective. Contrastly, 2.0mg/kg, IP, of diazepam had a similar anxiolytic effect, but did not affect locomotion. The pretreatment with 1.0mg/kg of WAY 100135 did not antagonize the effects of 0.5mg/kg of 8-OH-DPAT on the indexes of anxiety and locomotion. These

  15. INFLUENCE OF ARYLPIPERAZINES AROMATIC STRUCTURE OVER DIFFERENTIAL AFFINITY FOR 5-HT1A AND 5-HT2A RECEPTORS

    Directory of Open Access Journals (Sweden)

    Irene Rebelo

    2009-01-01

    Full Text Available Las piperazinas son una familia de compuestos químicos muy amplia y con una gran capacidad para interactuar con diversos receptores serotonérgicos (5-HT. Debido a estas propiedades, estos compuestos tienen un importante potencial farmacológico, sin embargo muestran también algunos efectos tóxicos asociados. En la actualidad el subtipo 1A del receptor serotonérgico (5-HT1A ha resultado ser un importante blanco para el tratamiento eficaz de la depresión y ansiedad, mientras que el subtipo 2A del receptor serotonérgico (5-HT2A ha sido asociado con numerables efectos adversos. En este estudio, se utilizan diversos métodos computacionales con el fin de efectuar una caracterización de los fragmentos estructurales y las propiedades químicas asociadas, responsables por la afinidad de las piperazinas para los receptores 5-HT1A Y 5-HT2A. En este trabajo, se discuten también, algunas propiedades de las estructuras aromáticas en las arilpiperazinas que son similares para los dos subtipos del receptor serotonérgico. Por otra parte se sugiere, que la substitución con calcógenos en la posición orto- y meta- así como el ligero incremento en el peso molecular son modificaciones que pueden aumentan la afinidad para el receptor 5-HT1A; mientras que las arilpiperazinas con substitución por halógenos en las mismas posiciones además de un pequeño decrecimiento en el peso molecular podrían incrementar la afinidad para el 5-HT2A receptor.

  16. The Versatile 2-Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5-HT1A Receptor.

    Science.gov (United States)

    Del Bello, Fabio; Cilia, Antonio; Carrieri, Antonio; Fasano, Domenico Claudio; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Micheli, Laura; Santini, Carlo; Diamanti, Eleonora; Giannella, Mario; Giorgioni, Gianfabio; Mammoli, Valerio; Paoletti, Corinne Dalila; Petrelli, Riccardo; Piergentili, Alessandro; Quaglia, Wilma; Pigini, Maria

    2016-10-19

    The involvement of the serotonin 5-HT1A receptor (5-HT1A -R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2-substituted imidazoline nucleus as a structural motif interact with 5-HT1A -R. Therefore, we examined the 5-HT1A -R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2-position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5-HT1A -R and to identify the structural features favoring 5-HT1A -R interaction. Structure-activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5-HT1A -R recognition and activation. We also highlighted the potent antidepressant-like effect (mouse forced swimming test) of (S)-(+)-19 [(S)-(+)-naphtyline] at very low dose (0.01 mg kg(-1) ). This effect was clearly mediated by 5-HT1A , as it was significantly reduced by pretreatment with the 5-HT1A antagonist WAY100635. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Synthesis and initial biological evaluation of a novel Tc-99m radioligand as a potential agent for 5-HT1A receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Abdelounis, Najoua Mejri; Saied, Nadia Malek; Essouissi, Imen; Guizani, Sihem; Saidi, Mouldi [CNSTN, Sidi Thabet (Tunisia). Research Unit of Medical, Agricultural and Environmental Use of Nuclear Applications

    2014-09-01

    The synthesis, characterization and biological evaluation of N-Tolueneferrocenecarboxamide labeled with technetium-99m ({sup 99m}Tc-TTCC) is reported. Biological studies in Wistar rats showed the ability of {sup 99m}Tc-TPCC to cross the intact blood-brain barrier. In vivo biodistribution indicated that this complex had good brain uptake (1.32%ID/g at 5 min and 0.64%ID/g at 60 min) and good retention (about 50% of the activity was retained in the brain at 60 min post-injection). Regional brain distribution study showed that hippocampus, where the 5-HT1A receptor density is high, had the highest uptake (0.73%ID/g at 5 min p.i.) and the cerebellum, where the 5-HT1A receptor density is low, had the lowest uptake (0.12%ID/gID/g at 5 min p.i.). After blocking with 8-hydroxy-2-(dipropylamino) tetralin, the uptake of hippocampus was decreased significantly from 0.73%ID/g to 0.20%ID/g at 5 min p.i., while the cerebellum had no significant decrease. This result indicates that 99mTc complex has specific binding to 5-HT1A receptor. (orig.)

  18. Morphology and distribution of neurons expressing serotonin 5-HT1A receptors in the rat hypothalamus and the surrounding diencephalic and telencephalic areas.

    Science.gov (United States)

    Marvin, Eric; Scrogin, Karie; Dudás, Bertalan

    2010-07-01

    Disorders of serotonergic neurotransmission are involved in disturbances of numerous hypothalamic functions including circadian rhythm, mood, neuroendocrine functions, sleep and feeding. Among the serotonin receptors currently recognized, 5-HT(1A) receptors have received considerable attention due to their importance in the etiology of mood disorders. While previous studies have shown the presence of 5-HT(1A) receptors in several regions of the rat brain, there is no detailed map of the cellular distribution of 5-HT(1A) receptors in the rat diencephalon. In order to characterize the distribution and morphology of the neurons containing 5-HT(1A) receptors in the diencephalon and the adjacent telencephalic areas, single label immunohistochemistry was utilized. Large, multipolar, 5-HT(1A)-immunoreactive (IR) neurons were mainly detected in the magnocellular preoptic nucleus and in the nucleus of diagonal band of Broca, while the supraoptic nucleus contained mainly fusiform neurons. Medium-sized 5-HT(1A)-IR neurons with triangular or round-shaped somata were widely distributed in the diencephalon, populating the zona incerta, lateral hypothalamic area, anterior hypothalamic nucleus, substantia innominata, dorsomedial and premamillary nuclei, paraventricular nucleus and bed nucleus of stria terminalis. The present study provides schematic mapping of 5-HT(1A)-IR neurons in the rat diencephalon. In addition, the morphology of the detected 5-HT(1A)-IR neural elements is also described. Since rat is a widely used laboratory animal in pharmacological models of altered serotoninergic neurotransmission, detailed mapping of 5-HT(1A)-IR structures is pivotal for the neurochemical characterization of the neurons containing 5-HT(1A) receptors.

  19. Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors.

    Science.gov (United States)

    Espejo-Porras, Francisco; Fernández-Ruiz, Javier; Pertwee, Roger G; Mechoulam, Raphael; García, Concepción

    2013-12-01

    The broad presence of CB1 receptors in the basal ganglia, mainly in GABA- or glutamate-containing neurons, as well as the presence of TRPV1 receptors in dopaminergic neurons and the identification of CB2 receptors in some neuronal subpopulations within the basal ganglia, explain the powerful motor effects exerted by those cannabinoids that can activate/block these receptors. By contrast, cannabidiol (CBD), a phytocannabinoid with a broad therapeutic profile, is generally presented as an example of a cannabinoid compound with no motor effects due to its poor affinity for the CB1 and the CB2 receptor, despite its activity at the TRPV1 receptor. However, recent evidence suggests that CBD may interact with the serotonin 5-HT1A receptor to produce some of its beneficial effects. This may enable CBD to directly influence motor activity through the well-demonstrated role of serotonergic transmission in the basal ganglia. We have investigated this issue in rats using three different pharmacological and neurochemical approaches. First, we compared the motor effects of various i.p. doses of CBD with the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; i.p.). Second, we investigated whether the motor effects of CBD are sensitive to 5-HT1A receptor blockade in comparison with CB1 receptor antagonism. Finally, we investigated whether CBD was able to potentiate the effect of a sub-effective dose of 8-OH-DPAT. Our results demonstrated that: (i) only high doses of CBD (>10 mg/kg) altered motor behavior measured in a computer-aided actimeter; (ii) these alterations were restricted to vertical activity (rearing) with only modest changes in other parameters; (iii) similar effects were produced by 8-OH-DPAT (1 mg/kg), although this agonist affected exclusively vertical activity, with no effects on other motor parameters, and it showed always more potency than CBD; (iv) the effects of 8-OH-DPAT (1 mg/kg) and CBD (20 mg/kg) on vertical activity

  20. 5-HT1A Receptor Activation Improves Anti-Cataleptic Effects of Levodopa in 6-Hydroxydopamine-Lesioned Rats

    Directory of Open Access Journals (Sweden)

    S. Reyhani-Rad

    2011-12-01

    Full Text Available Background and the purpose of the study: In Parkinsons disease (PD prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID. In this investigation the effect of 8-OHDAPT, as a 5-HT1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA lesioned male Wistar rats was investigated. Methods: Catalepsy was induced by unilateral injection of 6-OHDA (8 μg/2μl/rat into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p. L-DOPA (15 mg/kg twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. Results and major conclusion: The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p. and L-DOPA (15 mg/kg, ip. 8-Hydroxy-2-(di-n-propylamino tetralin (8-OHDAPT improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip was abolished by 1-(2-methyoxyphenyl-4-[4-(2-phthalamido butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p. as a 5-HT1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT1A and dopaminergic neurons.

  1. 5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Eriksson, Therese M; Holst, Sarah; Stan, Tiberiu L; Hager, Torben; Sjögren, Benita; Ogren, Sven Öve; Svenningsson, Per; Stiedl, Oliver

    2012-11-01

    This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT(7) receptors (5-HT(7)Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT(7)R binding affinity and 5-HT(7)R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT(1A)R antagonist NAD-299. This facilitation was blocked by the selective 5-HT(7)R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT(7)Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT(1A)Rs results in enhanced 5-HT stimulation of 5-HT(7)Rs. The putative 5-HT(7)R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT(7)R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT(1A)R/5-HT(7)R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT(7)R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT(1A)R activation, while 5-HT(7)Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone.

  2. 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects.

    Science.gov (United States)

    Stenkrona, Per; Halldin, Christer; Lundberg, Johan

    2013-10-01

    Vortioxetine (Lu AA21004) is a new potential substance for the treatment of anxiety and mood disorders. It has high affinity for the 5-HT transporter (5-HTT) and moderate affinity for the 5-HT1A receptor in vitro. Positron emission tomography (PET) has commonly been used to examine the relation between dose/plasma concentration and occupancy to predict relevant dose intervals in a clinical setting. In this study 11 control subjects were examined with PET and [¹¹C]MADAM at baseline, after a single dose and after 9 days of dosing with Lu AA21004 (2.5, 10 or 60 mg) for quantification of 5-HTT occupancy. Four subjects were examined with PET and [¹¹C]WAY 100635 at baseline, after a single dose and after 9 days of dosing of Lu AA21004 (30 mg) for quantification of 5-HT(1A) occupancy. To allow for quantification of binding in the raphe nuclei, PET data were analyzed using wavelet aided parametric imaging. 5-HTT occupancy ranged from 2 (mean, 2.5 mg day 1) to 97% (60 mg day 9). The apparent affinity of Lu AA21004 binding to 5-HTT (KD(ND)) was calculated to 16.7 nM (R=0.95), and the corresponding oral dose (KD(ND)-dose) to 8.5 mg (R=0.91). No significant occupancy of 5-HT(1A) receptors was found after dosing of 30 mg Lu AA21004. Based on the literature and the present [¹¹C]MADAM binding data, a dose of 20-30 mg Lu AA21004 is suggested to give clinically relevant occupancy of the 5-HTT.

  3. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.

    Science.gov (United States)

    Gomes, Felipe V; Del Bel, Elaine A; Guimarães, Francisco S

    2013-10-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L-NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose-dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders.

  4. Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison.

    Science.gov (United States)

    Caramaschi, Doretta; de Boer, Sietse F; Koolhaas, Jaap M

    2007-03-16

    Differential role of the 5-HT(1A) receptor in aggressive and non-aggressive mice: an across-strain comparison. PHYSIOL BEHAV 00(0) 000-000, 2006. According to the serotonin (5-HT)-deficiency hypothesis of aggression, highly aggressive individuals are characterized by low brain 5-HT neurotransmission. Key regulatory mechanisms acting on the serotonergic neuron involve the activation of the somatodendritic inhibitory 5-HT(1A) autoreceptor (short feedback loop) and/or the activation of postsynaptic 5-HT(1A) receptors expressed on neurons in cortico-limbic areas (long feedback loop). In this study, we examined whether low serotonin neurotransmission is associated with enhanced 5-HT(1A) (auto)receptor activity in highly aggressive animals. Male mice (SAL-LAL, TA-TNA, NC900-NC100) obtained through different artificial-selection breeding programs for aggression were observed in a resident-intruder test. The prefrontal cortex level of 5-HT and its metabolite 5-HIAA were determined by means of HPLC. The activity of the 5-HT(1A) receptors was assessed by means of the hypothermic response to the selective 5-HT(1A) agonists S-15535 (preferential autoreceptor agonist) and 8-OHDPAT (full pre- and postsynaptic receptor agonist). Highly aggressive mice had lower serotonin levels in the prefrontal cortex and two out of three aggressive strains had higher 5-HT(1A) (auto)receptor sensitivity. The results strengthen the validity of the serotonin-deficiency hypothesis of aggression and suggest that chronic exaggerated activity of the 5-HT(1A) receptor may be a causative link in the neural cascade of events leading to 5-HT hypofunction in aggressive individuals.

  5. Aminoalkyl Derivatives of 8-Alkoxypurine-2,6-diones: Multifunctional 5-HT1A /5-HT7 Receptor Ligands and PDE Inhibitors with Antidepressant Activity.

    Science.gov (United States)

    Chłoń-Rzepa, Grażyna; Zagórska, Agnieszka; Żmudzki, Paweł; Bucki, Adam; Kołaczkowski, Marcin; Partyka, Anna; Wesołowska, Anna; Kazek, Grzegorz; Głuch-Lutwin, Monika; Siwek, Agata; Starowicz, Gabriela; Pawłowski, Maciej

    2016-12-01

    In the search for potential psychotropic agents, a new series of 3,7-dimethyl- and 1,3-dimethyl-8-alkoxypurine-2,6-dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5-16 and 21-32) were synthesized and evaluated for 5-HT1A /5-HT7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-3,7-dimethyl-8-propoxypurine-2,6-dione (16) and 7-(2-hydroxyphenyl)piperazinylalkyl-1,3-dimethyl-8-ethoxypurine-2,6-diones (31 and 32) as potent dual 5-HT1A /5-HT7 receptor ligands with antagonistic activity produced an antidepressant-like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10(-5)  M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5-HT1 and 5-HT7 receptors, especially in the case of compounds 15 and 16. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.

  6. Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: An across-strain comparison

    OpenAIRE

    Caramaschi, Doretta; de Boer, Sietse F.; Koolhaas, Jaap M.

    2007-01-01

    Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison. PHYSIOL BEHAV 00(0) 000-000, 2006. According to the serotonin (5-HT)-deficiency hypothesis of aggression, highly aggressive individuals are characterized by low brain 5-HT neurotransmission. Key regulatory mechanisms acting on the serotonergic neuron involve the activation of the somatodendritic inhibitory 5-HT1A autoreceptor (short feedback loop) and/or the activation of postsynaptic ...

  7. Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat.

    Science.gov (United States)

    Gui, Z H; Zhang, Q J; Liu, J; Zhang, L; Ali, U; Hou, C; Fan, L L; Sun, Y N; Wu, Z H; Hui, Y P

    2011-10-01

    5-Hydroxytryptamine(1A) (5-HT(1A)) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5-HT(1A) receptor agonist 8-OH-DPAT and change in expression of 5-HT(1A) receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 μg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 μg/kg) was significantly higher than that of sham-operated rats (27 μg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 μg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT(1A) receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT(1A) receptor stimulation, which attributes to down-regulation of 5-HT(1A) receptor expression in these interneurons.

  8. Decreased expression of Freud-1/CC2D1A, a transcriptional repressor of the 5-HT1A receptor, in the prefrontal cortex of subjects with major depression.

    Science.gov (United States)

    Szewczyk, Bernadeta; Albert, Paul R; Rogaeva, Anastasia; Fitzgibbon, Heidi; May, Warren L; Rajkowska, Grazyna; Miguel-Hidalgo, Jose J; Stockmeier, Craig A; Woolverton, William L; Kyle, Patrick B; Wang, Zhixia; Austin, Mark C

    2010-09-01

    Serotonin1A (5-HT(1A)) receptors are reported altered in the brain of subjects with major depressive disorder (MDD). Recent studies have identified transcriptional regulators of the 5-HT(1A) receptor and have documented gender-specific alterations in 5-HT(1A) transcription factor and 5-HT(1A) receptors in female MDD subjects. The 5' repressor element under dual repression binding protein-1 (Freud-1) is a calcium-regulated repressor that negatively regulates the 5-HT(1A) receptor gene. This study documented the cellular expression of Freud-1 in the human prefrontal cortex (PFC) and quantified Freud-1 protein in the PFC of MDD and control subjects as well as in the PFC of rhesus monkeys chronically treated with fluoxetine. Freud-1 immunoreactivity was present in neurons and glia and was co-localized with 5-HT(1A) receptors. Freud-1 protein level was significantly decreased in the PFC of male MDD subjects (37%, p=0.02) relative to gender-matched control subjects. Freud-1 protein was also reduced in the PFC of female MDD subjects (36%, p=0.18) but was not statistically significant. When the data was combined across genders and analysed by age, the decrease in Freud-1 protein level was greater in the younger MDD subjects (48%, p=0.01) relative to age-matched controls as opposed to older depressed subjects. Similarly, 5-HT(1A) receptor protein was significantly reduced in the PFC of the younger MDD subjects (48%, p=0.01) relative to age-matched controls. Adult male rhesus monkeys administered fluoxetine daily for 39 wk revealed no significant change in cortical Freud-1 or 5-HT(1A) receptor proteins compared to vehicle-treated control monkeys. Reduced protein expression of Freud-1 in MDD subjects may reflect dysregulation of this transcription factor, which may contribute to the altered regulation of 5-HT(1A) receptors observed in subjects with MDD. These data may also suggest that reductions in Freud-1 protein expression in the PFC may be associated with early onset of

  9. Antagonism of 5-HT1A receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT7 receptors

    NARCIS (Netherlands)

    Bosker, Fokko J.; Folgering, Joost H. A.; Gladkevich, Anatoliy V.; Schmidt, Anne; van der Hart, Marieke C. G.; Sprouse, Jeffrey; den Boer, Johan A.; Westerink, Ben H. C.; Cremers, Thomas I. F. H.

    2009-01-01

    Both microdialysis and electrophysiology were used to investigate whether another serotonin (5-HT) receptor subtype next to the 5-HT1A autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5-HT neuronal activity. On the basis of a previous study, we decided to

  10. The differential effects of 5-HT(1A) receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat.

    Science.gov (United States)

    Dupre, Kristin B; Eskow, Karen L; Negron, Giselle; Bishop, Christopher

    2007-07-16

    Serotonin 1A receptor (5-HT(1A)R) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson's disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT(1A)R stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT(1A)R stimulation on DA receptor-mediated behaviors. Male Sprague-Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH(2)O) or the 5-HT(1A)R agonist +/-8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg+benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT(1A)R stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT(1A)R and DA receptor interactions may contribute to the unique profile of 5-HT(1A)R agonists for the improvement of PD treatment.

  11. Exploring the Role of 5-HT1A Receptors in the Regulation of Prepulse Inhibition in Mice: Implications for Cross-Species Comparisons

    Science.gov (United States)

    2012-01-01

    Prepulse inhibition (PPI) is a model of sensorimotor gating, a sensory filtering mechanism which is disrupted in schizophrenia. Here, investigation of the role of the serotonin-1A (5-HT1A) receptor in the regulation of PPI in two mouse strains, C57Bl/6 and Balb/c, was used to address findings in the PPI literature on species and mouse strain differences that question the usefulness of PPI as a cross-species preclinical test. Although the full 5-HT1A receptor agonist, 8-OH-DPAT, induced markedly different strain-specific responses in PPI, other selective 5-HT1A receptor ligands with partial agonist or antagonist activity elicited similar effects across strains. Pretreatment with the serotonin precursor, 5-HTP, to increase serotonergic activity in the brain, unmasked a decrease in PPI caused by 8-OH-DPAT in C57Bl/6 mice. Pretreatment with the serotonin synthesis inhibitor, PCPA, to decrease serotonergic activity in the brain, unmasked an 8-OH-DPAT-induced increase in PPI in this strain. These studies show that the strain-dependent involvement of 5-HT1A receptors in PPI can be modulated by the type of 5-HT1A ligand used, or increasing or decreasing serotonin levels in the brain. These results help to clarify some of the mouse strain and species differences in PPI regulation and strengthen its usefulness as a cross-species measure of sensorimotor gating. PMID:23336054

  12. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience.

    Science.gov (United States)

    Fogaça, M V; Reis, F M C V; Campos, A C; Guimarães, F S

    2014-03-01

    The prelimbic medial prefrontal cortex (PL) is an important encephalic structure involved in the expression of emotional states. In a previous study, intra-PL injection of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, reduced the expression of fear conditioning response. Although its mechanism remains unclear, CBD can facilitate 5HT1A receptor-mediated neurotransmission when injected into several brain structures. This study was aimed at verifying if intra-PL CBD could also induce anxiolytic-like effect in a conceptually distinct animal model, the elevated plus maze (EPM). We also verified if CBD effects in the EPM and contextual fear conditioning test (CFC) depend on 5HT1A receptors and previous stressful experience. CBD induced opposite effects in the CFC and EPM, being anxiolytic and anxiogenic, respectively. Both responses were prevented by WAY100,635, a 5HT1A receptor antagonist. In animals that had been previously (24h) submitted to a stressful event (2h-restraint) CBD caused an anxiolytic, rather than anxiogenic, effect in the EPM. This anxiolytic response was abolished by previous injection of metyrapone, a glucocorticoid synthesis blocker. Moreover, restraint stress increased 5HT1A receptors expression in the dorsal raphe nucleus, an effect that was attenuated by injection of metyrapone before the restraint procedure. Taken together, these results suggest that CBD modulation of anxiety in the PL depend on 5HT1A-mediated neurotransmission and previous stressful experience.

  13. Distribution and Localization of 5-HT1A Receptors in the Rat Lumbar Spinal Cord after Transection and Deafferentation

    Science.gov (United States)

    Otoshi, Chad K.; Walwyn, Wendy M.; Tillakaratne, Niranjala J.K.; Zhong, Hui; Roy, Roland R.

    2009-01-01

    Abstract The serotonergic system is highly plastic, capable of adapting to changing afferent information in diverse mammalian systems. We hypothesized that removing supraspinal and/or peripheral input would play an important role in defining the distribution of one of the most prevalent serotonergic receptors, the 5-HT1A receptor (R), in the spinal cord. We investigated the distribution of this receptor in response to a complete thoracic (T7–T8) spinal cord transection (eliminating supraspinal input), or to spinal cord isolation (eliminating both supraspinal and peripheral input) in adult rats. Using two antibodies raised against either the second extracellular region (ECL2) or the third intracellular region (ICL3) of the 5-HT1AR, we compared the 5-HT1AR levels and distributions in specific laminae of the L3–L5 segments among the control, spinal cord–transected, and spinal cord–isolated groups. Each antibody labeled different populations of 5-HT1AR: ECL2 labeled receptors in the axon hillock, whereas ICL3 labeled receptors predominantly throughout the soma and proximal dendrites. Spinal cord transection increased the number of ECL2-positive cells in the medial region of laminae III–IV and lamina VII, and the mean length of the labeled axon hillocks in lamina IX. The number of ICL3-labeled cells was higher in lamina VII and in both the medial and lateral regions of lamina IX in the spinal cord–transected compared to the control group. In contrast, the length and number of ECL2-immunolabeled processes and ICL3-immunolabeled cells were similar in the spinal cord–isolated and control groups. Combined, these data demonstrate that the upregulation in 5-HT1AR that occurs with spinal cord transection alone is dependent on the presence of sensory input. PMID:19260781

  14. Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI.

    Science.gov (United States)

    Maraschin, Jhonatan Christian; Almeida, Camila Biesdorf; Rangel, Marcel Pereira; Roncon, Camila Marroni; Sestile, Caio César; Zangrossi, Hélio; Graeff, Frederico Guilherme; Audi, Elisabeth Aparecida

    2017-06-01

    Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1A receptor (5-HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM) and the dPAG electrical stimulation test (EST). We also evaluated whether activation of the 5-HT1A-R or the μ-opioid receptor (MOR) in the dPAG contributes to the Nor-BNI effects. The results showed that systemic administration of Nor-BNI, either subcutaneously (2.0 and 4.0mg/kg) or intraperitoneally (2.0mg/kg), impaired escape in the EST, indicating a panicolytic-like effect. Intra-dPAG injection of this antagonist (6.8nmol) caused the same effect in the EST and in the ETM. Association of ineffective doses of Nor-BNI and the 5-HT1A-R agonist 8-OH-DPAT caused panicolytic-like effect in these two tests. Previous administration of the 5-HT1A-R antagonist WAY-100635, but not of the MOR antagonist CTOP, blocked the panicolytic-like effect of Nor-BNI. These results indicate that KOR enhances proximal defense in the dPAG through 5-HT1A-R modulation, independently of MOR. Because former results indicate that the 5-HT1A-R is involved in the antipanic action of antidepressants, KOR antagonists may be useful as adjunctive or alternative drug treatment of panic disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Dopamine D2 and serotonin 5-HT1A receptor interaction in the context of the effects of antipsychotics - in vitro studies.

    Science.gov (United States)

    Łukasiewicz, Sylwia; Błasiak, Ewa; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2016-05-01

    The serotonin 5-HT1A receptor (5-HT1 A R) and dopamine D2 receptor (D2 R) have been implicated as important sites of action in antipsychotics. Several lines of evidence indicate the key role of G protein-coupled receptors (GPCRs) heteromers in pathophysiology of schizophrenia and highlight these complexes as novel drug targets. Because heterodimers can form only on those cells co-expressing constituent receptors, they present a target of high pharmacological specificity in the context of biochemical effects induced by antipsychotic drugs. In studies conducted in the HEK 293 cell line, we demonstrated that 5-HT1 A R and D2 R are able to form constitutive heterodimers, and antipsychotic drugs (clozapine, olanzapine, aripiprazole, and lurasidone) enhanced this process, with clozapine being most effective. Various functional tests (cAMP and IP1 as well as ERK activation) indicated that the drugs had different effects on signal transduction by the heteromer. Interestingly, co-incubation of heterodimer-expressing HEK 293 cells with clozapine and the 5-HT1 A R agonist 8-OH DPAT potentiated post-synaptic effects, especially with respect to ERK activation. Our results indicate that the D2 -5-HT1A complex possesses biochemical, pharmacological, and functional properties distinct from those of mono- and homomers. This result has implications for the development of improved pharmacotherapy for schizophrenia or other disorders (activating the heteromer might be cognitive enhancing, since it is expressed in frontal cortex) through the specific targeting of heterodimers. We reported the constitutive formation of D2 -5-HT1A heteromers, which possess biochemical, pharmacological, and functional properties distinct from those of mono- and homomers, as revealed by antipsychotics action. We also showed that these two receptors are co-expressed in mouse cortical neurons; therefore their potential to heterodimerize may comprise an essential target for the development of novel strategies

  16. The Antidepressant-Like Effect of Fish Oil: Possible Role of Ventral Hippocampal 5-HT1A Post-synaptic Receptor.

    Science.gov (United States)

    Carabelli, Bruno; Delattre, Ana Marcia; Pudell, Claudia; Mori, Marco Aurélio; Suchecki, Deborah; Machado, Ricardo B; Venancio, Daniel Paulino; Piazzetta, Sílvia Regina; Hammerschmidt, Ivilim; Zanata, Sílvio M; Lima, Marcelo M S; Zanoveli, Janaína Menezes; Ferraz, Anete Curte

    2015-08-01

    The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.

  17. Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease: role of NMDA vs. 5-HT1A receptors

    Science.gov (United States)

    Paquette, Melanie A.; Martinez, Alex A.; Macheda, Teresa; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul; Giuffrida, Andrea

    2013-01-01

    Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson’s disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT1A receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT1A agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT1A antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT1A agonism. Combined with previous work from our group, our results support the investigation of 5-HT1A agonists as pharmacotherapies for LID in PD patients. PMID:22861201

  18. Operant learning and differential-reinforcement-of-low-rate 36-s responding in 5-HT1A and 5-HT1B receptor knockout mice.

    NARCIS (Netherlands)

    Pattij, T.; Broersen, L.M.; Linde, J. van der; Groenink, L.; Gugten, J. van der; Maes, R.A.A.; Olivier, B.

    2003-01-01

    Previous studies with mice lacking 5-HT(1A) (1AKO) and 5-HT(1B) (1BKO) receptors in hippocampus-dependent learning and memory paradigms, suggest that these receptors play an important role in learning and memory, although their precise role is unclear. In the present study, 1AKO and 1BKO mice were s

  19. Serotonergic activation of 5HT1A and 5HT2 receptors modulates sexually dimorphic communication signals in the weakly electric fish Apteronotus leptorhynchus.

    Science.gov (United States)

    Smith, G Troy; Combs, Nicole

    2008-06-01

    Serotonin modulates agonistic and reproductive behavior across vertebrate species. 5HT(1A) and 5HT(1B) receptors mediate many serotonergic effects on social behavior, but other receptors, including 5HT(2) receptors, may also contribute. We investigated serotonergic regulation of electrocommunication signals in the weakly electric fish Apteronotus leptorhynchus. During social interactions, these fish modulate their electric organ discharges (EODs) to produce signals known as chirps. Males chirp more than females and produce two chirp types. Males produce high-frequency chirps as courtship signals; whereas both sexes produce low-frequency chirps during same-sex interactions. Serotonergic innervation of the prepacemaker nucleus, which controls chirping, is more robust in females than males. Serotonin inhibits chirping and may contribute to sexual dimorphism and individual variation in chirping. We elicited chirps with EOD playbacks and pharmacologically manipulated serotonin receptors to determine which receptors regulated chirping. We also asked whether serotonin receptor activation generally modulated chirping or more specifically targeted particular chirp types. Agonists and antagonists of 5HT(1B/1D) receptors (CP-94253 and GR-125743) did not affect chirping. The 5HT(1A) receptor agonist 8OH-DPAT specifically increased production of high-frequency chirps. The 5HT(2) receptor agonist DOI decreased chirping. Receptor antagonists (WAY-100635 and MDL-11939) opposed the effects of their corresponding agonists. These results suggest that serotonergic inhibition of chirping may be mediated by 5HT(2) receptors, but that serotonergic activation of 5HT(1A) receptors specifically increases the production of high-frequency chirps. The enhancement of chirping by 5HT(1A) receptors may result from interactions with cortisol and/or arginine vasotocin, which similarly enhance chirping and are influenced by 5HT(1A) activity in other systems.

  20. Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors for Developing Effective Antipsychotics

    DEFF Research Database (Denmark)

    Brindisi, Margherita; Butini, Stefania; Franceschini, Silvia;

    2014-01-01

    Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid...

  1. Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT neurons in mice with altered 5-HT homeostasis

    Directory of Open Access Journals (Sweden)

    Naozumi eAraragi

    2013-08-01

    Full Text Available Firing activity of serotonin (5-HT neurons in the dorsal raphe nucleus (DRN is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert -/- and tryptophan hydroxylase-2 knockout (Tph2 -/- mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+-8-hydroxy-2-(di-n-propylaminotetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2 -/- mice and Sert -/- mice, respectively. While 5-HT neurons from Tph2 -/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert -/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP, neurons from both Tph2 -/- and Sert -/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.

  2. Differential involvement of 5-HT(1A) and 5-HT(1B/1D) receptors in human interferon-alpha-induced immobility in the mouse forced swimming test.

    Science.gov (United States)

    Zhang, Hongmei; Wang, Wei; Jiang, Zhenzhou; Shang, Jing; Zhang, Luyong

    2010-01-01

    Although Interferon-alpha (IFN-alpha, CAS 9008-11-1) is a powerful drug in treating several viral infections and certain tumors, a considerable amount of neuropsychiatric side-effects such as depression and anxiety are an unavoidable consequence. Combination with the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine (CAS 56296-78-7) significantly improved the situation. However, the potential 5-HT(1A) receptor- and 5-HT(1B) receptor-signals involved in the antidepressant effects are still unclear. The effects of 5-HT(1A) receptor- and 5-HT(1B) receptor signals were analyzed by using the mouse forced swimming test (FST), a predictive test of antidepressant-like action. The present results indicated that (1) fluoxetine (administrated intragastrically, 30 mg/kg; not subactive dose: 15 mg/kg) significantly reduced IFN-alpha-induced increase of the immobility time in the forced swimming test; (2) 5-HT(1A) receptor- and 5-HT(1B) receptor ligands alone or in combination had no effects on IFN-alpha-induced increase of the immobility time in the FST; (3) surprisingly, WAY 100635 (5-HT(1A) receptor antagonist, 634908-75-1) and 8-OH-DPAT(5-HT(1A) receptor agonist, CAS 78950-78-4) markedly enhanced the antidepressant effect of fluoxetine at the subactive dose (15 mg/kg, i. g.) on the IFN-alpha-treated mice in the FST. Further investigations showed that fluoxetine combined with WAY 100635 and 8-OH-DPAT failed to produce antidepressant effects in the FST. (4) Co-application of CGS 12066A (5-HT(1B) receptor agonist, CAS 109028-09-3) or GR 127935 (5-HT(1B/1D) receptor antagonist, CAS 148642-42-6) with fluoxetine had no synergistic effects on the IFN-alpha-induced increase of immobility time in FST. (5) Interestingly, co-administration of GR 127935, WAY 100635 and fluoxetine significantly reduced the IFN-alpha-induced increase in immobility time of FST, being more effective than co-administration of WAY 100635 and fluoxetine. All results suggest that (1) compared to

  3. Role of dorsal raphe nucleus 5-HT(1A) and 5-HT(2) receptors in tonic immobility modulation in guinea pigs.

    Science.gov (United States)

    Ferreira, Mateus Dalbem; Menescal-de-Oliveira, Leda

    2009-08-18

    Tonic immobility (TI) is an innate defensive behavior characterized by a state of physical inactivity and diminished responsiveness to environmental stimuli. Behavioral adaptations to changes in the external and internal milieu involve complex neuronal network activity and a large number of chemical neurotransmitters. The TI response is thought to be influenced by serotonin (5-HT) activity in the central nervous system (CNS) of vertebrates, but the neuronal groups involved in the mechanisms underlying this behavior are poorly understood. Owing to its extensive afferents and efferents, the dorsal raphe nucleus (DRN) has been implicated in a great variety of physiological and behavioral functions. In the current study, we investigated the influence of serotonergic 5-HT(1A) and 5-HT(2) receptor activity within the DRN on the modulation of TI behavior in the guinea pig. Microinjection of a 5-HT(1A) receptor agonist (8-OH-DPAT, 0.01 and 0.1 microg) decreased TI behavior, an effect blocked by pretreatment with WAY-100635 (0.033 microg), a 5-HT(1A) antagonist. In contrast, activation of 5-HT(2) receptors within the DRN (alpha-methyl-5-HT, 0.5 microg) increased the TI duration, and this effect could be reversed by pretreatment with an ineffective dose (0.01 microg) of ketanserine. Since the 5-HT(1A) and 5-HT(2) agonists decreased and increased, respectively, the duration of TI, different serotonin receptor subtypes may play distinct roles in the modulation of TI in the guinea pig.

  4. Limited participation of 5-HT1A and 5-HT2A/2C receptors in the clozapine-induced Fos-protein expression in rat forebrain regions

    NARCIS (Netherlands)

    Sebens, JB; Kuipers, SD; Koch, T; Ter Horst, GJ; Korf, J

    2000-01-01

    Through the development of tolerance following long-term clozapine treatment, we investigated whether 5-HT1A and 5-HT2A/2C receptors participate in the clozapine-induced Fos-protein expression in the rat forebrain. Tolerance exists when the acutely increased Fos responses to a challenge dose of the

  5. [carbonyl-C-11]desmethyl-WAY-100635 (DWAY) is a potent and selective radioligand for central 5-HT1A receptors in vitro and in vivo

    NARCIS (Netherlands)

    Pike, VW; Halldin, C; McCarron, JA; Lundkvist, C; Hirani, E; Olsson, H; Hume, SP; Karlsson, P; Osman, S; Swahn, CG; Hall, H; Wikstrom, H; Mensonidas, M; Poole, KG; Farde, L

    1998-01-01

    [carbonyl-C-11]Desmethyl-WAY-100635 (DWAY) is possibly a low-level metabolite appearing in plasma after intravenous administration of [carbonyl(11)C]WAY-100635 to human subjects for positron emission tomographic (PET) imaging of brain 5-HT1A receptors. In this study we set out to assess the ability

  6. Differences in the effects of 5-HT1A receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice

    NARCIS (Netherlands)

    Veenema, AH; Cremers, TIFH; Jongsma, ME; Steenbergen, PJ; de Boer, SF; Koolhaas, JM; Jongsma, Minke E.; Koolhaas, Jaap M.

    2005-01-01

    Rationale: Male wild house- mice genetically selected for long attack latency ( LAL) and short attack latency ( SAL) differ in structural and functional properties of postsynaptic serotonergic- 1A ( 5- HT1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming

  7. Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice : An across-strain comparison

    NARCIS (Netherlands)

    Caramaschi, Doretta; de Boer, Sietse F.; Koolhaas, Jaap M.

    2007-01-01

    Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison. PHYSIOL BEHAV 00(0) 000-000, 2006. According to the serotonin (5-HT)-deficiency hypothesis of aggression, highly aggressive individuals are characterized by low brain 5-HT neurotransmission.

  8. Tolerance in the anxiolytic profile following repeated administration of diazepam but not buspirone is associated with a decrease in the responsiveness of postsynaptic 5-HT-1A receptors.

    Science.gov (United States)

    Khan, Asma; Haleem, D J

    2007-12-01

    To understand the role of serotonin (5-hydroxytryptamine; 5-HT)-1A receptors in the treatment of anxiety and the development of tolerance to benzodiazepines the present study was designed to monitor the responsiveness of postsynaptic 5-HT-1A receptors following repeated administration of diazepam and buspirone. Results show that tolerance in the anxiolytic profile is produced following repeated administration (2 weeks) of diazepam (2 mg/kg) but not buspirone (0.5 mg/kg). The behavioral effects of 8-OH-DPAT at a dose of 0.25 mg/kg were monitored 3 days after repeated administration of saline or buspirone or diazepam. The results show that 8-OH-DPAT elicited forepaw treading was smaller in repeated diazepam but not repeated buspirone injected rats, while hyperlocomotive effects of 8-OH-DPAT were smaller in both repeated buspirone and repeated diazepam injected rats. The results suggest that postsynaptic 5-HT-1A receptor-dependent responses were attenuated following long-term administration of diazepam but not buspirone. Role of 5-HT-1A receptors in the development of tolerance to the anxiolytic effects of diazepam but not buspirone is discussed.

  9. A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAY x 3702) in ischemic stroke

    NARCIS (Netherlands)

    Luiten, PGM; Nyakas, C

    2005-01-01

    Repinotan HCl (repinotan, BAY x 3702), a highly selective 5-HT1A receptor agonist with a good record of safety was found to have pronounced neuroprotective effects in experimental models that mimic various aspects of brain injury. Repinotan caused strong, dose-dependent infarct reductions in

  10. [CROSS-TALK BETWEEN 5-HT1A AND 5-HT7 RECEPTORS: ROLE IN THE AUTOREGULATION OF THE BRAIN SEROTONIN SYSTEM AND IN MECHANISM OF ANTIDEPRESSANTS ACTION].

    Science.gov (United States)

    Popova, N K; Ponimaskin, E G; Naumenko, V S

    2015-11-01

    Recent studies considerably extended our knowledge of the mechanisms and physiological role of the interaction between different receptors in the brain. Current review summarizes data on the formation of receptor complexes and the role of such complexes in the autoregulation of the brain serotonin system, behavioral abnormalities and mechanism of antidepressants action. Particular attention is paid to 5-HT1A and 5-HT7 receptor heterodimers. The results described in the present review indicate that: i) dimerization and formation of mobile receptor complexes is a common feature for the members of G-protein coupled receptor superfamily; ii) 5-HT7 receptor appears to be a modulator for 5-HT1A receptor - the key autoregulator of the brain serotonin system; iii) 5-HT1A/5-HT7 receptor complexes formation is one of the mechanisms for inactivation and desensitization of the 5-HTIA receptors in the brain; iv) differences in the 5-HT7 receptor and 5-HTIA/5-HT7 heterodimers density define different sensitivity of pre- and postsynaptic 5-HTlA receptors to chronic treatment with selective serotonin reuptake inhibitors.

  11. 5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze.

    Science.gov (United States)

    Gonzalez, L E; Andrews, N; File, S E

    1996-09-01

    In order to investigate the role of the 5-HT1A receptors of the amygdala in modulating anxiety, rats were implanted with bilateral cannulae aimed at the basolateral nucleus of the amygdala complex and infused with either artificial cerebrospinal fluid (aCSF) or the selective 5-HT1A receptor agonist 8-OH-DPAT (50-200 ng) and tested in two animal models of anxiety. In the elevated plus-maze test, no significant effects were detected in this dose range. In contrast, 8-OH-DPAT caused an overall reduction in levels of social investigation, thus indicating anxiogenic actions in the social interaction test. At 50 ng, 8-OH-DPAT had a selective action on anxiety, while at 200 ng there was a concomitant reduction in locomotor activity and, in some animals, signs of the 5-HT1A syndrome. Evidence that the anxiogenic effect of 8-OH-DPAT (50 ng) was due to activation of 5-HT1A receptors came from the finding that (-)-tertatolol, a 5-HT1A receptor antagonist, reversed this effect at a dose (1.5 micrograms) which was silent when given alone. The benzodiazepine receptor agonist, midazolam (1 and 2 micrograms) was bilaterally administered into the basolateral nucleus of the amygdala and evoked clear-cut anxiolytic effects in the social interaction test. These data indicate that the agonist activation of post-synaptic 5-HT1A receptors in the basolateral nucleus of the amygdala may produce anxiogenic effects, while agonist activation of BDZ receptors in the same areas evokes anxiolytic effects. Our results from the social interaction test are similar to those previously reported from tests of anxiety using punished paradigms, but contrast with those found in the elevated plus-maze. Thus, it is concluded that either the two tests have different sensitivities to midazolam and 8-OH-DPAT or more intriguingly, the tests are evoking fundamentally different states of anxiety, with that evoked by the plus-maze being mediated via brain areas or receptors different from those studied here.

  12. On the role of brain 5-HT7 receptor in the mechanism of hypothermia: comparison with hypothermia mediated via 5-HT1A and 5-HT3 receptor.

    Science.gov (United States)

    Naumenko, Vladimir S; Kondaurova, Elena M; Popova, Nina K

    2011-12-01

    Intracerebroventricular administration of selective agonist of serotonin 5-HT(7) receptor LP44 (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-pyperasinehexanamide hydrochloride; 10.3, 20.5 or 41.0 nmol) produced considerable hypothermic response in CBA/Lac mice. LP44-induced (20.5 nmol) hypothermia was significantly attenuated by the selective 5-HT(7) receptor antagonist SB 269970 (16.1 fmol, i.c.v.) pretreatment. At the same time, intraperitoneal administration of LP44 in a wide range of doses 1.0, 2.0 or 10.0 mg/kg (2.0, 4.0, 20.0 μmol/kg) did not cause considerable hypothermic response. These findings indicate the implication of central, rather than peripheral 5-HT(7) receptors in the regulation of hypothermia. The comparison of LP44-induced (20.5 nmol) hypothermic reaction in eight inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J, C3H and Asn) was performed and a significant effect of genotype was found. In the same eight mouse strains, functional activity of 5-HT(1A) and 5-HT(3) receptors was studied. The comparison of hypothermic responses produced by 5-HT(7) receptor agonist LP44 (20.5 nmol, i.c.v.) and 5-HT(1A) receptor agonist 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg), 5-HT(3) receptor agonist m-CPBG (40.0 nmol, i.c.v.) did not reveal considerable interstrain correlations between 5-HT(7) and 5-HT(1A) or 5-HT(3) receptor-induced hypothermia. The selective 5-HT(7) receptor antagonist SB 269970 (16.1 fmol, i.c.v.) failed to attenuate the hypothermic effect of 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg) and m-CPBG (40.0 nmol, i.c.v.) indicating that the brain 5-HT(7) receptor is not involved in the hypothermic effects of 8-OH-DPAT or m-CPBG. The obtained results suggest that the central 5-HT(7) receptor plays an essential role in the mediation of thermoregulation independent of 5-HT(1A) and 5-HT(3) receptors.

  13. Relación del efecto analgésico de fentanilo agudo con la regulación a la alta de los receptores 5-HT1A cerebrales en la rata Relationship between the analgesic effect of acute fentanyl and upregulation of brain 5-HT1A receptors in the rat

    Directory of Open Access Journals (Sweden)

    I. Bellido

    2004-07-01

    Full Text Available Los agonistas 5-HT1A presentan efecto analgésico. El efecto analgésico de los agonistas µ puede ser bloqueado por antagonistas selectivos 5-HT1A. Para determinar el mecanismo de producción del sinergismo observado entre los receptores µ y serotoninérgico 5-HT1A en relación con su efecto antinociceptivo, determinamos el efecto analgésico de fentanilo tras estímulo nociceptivo de tipo térmico y mecánico en la rata relacionándolo con la afinidad y la densidad máxima de los receptores 5-HT1A de trece áreas cerebrales mediante técnicas de autorradiografía. Fentanilo presentó un efecto analgésico dosis y tiempo dependiente ante los dos estímulos nociceptivos. Paralelamente a la aparición del efecto analgésico, fentanilo originó una regulación a la alta de los receptores 5-HT1A al incrementar de forma dosis-dependiente su densidad sin modificar su afinidad. La dosis mayor de fentanilo (12,8 µg.kg-1 originó un incremento de la densidad de los receptores 5-HT1A estadísticamente significativo y que se correlacionó de forma positiva con su efecto analgésico en las áreas terminales corticales fronto-parietal externa (+64%, interna (+69% y piriforme (+113%, las regiones del hipocampo CA1 (+111% y DGm (+60%, los núcleos amigdalinos PMCo (+101% y AHiAL (+91% y el hipotálamo (+127%. El efecto analgésico de fentanilo en tratamiento agudo se explicaría, al menos, por dos mecanismos. Su capacidad de estimular la neurotransmisión opiácea actuando directamente sobre los receptores opiáceos µ. Y porque, al incrementar los niveles de 5-HT a nivel central y al regular a la alta los receptores 5-HT1A de zonas cerebrales terminales, se facilitaría la estimulación de estos receptores. Dado que los receptores 5-HT1A postsinápticos actúan como heteroreceptores de efecto inhibidor sobre neuronas no serotoninérgicas originando una hiperpolarización neuronal, fentanilo, al facilitar el estímulo de estos receptores originaría una

  14. The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors

    Directory of Open Access Journals (Sweden)

    Eri Segi-Nishida

    2017-05-01

    Full Text Available Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs specifically increase serotonin (5-HT levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG, is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs to revert to immature-like phenotypes defined as a “dematured” state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty-suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs.

  15. Holographic Quantitative Structure-Activity Relationships of Tryptamine Derivatives at NMDA, 5HT1A and 5HT2A Receptors

    Directory of Open Access Journals (Sweden)

    Peter Wolschann

    2013-07-01

    Full Text Available Tryptamine derivatives (Ts were found to inhibit the binding of [3H]MK-801, [3H]ketanserin and [3H]8-OH-DPAT to rat brain membranes. [3H]MK-801 labels the NMDA (N-methyl-D-aspartate receptor, a ionotropic glutamate receptor which controls synaptic plasticity and memory function in the brain, whereas [3H]ketanserin and [3H]8-OH-DPAT label 5HT2A and 5HT1A receptors, respectively. The inhibitory potencies of 64 Ts (as given by IC50 values were correlated with their structural properties by using the Holographic QSAR procedure (HQSAR. This method uses structural fragments and connectivities as descriptors which were encoded in a hologram thus avoiding the usual problems with conformation and alignment of the structures. Four correlation equations with high predictive ability and appropriate statistical test values could be established. The results are visualized by generation of maps reflecting the contribution of individual structural parts to the biological activities.

  16. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.

    Science.gov (United States)

    Linge, Raquel; Jiménez-Sánchez, Laura; Campa, Leticia; Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Pazos, Angel; Adell, Albert; Díaz, Álvaro

    2016-04-01

    Cannabidiol (CBD), the main non-psychotomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated the effects of CBD following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism.

  17. New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7 and 5-HT1A receptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies.

    Science.gov (United States)

    Intagliata, Sebastiano; Modica, Maria N; Pittalà, Valeria; Salerno, Loredana; Siracusa, Maria A; Cagnotto, Alfredo; Salmona, Mario; Kurczab, Rafał; Romeo, Giuseppe

    2017-02-01

    Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT7 and 5-HT1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds. A 4-arylpiperazine moiety through a five methylene chain was anchored at the nitrogen or oxygen atom of the heterocyclic scaffolds. The substituents borne by the piperazine nucleus were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Binding tests, performed on human cloned 5-HT7 and 5-HT1A receptors, showed that, among the newly synthesized derivatives, 4-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentoxy]-6-phenyl-pyrimidine (13) and 3-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentyl]-2-methyl-4(3H)-quinazolinone (20) displayed the best affinity values, Ki=23.5 and 8.42nM for 5-HT7 and 6.96 and 2.99nM for 5-HT1A receptors, respectively. Moreover, the functional properties for both compounds were further evaluated using the cAMP assay. Finally, a molecular modeling study has been performed for 5-HT7 and 5-HT1A receptor homology models to investigate the binding mode of N- and O-alkylated pyrimidinones/pyrimidines 4-13, 2-methylquinazolinones/quinazolines 17-22, and previously reported 2- and 3-substituted quinazolinones 23-30.

  18. Alternative methods for labeling the 5-HT1A receptor agonist, 1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piperazine (S14506), with carbon-11 or fluorine-18

    NARCIS (Netherlands)

    Lu, SY; Hong, J; Musachio, JL; Chin, FT; Vermeulen, ES; Wikstrom, HV; Pike, VW

    2005-01-01

    1-[2-(4-Fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piperazine (S14506) is one of the most potent and selective agonists at 5-HT1A receptors. For the purpose of prospective 5-HT1A receptor imaging with positron emission tomography and the investigation of radioligand metabolic pathways, S14506 wa

  19. Role of 5-HT(1A) and 5-HT(1B) receptors in the antidepressant-like effect of piperine in the forced swim test.

    Science.gov (United States)

    Mao, Qing-Qiu; Huang, Zhen; Ip, Siu-Po; Xian, Yan-Fang; Che, Chun-Tao

    2011-10-24

    Our previous studies have showed that treating mice with piperine significantly decreased the immobility time of the animals in the forced swim test and tail suspension test, which was related to up-regulation of serotonin (5-HT) level in the brain. The purpose of this study is to explore the contribution of 5-HT receptors in the antidepressant-like effect of piperine. The results showed that pre-treating mice with methiothepin (a non-selective 5-HT receptor antagonist, 0.1mg/kg, intraperitoneally), 4-(2'-methoxy-phenyl)-1-[2'-(n-2″-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (a selective 5-HT(1A) receptor antagonist, 1mg/kg, subcutaneously) or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (a 5-HT(1B) receptor antagonist, 2.5mg/kg, intraperitoneally) was found to abolish the anti-immobility effect of piperine (10mg/kg, intraperitoneally) in the forced swim test. On the other hand, a sub-effective dose of piperine (1mg/kg, intraperitoneally) produced a synergistic antidepressant-like effect with (+)-8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT(1A) receptor agonist, 1mg/kg, intraperitoneally) or anpirtoline (a 5-HT(1B) receptor agonist, 0.25mg/kg, intraperitoneally). Taken together, these results suggest that the antidepressant-like effect of piperine in the mouse forced swim test may be mediated, at least in part, by the activation of 5-HT(1A) and 5-HT(1B) receptors.

  20. Synthesis, Docking Studies and Biological Evaluation of Benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl-propan-1-one Derivatives on 5-HT1A Serotonin Receptors

    Directory of Open Access Journals (Sweden)

    Ramiro Araya-Maturana

    2012-02-01

    Full Text Available A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl-propan-1-one derivatives 6a–f, 7a–f and their corresponding alcohols 8a–f were synthesized and evaluated for their affinity towards 5-HT1A receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl-3-(4-(pyridin-2-ylpiperazin-1-ylpropan-1-one (7e displayed micromolar affinity (Ki = 2.30 μM toward 5-HT1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.

  1. Quinolinesulfonamides of aryloxy-/arylthio-ethyl piperidines: influence of an arylether fragment on 5-HT1A/5-HT7 receptor selectivity.

    Science.gov (United States)

    Grychowska, Katarzyna; Marciniec, Krzysztof; Canale, Vittorio; Szymiec, Michał; Glanowski, Grzegorz; Satała, Grzegorz; Maślankiewicz, Andrzej; Pawłowski, Maciej; Bojarski, Andrzej J; Zajdel, Paweł

    2013-03-01

    The solid-phase synthesis of a new series of 19 biomimetics of long-chain arylpiperazines, namely flexible quinoline sulfonamides of aryl(heteroaryl)oxy-/heteroarylthio-ethyl 4-aminomethylpiperidines, is reported. Various structural modifications applied followed by biological evaluation for 5-HT1A, 5-HT6, and 5-HT7 receptors gave further support of a possible replacement of arylpiperazine with aryloxy-/arylthio-ethyl derivatives of alicyclic amines and control of receptor selectivity upon diversification in the aryl(heteroaryl)oxy-/heteroarylthio-ethyl fragment.

  2. Facilitating antidepressant-like actions of estrogens are mediated by 5-HT1A and estrogen receptors in the rat forced swimming test.

    Science.gov (United States)

    Estrada-Camarena, E; López-Rubalcava, C; Fernández-Guasti, A

    2006-09-01

    Previous studies have shown that 17beta-estradiol (E2) induces antidepressant-like actions per se and potentiates those produced by fluoxetine (FLX) in the forced swimming test (FST). The aim of the present work was to explore the participation of serotonin 1A receptors (5-HT1A) and estrogen receptors (ERs) in the antidepressant-like actions of E2, FLX or their combination in the FST. Although all antidepressants reduce behavioral immobility, antidepressants that modulate serotonergic neurotransmission increase swimming behavior whereas those that modulate the catecholaminergic neurotransmission increase climbing behavior. Thus, using this animal model, it is possible to infer which neurotransmitter system is modulating the action of an antidepressant compound. Ovariectomized female Wistar rats were used in all experiments. In the first experiment, an effective dose of E2 (10 microg/rat, -48 h) was combined with several doses (0.5, 1.0 and 2 mg/kg) of RU 58668 (a pure ER antagonist) 48 h previous to the FST. The second experiment evaluated the action of (1 mg/kg, -48 h or -23, -5 and -1 h) WAY 100635 (5-HT1A receptor antagonist) on the antidepressant-like action of FLX (10 mg/kg, -23, -5 and -1 h). In the third experiment, the effect of RU 58668 (2 mg/kg, -48) or WAY 100635 (1 mg/kg, -48 h) on the antidepressant-like action of the combination of a sub-optimal dose of E2 (2.5 microg/rat, -48 h) plus a non-effective dose of FLX (2.5 mg/kg, -23,-5 and -1 h) was evaluated. The results showed that RU 58668, the antagonist to the ER, canceled the antidepressant-like action of E2 in a dose-dependent manner. The antagonist to the 5-HT1A receptor blocked the antidepressant action of FLX only when administered simultaneously with FLX, i.e. -23, -5 and -1 h before the FST. Finally, the administration of both RU 58668, and WAY100635 canceled the antidepressant-like action of the combination of E2/FLX. These results imply that both 5-HT1A receptors and ERs participate in the

  3. Prophylactic effects of asiaticoside-based standardized extract of Centella asiatica (L.) Urban leaves on experimental migraine: Involvement of 5HT1A/1B receptors.

    Science.gov (United States)

    Bobade, Vijeta; Bodhankar, Subhash L; Aswar, Urmila; Vishwaraman, Mohan; Thakurdesai, Prasad

    2015-04-01

    The present study aimed at evaluation of prophylactic efficacy and possible mechanisms of asiaticoside (AS) based standardized extract of Centella asiatica (L.) Urban leaves (INDCA) in animal models of migraine. The effects of oral and intranasal (i.n.) pretreatment of INDCA (acute and 7-days subacute) were evaluated against nitroglycerine (NTG, 10 mg·kg(-1), i.p.) and bradykinin (BK, 10 μg, intra-arterial) induced hyperalgesia in rats. Tail flick latencies (from 0 to 240 min) post-NTG treatment and the number of vocalizations post-BK treatment were recorded as a measure of hyperalgesia. Separate groups of rats for negative (Normal) and positive (sumatriptan, 42 mg·kg(-1), s.c.) controls were included. The interaction of INDCA with selective 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonists (NAN-190, Isamoltane hemifumarate, and BRL-15572 respectively) against NTG-induced hyperalgesia was also evaluated. Acute and sub-acute pre-treatment of INDCA [10 and 30 mg·kg(-1) (oral) and 100 μg/rat (i.n.) showed significant anti-nociception activity, and reversal of the NTG-induced hyperalgesia and brain 5-HT concentration decline. Oral pre-treatment with INDCA (30 mg·kg(-1), 7 d) showed significant reduction in the number of vocalization. The anti-nociceptive effects of INDCA were blocked by 5-HT1A and 5-HT1B but not 5-HT1D receptor antagonists. In conclusion, INDCA demonstrated promising anti-nociceptive effects in animal models of migraine, probably through 5-HT1A/1B medicated action.

  4. Cooperative regulation of anxiety and panic-related defensive behaviors in the rat periaqueductal grey matter by 5-HT1A and μ-receptors.

    Science.gov (United States)

    Roncon, Camila M; Biesdorf, Carla; Coimbra, Norberto C; Audi, Elisabeth A; Zangrossi, Hélio; Graeff, Frederico G

    2013-12-01

    Previous results with the elevated T-maze (ETM) test indicate that the antipanic action of serotonin (5-HT) in the dorsal periaqueductal grey (dPAG) depends on the activation endogenous opioid peptides. The aim of the present work was to investigate the interaction between opioid- and serotonin-mediated neurotransmission in the modulation of defensive responses in rats submitted to the ETM. The obtained results showed that intra-dPAG administration of morphine significantly increased escape latency, a panicolytic-like effect that was blocked by pre-treatment with intra-dPAG injection of either naloxone or the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl] ethyl] -N- 2- pyridinyl-ciclohexanecarboxamide maleate (WAY-100635). In addition, previous administration of naloxone antagonized both the anti-escape and the anti-avoidance (anxiolytic-like) effect of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), but did not affect the anti-escape effect of the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). Moreover, the combination of sub-effective doses of locally administered 5-HT and morphine significantly impaired ETM escape performance. Finally, the µ-antagonist D-PHE-CYS-TYR-D-TRP-ORN-THR-PEN (CTOP) blocked the anti-avoidance as well as the anti-escape effect of 8-OHDPAT, and the association of sub-effective doses of the µ-opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate salt (DAMGO) and of 8-OHDPAT had anti-escape and anti-avoidance effects in the ETM. These results suggest a synergic interaction between the 5-HT1A and the µ-opioid receptor at post-synaptic level on neurons of the dPAG that regulate proximal defense, theoretically related to panic attacks.

  5. μ-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses.

    Science.gov (United States)

    Roncon, Camila Marroni; Yamashita, Paula Shimene de Melo; Frias, Alana Tercino; Audi, Elisabeth Aparecida; Graeff, Frederico Guilherme; Coimbra, Norberto Cysne; Zangrossi, Helio

    2017-06-01

    The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving µ-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective μ-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY-100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between µ-opioid and 5-HT1A receptors, as previously described in the DPAG.

  6. Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats

    NARCIS (Netherlands)

    Kole, MHP; Fuchs, E; Ziemann, U; Paulus, W; Ebert, U

    1999-01-01

    The effects of a single rapid-rate transcranial magnetic stimulation (rTMS) exposure on neurotransmitter binding sites in the rat brain 24 h after the stimulation were examined. Quantification by in vitro-autoradiography showed no differences for H-3-paroxetine binding (5-HT uptake sites) between rT

  7. The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium.

    Directory of Open Access Journals (Sweden)

    Prajitha Thampi

    Full Text Available Age-related macular degeneration (AMD, a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT(1A receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE cells in the presence or absence of the 5-HT(1A receptor agonist, 8-OH DPAT. 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagy- and POS-derived lipofuscin compared to control. Reduction in autophagy-induced lipofuscin was sustained for 4 weeks following removal of the drug. The ability of 8-OH DPAT to reduce oxidative damage following exposure to 200 µM H(2O(2 was assessed. 8-OH DPAT reduced superoxide generation and increased mitochondrial superoxide dismutase (MnSOD levels and the ratio of reduced glutathione to the oxidized form of glutathione in H(2O(2-treated cells compared to controls and protected against H(2O(2-initiated lipid peroxidation, nitrotyrosine levels and mitochondrial damage. SOD2 knockdown mice, which have an AMD-like phenotype, received daily subcutaneous injections of either saline, 0.5 or 5.0 mg/kg 8-OH DPAT and were evaluated at monthly intervals. Systemic administration of 8-OH DPAT improved the electroretinogram response in SOD2 knockdown eyes of mice compared to knockdown eyes receiving vehicle control. There was a significant increase in the ONL thickness in mice treated with 8-OH DPAT at 4 months past the time of MnSOD knockdown compared to untreated controls together with a 60% reduction in RPE lipofuscin. The data indicate that 5-HT(1A agonists can reduce lipofuscin accumulation and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT

  8. 5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence.

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    Kondaurova, Elena M; Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

    2016-09-01

    Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats. These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior.

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    Holmes, Andrew; Yang, Rebecca J; Lesch, Klaus-Peter; Crawley, Jacqueline N; Murphy, Dennis L

    2003-12-01

    The serotonin transporter (5-HTT) regulates serotonergic neurotransmission via clearance of extracellular serotonin. Abnormalities in 5-HTT expression or function are found in mood and anxiety disorders, and the 5-HTT is a major target for antidepressants and anxiolytics. The 5-HTT is further implicated in the pathophysiology of these disorders by evidence that genetic variation in the promoter region of the HTT (SLC6A4) is associated with individual differences in anxiety and neural responses to fear. To further evaluate the role of the 5-HTT in anxiety, we employed a mouse model in which the 5-HTT gene (htt) was constitutively inactivated. 5-HTT -/- mice were characterized for anxiety-related behaviors using a battery of tests (elevated plus maze, lightdark exploration test, emergence test, and open field test). Male and female 5-HTT -/- mice showed robust phenotypic abnormalities as compared to +/+ littermates, suggestive of increased anxiety-like behavior and inhibited exploratory locomotion. The selective 5-HT(1A) receptor antagonist, WAY 100635 (0.05-0.3 mg/kg), produced a significant anxiolytic-like effect in the elevated plus maze in 5-HTT -/- mice, but not +/+ controls. The present findings demonstrate abnormal behavioral phenotypes in 5-HTT null mutant mice in tests for anxiety-like and exploratory behavior, and suggest a role for the 5-HT(1A) receptor in mediating these abnormalities. 5-HTT null mutant mice provide a model to investigate the role of the 5-HTT in mood and anxiety disorders.

  10. Anxiolytic-like effect of (S)-WAY 100135, a 5-HT1A receptor antagonist, in the murine elevated plus-maze test.

    Science.gov (United States)

    Rodgers, R J; Cole, J C

    1994-08-22

    The effects of (S)-WAY 100135 ((S)-N-tert-butyl-3-(4-(2-methoxyphenyl)- piperazin-1-yl)-2-phenyl-propanamide dihydrochloride; 2.5-20.0 mg/kg), a 5-HT1A receptor antagonist, on the behaviour of male mice were examined in the elevated plus-maze test of anxiety. An ethological scoring technique was used to provide a comprehensive profile of drug action. Only minor changes in behaviour were observed at 2.5 and 5.0 mg/kg, and consisted of reductions in some (though not all) risk assessment measures. At 10 mg/kg, the compound increased percent open arm entries and percent open arm time, without altering general activity levels. This classic anxiolytic-like profile was confirmed by major reductions in risk assessment measures including protected head-dips and protected stretched attend postures. Although many of the same changes were also observed at 20 mg/kg, the absence of an effect on percent open arm time and a tendency towards increased non-exploratory behaviour suggested (1) some loss of anxiolytic activity and (2) a possible contribution of non-specific factors at higher doses. Present findings indicate that (S)-WAY 100135 produces clear anxiolytic-like effects in the murine elevated plus-maze, a profile that can be distinguished from that produced by 5-HT1A receptor partial agonists in the same test.

  11. Role of 5-HT(1A) and 5-HT(7) receptors in the facilitatory response induced by 8-OH-DPAT on learning consolidation.

    Science.gov (United States)

    Meneses, A; Terrón, J A

    2001-06-01

    The present study further explored the mechanisms involved in the facilitatory effect induced by (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on learning consolidation. For this purpose, we analyzed in parallel the effects of LY215840 and ritanserin, two 5-HT(2) receptor antagonists with high affinity for the 5-HT(7) receptor, and WAY100635, a selective 5-HT(1A) receptor antagonist, on the facilitatory effect induced by 8-OH-DPAT on learning consolidation. We also determined whether LY215840 and/or ritanserin could be beneficial in restoring a deficient learning condition. Using the model of autoshaping task, post-training injection of LY215840 or WAY100635 had no effect on learning consolidation. However, both drugs abolished the enhancing effect of 8-OH-DPAT, with LY215840 being slightly more effective than WAY100635 in this respect. Ritanserin produced an increase in performance by itself and also abolished the effect of 8-OH-DPAT. Remarkably, selective blockade of 5-HT(2A) and 5-HT(2B/2C) receptors with MDL100907 and SB200646, respectively, failed to alter the 8-OH-DPAT effect. LY215840 and ritanserin, at the doses that inhibited the 8-OH-DPAT-induced response, reversed the learning deficits induced by scopolamine and dizocilpine. The present results suggest that the enhancing effect produced by 8-OH-DPAT on learning consolidation involves activation of 5-HT(1A) receptors and an additional mechanism, probably related to the 5-HT(7) receptor. Blockade of 5-HT(2) receptors, and perhaps of 5-HT(7) receptors as well, may provide some benefit in reversing learning deficits associated with decreased cholinergic and/or glutamatergic neurotransmission.

  12. Distinct effect of 5-HT1A and 5-HT2A receptors in the medial nucleus of the amygdala on tonic immobility behavior.

    Science.gov (United States)

    de Paula, Bruna Balbino; Leite-Panissi, Christie Ramos Andrade

    2016-07-15

    The tonic immobility (TI) response is an innate fear behavior associated with intensely dangerous situations, exhibited by many species of invertebrate and vertebrate animals. In humans, it is possible that TI predicts the severity of posttraumatic stress disorder symptoms. This behavioral response is initiated and sustained by the stimulation of various groups of neurons distributed in the telencephalon, diencephalon and brainstem. Previous research has found the highest Fos-IR in the posteroventral part of the medial nucleus of the amygdala (MEA) during TI behavior; however, the neurotransmission of this amygdaloid region involved in the modulation of this innate fear behavior still needs to be clarified. Considering that a major drug class used for the treatment of psychopathology is based on serotonin (5-HT) neurotransmission, we investigated the effects of serotonergic receptor activation in the MEA on the duration of TI. The results indicate that the activation of the 5HT1A receptors or the blocking of the 5HT2 receptors of the MEA can promote a reduction in fear and/or anxiety, consequently decreasing TI duration in guinea pigs. In contrast, blocking the 5HT1A receptors or activating the 5HT2 receptors in this amygdalar region increased the TI duration, suggesting an increase in fear and/or anxiety. These alterations do not appear to be due to a modification of spontaneous motor activity, which might non-specifically affect TI duration. Thus, these results suggest a distinct role of the 5HT receptors in the MEA in innate fear modulation.

  13. Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT(1A) receptor knockout mice: implications for schizophrenia.

    Science.gov (United States)

    van den Buuse, Maarten; Ruimschotel, Emma; Martin, Sally; Risbrough, Victoria B; Halberstadt, Adam L

    2011-01-01

    Serotonin-1A (5-HT(1A)) receptors may play a role in schizophrenia and the effects of certain antipsychotic drugs. However, the mechanism of interaction of 5-HT(1A) receptors with brain systems involved in schizophrenia, remains unclear. Here we show that 5-HT(1A) receptor knockout mice display enhanced locomotor hyperactivity to acute treatment with amphetamine, a widely used animal model of hyperdopaminergic mechanisms in psychosis. In contrast, the effect of MK-801 on locomotor activity, modeling NMDA receptor hypoactivity, was unchanged in the knockouts. The effect of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) was markedly reduced in 5-HT(1A) receptor knockout mice. There were no changes in apomorphine-induced disruption of PPI, a model of sensory gating deficits seen in schizophrenia. Similarly, there were no major changes in density of dopamine transporters (DAT) or dopamine D(1) or D(2) receptors which could explain the behavioural changes observed in 5-HT(1A) receptor knockout mice. These results extend our insight into the possible role of these receptors in aspects of schizophrenia. As also suggested by previous studies using agonist and antagonist drugs, 5-HT(1A) receptors may play an important role in hallucinations and to modulate dopaminergic activity in the brain.

  14. The paradox of 5-methoxy-N,N-dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors.

    Science.gov (United States)

    Winter, J C; Filipink, R A; Timineri, D; Helsley, S E; Rabin, R A

    2000-01-01

    Stimulus control was established in rats trained to discriminate either 5-methoxy-N,N-dimethyltryptamine (3 mg/kg) or (-)-2,5-dimethoxy-4-methylamphetamine (0.56 mg/kg) from saline. Tests of antagonism of stimulus control were conducted using the 5-HT1A antagonists (+/-)-pindolol and WAY-100635, and the 5-HT2 receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635 both produced a significant degree of antagonism of stimulus control, but pirenperone was much less effective. Likewise, the full generalization of 5-MeO-DMT to the selective 5-HT1A agonist [+/-]-8-hydroxy-dipropylaminotetralin was blocked by WAY-100635, but unaffected by pirenperone. In contrast, the partial generalization of 5-MeO-DMT to the 5-HT2 agonist DOM was completely antagonized by pirenperone, but was unaffected by WAY-100635. Similarly, in rats trained with (-)-DOM, pirenperone completely blocked stimulus control, but WAY-100635 was inactive. The results obtained in rats trained with (-)-DOM and tested with 5-MeO-DMT were more complex. Although the intraperitoneal route had been used for both training drugs, a significant degree of generalization of (-)-DOM to 5-MeO-DMT was seen only when the latter drug was administered subcutaneously. Furthermore, when the previously effective dose of pirenperone was given in combination with 5-MeO-DMT (s.c.), complete suppression of responding resulted. However, the combination of pirenperone and WAY-100635 given prior to 5-MeO-DMT restored responding in (-)-DOM-trained rats, and provided evidence of antagonism of the partial substitution of 5-MeO-DMT for (-)-DOM. The present data indicate that 5-MeO-DMT-induced stimulus control is mediated primarily by interactions with 5-HT1A receptors. In addition, however, the present findings suggest that 5-MeO-DMT induces a compound stimulus that includes an element mediated by interactions with a 5-HT2 receptors. The latter component is not essential for 5-MeO-DMT-induced stimulus

  15. 5-HT1A receptor blockade targeting the basolateral amygdala improved stress-induced impairment of memory consolidation and retrieval in rats.

    Science.gov (United States)

    Sardari, M; Rezayof, A; Zarrindast, M-R

    2015-08-06

    The aim of the present study was to investigate the possible role of basolateral amygdala (BLA) 5-HT1A receptors in memory formation under stress. We also examined whether the blockade of these receptors is involved in stress-induced state-dependent memory. Adult male Wistar rats received cannula implants that bilaterally targeted the BLA. Long-term memory was examined using the step-through type of passive avoidance task. Behavioral stress was evoked by exposure to an elevated platform (EP) for 10, 20 and 30min. Post-training exposure to acute stress (30min) impaired the memory consolidation. In addition, pre-test exposure to acute stress-(20 and 30min) induced the impairment of memory retrieval. Interestingly, the memory impairment induced by post-training exposure to stress was restored in the animals that received 20- or 30-min pre-test stress exposure, suggesting stress-induced state-dependent memory retrieval. Post-training BLA-targeted injection of a selective 5-HT1A receptor antagonist, (S)-WAY-100135 (2μg/rat), prevented the impairing effect of stress on memory consolidation. Pre-test injection of the same doses of (S)-WAY-100135 that was targeted to the BLA also reversed stress-induced memory retrieval impairment. It should be considered that post-training or pre-test BLA-targeted injection of (S)-WAY-100135 (0.5-2μg/rat) by itself had no effect on the memory formation. Moreover, pre-test injection of (S)-WAY-100135 (2μg/rat) that targeted the BLA inhibited the stress-induced state-dependent memory retrieval. Taken together, our findings suggest that post-training or pre-test exposure to acute stress induced the impairment of memory consolidation, retrieval and state-dependent learning. The BLA 5-HT1A receptors have a critical role in learning and memory under stress. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Third Trimester Equivalent Alcohol Exposure Reduces Modulation of Glutamatergic Synaptic Transmission by 5-HT1A Receptors in the Rat Hippocampal CA3 Region.

    Science.gov (United States)

    Morton, Russell A; Valenzuela, C Fernando

    2016-01-01

    Fetal alcohol exposure has been associated with many neuropsychiatric disorders that have been linked to altered serotonin (5-hydroxytryptamine; 5-HT) signaling, including depression and anxiety. During the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) 5-HT neurons undergo significant functional maturation and their axons reach target regions in the forebrain (e.g., cortex and hippocampus). The objective of this study was to identify the effects of third trimester ethanol (EtOH) exposure on hippocampal 5-HT signaling. Using EtOH vapor inhalation chambers, we exposed rat pups to EtOH for 4 h/day from postnatal day (P) 2 to P12. The average serum EtOH concentration in the pups was 0.13 ± 0.04 g/dl (legal intoxication limit in humans = 0.08 g/dl). We used brain slices to assess the modulatory actions of 5-HT on field excitatory postsynaptic potentials in the hippocampal CA3 region at P13-P15. Application of the GABAA/glycine receptor antagonist, picrotoxin, caused broadening of field excitatory postsynaptic potentials (fEPSPs), an effect that was reversed by application of 5-HT in slices from air exposed rats. However, this effect of 5-HT was absent in EtOH exposed animals. In slices from naïve animals, application of a 5-HT1A receptor antagonist blocked the effect of 5-HT on the fEPSPs recorded in presence of picrotoxin, suggesting that third trimester ethanol exposure acts by inhibiting the function of these receptors. Studies indicate that 5-HT1A receptors play a critical role in the development of hippocampal circuits. Therefore, inhibition of these receptors by third trimester ethanol exposure could contribute to the pathophysiology of fetal alcohol spectrum disorders.

  17. Involvement of 5-HT1A Receptors in the Anxiolytic-Like Effects of Quercitrin and Evidence of the Involvement of the Monoaminergic System

    Directory of Open Access Journals (Sweden)

    Jian Li

    2016-01-01

    Full Text Available Quercitrin is a well-known flavonoid that is contained in Flos Albiziae, which has been used for the treatment of anxiety. The present study investigated the anxiolytic-like effects of quercitrin in experimental models of anxiety. Compared with the control group, repeated treatment with quercitrin (5.0 and 10.0 mg/kg/day, p.o. for seven days significantly increased the percentage of entries into and time spent on the open arms of the elevated plus maze. In the light/dark box test, quercitrin exerted an anxiolytic-like effect at 5 and 10 mg/kg. In the marble-burying test, quercitrin (5.0 and 10.0 mg/kg also exerted an anxiolytic-like effect. Furthermore, quercitrin did not affect spontaneous locomotor activity. The anxiolytic-like effects of quercitrin in the elevated plus maze and light/dark box test were blocked by the serotonin-1A (5-hydroxytryptamine-1A (5-HT1A receptor antagonist WAY-100635 (3.0 mg/kg, i.p. but not by the γ-aminobutyric acid-A (GABAA receptor antagonist flumazenil (0.5 mg/kg, i.p.. The levels of brain monoamines (5-HT and dopamine and their metabolites (5-hydroxy-3-indoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were decreased after quercitrin treatment. These data suggest that the anxiolytic-like effects of quercitrin might be mediated by 5-HT1A receptors but not by benzodiazepine site of GABAA receptors. The results of the neurochemical studies suggest that these effects are mediated by modulation of the levels of monoamine neurotransmitters.

  18. An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models.

    Science.gov (United States)

    Canal, Clinton E; Felsing, Daniel E; Liu, Yue; Zhu, Wanying; Wood, JodiAnne T; Perry, Charles K; Vemula, Rajender; Booth, Raymond G

    2015-07-15

    Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.

  19. Antidepressant-like activity of Tagetes lucida Cav. is mediated by 5-HT(1A) and 5-HT(2A) receptors.

    Science.gov (United States)

    Bonilla-Jaime, H; Guadarrama-Cruz, G; Alarcon-Aguilar, F J; Limón-Morales, O; Vazquez-Palacios, G

    2015-10-01

    It has been demonstrated that the aqueous extract of Tagetes lucida Cav. shows an antidepressant-like effect on the forced swimming test (FST) in rats. The aim of this study was to analyze the participation of the serotoninergic system in the antidepressant-like effect of the aqueous extract of T. lucida. Different doses of the extract of T. lucida were administered at 72, 48, 24, 18 and 1 h before FST. The animals were pretreated with a 5-HT1A receptor antagonist (WAY-100635, 0.5 mg/kg), a 5-HT2A receptor antagonist (ketanserin, 5 mg/kg), a β-noradrenergic receptor antagonist (propranolol, 200 mg/kg), and with a α2-noradrenergic receptor antagonist (yohimbine, 1 mg/kg) alone or combined with the extract and pretreated with a serotonin synthesis inhibitor (PCPA) before treatment with 8-OH-DPAT + the extract of T. lucida. In addition, suboptimal doses of the 5-HT1A agonist (8-OH-DPAT) + non-effective dose of extract was analyzed in the FST. To determine the presence of flavonoids, the aqueous extract of T. lucida (20 µl, 4 mg/ml) was injected in HPLC; however, a quercetin concentration of 7.72 mg/g of extract weight was detected. A suboptimal dose of 8-OH-DPAT + extract of T. lucida decreased immobility and increased swimming and climbing. An antidepressant-like effect with the aqueous extract of T. lucida at doses of 100 and 200 mg/kg was observed on the FST with decreased immobility behavior and increased swimming; however, this effect was blocked by WAY-100635, ketanserin and PCPA but not by yohimbine and propranolol, suggesting that the extract of T. lucida could be modulating the release/reuptake of serotonin.

  20. Prelimbic cortex 5-HT1A and 5-HT2C receptors are involved in the hypophagic effects caused by fluoxetine in fasted rats.

    Science.gov (United States)

    Stanquini, Laura A; Resstel, Leonardo B M; Corrêa, Fernando M A; Joca, Sâmia R L; Scopinho, América A

    2015-09-01

    The regulation of food intake involves a complex interplay between the central nervous system and the activity of organs involved in energy homeostasis. Besides the hypothalamus, recognized as the center of this regulation, other structures are involved, especially limbic regions such as the ventral medial prefrontal cortex (vMPFC). Monoamines, such as serotonin (5-HT), play an important role in appetite regulation. However, the effect in the vMPFC of the selective serotonin reuptake inhibitor (SSRI), fluoxetine, on food intake has not been studied. The aim of the present study was to study the effects on food intake of fed and fasted rats evoked by fluoxetine injection into the prelimbic cortex (PL), a sub-region of the vMPFC, or given systemically, and which 5-HT receptors in the PL are involved in fluoxetine responses. Fluoxetine was injected into the PL or given systemically in male Wistar rats. Independent groups of rats were pretreated with intra-PL antagonists of 5-HT receptors: 5-HT1A (WAY100635), 5-HT2C (SB242084) or 5-HT1B (SB216641). Fluoxetine (0.1; 1; 3; 10nmol/200nL) injected into the PL induced a dose-dependent hypophagic effect in fasted rats. This effect was reversed by prior local treatment with WAY100635 (1; 10nmol) or SB242084 (1; 10nmol), but not with SB216641 (0.2; 2.5; 10nmol). Systemic fluoxetine induced a hypophagic effect, which was blocked by intra-PL 5-HT2C antagonist (10nmol) administration. Our findings suggest that PL 5-HT neurotransmission modulates the central control of food intake and 5-HT1A and 5-HT2C receptors in the PL could be potential targets for the action of fluoxetine.

  1. Ex vivo study of 5-HT(1A) and 5-HT(7) receptor agonists and antagonists on cAMP accumulation during memory formation and amnesia.

    Science.gov (United States)

    Perez-García, G; Meneses, A

    2008-12-16

    The cyclic adenosine monophosphate (cAMP) is a second messenger and a central component of intracellular signaling pathways that regulate a wide range of biological functions, including memory. Hence, in this work, firstly the time-course of memory formation was determined in an autoshaping learning task, which had allowed the identification of testing times for increases or decreases in performance. Next, untrained, trained and overtrained groups were compared in cAMP production. Moreover, selective stimulation and antagonism of 5-HT(1A) and 5-HT(7) receptors during memory formation and cAMP production were determined. Finally, since there is scarce information about how pharmacological models of amnesia affect cAMP production, the cholinergic or glutamatergic antagonists, scopolamine and dizocilpine, were tested. The major findings of this work showed that when the time-course was determined inasmuch as training and testing sessions occurred, memory performance was graduate and progressive. Notably, for the fourth to seventh (i.e., 48-120 h following autoshaping training session) testing session performance was significantly higher from the previous ones. When animals received 5-HT(1A) and 5-HT(7) receptor agonists and antagonists or amnesic drugs significant increases or decrements in memory performance were observed at 24 and 48 h. Moreover, when ex vivo cAMP production from trained and overtrained groups were compared to untrained ones, significant differences were observed among groups and brain areas. Trained animals treated with 8-OHDPAT, AS19, 8-OHDPAT plus AS19, WAY100635, SB-269970, scopolamine or dizocilpine were compared to similar untrained groups, and eightfold-reduced cAMP production was evident, showing the importance of cAMP production in the signaling case in mammalian memory formation.

  2. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus.

    Science.gov (United States)

    Katsidoni, Vicky; Anagnostou, Ilektra; Panagis, George

    2013-03-01

    Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

  3. Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine.

    Science.gov (United States)

    Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P; Wigestrand, Mattis B; Blakeman, Sam; Newbold, Sylvia A; Picciotto, Marina R

    2015-03-01

    Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

  4. Expression of the 5-HT1A Serotonin Receptor in the Hippocampus Is Required for Social Stress Resilience and the Antidepressant-Like Effects Induced by the Nicotinic Partial Agonist Cytisine

    Science.gov (United States)

    Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P; Wigestrand, Mattis B; Blakeman, Sam; Newbold, Sylvia A; Picciotto, Marina R

    2015-01-01

    Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders. PMID:25288485

  5. Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice.

    Science.gov (United States)

    Souza, Leandro C; de Gomes, Marcelo G; Goes, André T R; Del Fabbro, Lucian; Filho, Carlos B; Boeira, Silvana P; Jesse, Cristiano R

    2013-01-10

    The present study investigated a possible antidepressant-like activity of hesperidin using two predictive tests for antidepressant effect in mice: the forced swimming test (FST) and the tail suspension test (TST). Results demonstrated that hesperidin (0.1, 0.3 and 1 mg/kg, intraperitoneal, i.p.) decreased the immobility time in the FST and TST without affecting the locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) on the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (pCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) and WAY100635 (0.1 mg/kg, subcutaneous, s.c., a selective 5-HT(1A) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), AMPT (100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or MDL72222 (1 mg/kg, i.p., a 5-HT(3) receptor antagonist) did not block the antidepressant-like effect of hesperidin (0.3 mg/kg, i.p.) in the TST. Administration of hesperidin (0.01 mg/kg, i.p.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. The antidepressant-like effect caused by hesperidin in mice in the TST was dependent on an interaction with the serotonergic 5-HT(1A) receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like property and may be of interest source for therapeutic agent for the treatment of depressive disorders.

  6. Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.

    Science.gov (United States)

    Jiang, Xi-Ling; Shen, Hong-Wu; Yu, Ai-Ming

    2015-02-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.

  7. 5-HT1A/1B receptors as targets for optimizing pigmentary responses in C57BL/6 mouse skin to stress.

    Directory of Open Access Journals (Sweden)

    Hua-Li Wu

    Full Text Available Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR and tyrosinase-related proteins (TRP1 and TRP2 expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs, 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs, the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP, a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253, finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT

  8. Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze.

    Science.gov (United States)

    Dunn, R W; Corbett, R; Fielding, S

    1989-10-01

    The effects of several 5-HT1A agonists and excitatory amino acid antagonists were compared to the standard benzodiazepines, diazepam and chlordiazepoxide (CDP) in two assays predictive of anxiolytic activity, the social interaction and elevated plus maze procedures. Indicative of anxiolytic effects the 5-HT1A agonists, buspirone, gepirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) all significantly increased social interaction time and open arm exploration time in the social interaction and elevated plus maze procedures, respectively. Likewise, anxiolytic activity in these assays were also produced by the competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (AP-5), 2-amino-7-phosphonoheptanoic acid (AP-7), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the non-competitive NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) while NMDA produced anxiogenic effects. Furthermore, the anxiolytic effects of these agents were of equal magnitude to the benzodiazepines. These two classes of compounds were differentiated in the yohimbine-induced seizure assay, with the NMDA antagonists dose dependently antagonizing seizures similar to the benzodiazepines while the 5-HT1A agonists were inactive. These results suggest that the 5-HT1A agonists and the NMDA antagonists may be potential non-classical anxiolytic agents with different mechanisms of action.

  9. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism.

    Science.gov (United States)

    du Jardin, Kristian Gaarn; Jensen, Jesper Bornø; Sanchez, Connie; Pehrson, Alan L

    2014-01-01

    We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

  10. No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation.

    Directory of Open Access Journals (Sweden)

    Kim P C Kuypers

    Full Text Available The present study aimed at investigating the effect of MDMA on measures of empathy and social interaction, and the roles of oxytocin and the 5-HT1A receptor in these effects. The design was placebo-controlled within-subject with 4 treatment conditions: MDMA (75 mg, with or without pindolol (20 mg, oxytocin nasal spray (40 IU+16 IU or placebo. Participants were 20 healthy poly-drug MDMA users, aged between 18-26 years. Cognitive and emotional empathy were assessed by means of the Reading the Mind in the Eyes Test and the Multifaceted Empathy Test. Social interaction, defined as trust and reciprocity, was assessed by means of a Trust Game and a Social Ball Tossing Game. Results showed that MDMA selectively affected emotional empathy and left cognitive empathy, trust and reciprocity unaffected. When combined with pindolol, these effects remained unchanged. Oxytocin did not affect measures of empathy and social interaction. Changes in emotional empathy were not related to oxytocin plasma levels. It was concluded that MDMA (75 mg selectively enhances emotional empathy in humans. While the underlying neurobiological mechanism is still unknown, it is suggested that peripheral oxytocin does not seem to be the main actor in this; potential candidates are the serotonin 2A and the vasopressin 1A receptors. Trial registration: MDMA & PSB NTR 2636.

  11. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior

    DEFF Research Database (Denmark)

    Butini, Stefania; Gemma, Sandra; Campiani, Giuseppe;

    2009-01-01

    Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together...... with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c...

  12. Effect of treadmill exercise on 5-HT, 5-HT1A receptor and brain derived neurophic factor in rats after permanent middle cerebral artery occlusion.

    Science.gov (United States)

    Lan, Xiaofang; Zhang, Meng; Yang, Wan; Zheng, Zongju; Wu, Yuan; Zeng, Qian; Liu, Shudong; Liu, Ke; Li, Guangqin

    2014-05-01

    It has been well documented that exercise promotes neurological rehabilitation in patients with cerebral ischemia. However, the exact mechanisms have not been fully elucidated. This study aimed to discuss the effect of treadmill exercise on expression levels of 5-HT, 5-HT1A receptor (5-HT1AR) and brain derived neurophic factor (BDNF) in rat brains after permanent middle cerebral artery occlusion (pMCAO). A total of 55 rats were randomly divided into 3 groups: pMCAO group, pMCAO and treadmill exercise (pMCAO + Ex) group, and sham-operated group. Rats in pMCAO + Ex group underwent treadmill exercise for 16 days. Neurological function was evaluated by modified Neurological Severity Scores (mNSS). High-performance liquid chromatography-electrochemical detection system was used to determine the content of 5-HT in cortex tissues. The protein levels of 5-HT1AR, BDNF and synaptophysin were measured by Western blot. The mNSS in pMCAO + Ex group was lower than that in pMCAO group on day 19 post-MCAO (p exercise (p exercise improves neurologic function, enhances neuronal plasticity and upregulates the levels of 5-HT, 5-HT1AR and BDNF in rats with pMCAO.

  13. An Algorithm to Identify Target-Selective Ligands – A Case Study of 5-HT7/5-HT1A Receptor Selectivity

    Science.gov (United States)

    Kurczab, Rafał; Canale, Vittorio; Zajdel, Paweł; Bojarski, Andrzej J.

    2016-01-01

    A computational procedure to search for selective ligands for structurally related protein targets was developed and verified for serotonergic 5-HT7/5-HT1A receptor ligands. Starting from a set of compounds with annotated activity at both targets (grouped into four classes according to their activity: selective toward each target, not-selective and not-selective but active) and with an additional set of decoys (prepared using DUD methodology), the SVM (Support Vector Machines) models were constructed using a selective subset as positive examples and four remaining classes as negative training examples. Based on these four component models, the consensus classifier was then constructed using a data fusion approach. The combination of two approaches of data representation (molecular fingerprints vs. structural interaction fingerprints), different training set sizes and selection of the best SVM component models for consensus model generation, were evaluated to determine the optimal settings for the developed algorithm. The results showed that consensus models with molecular fingerprints, a larger training set and the selection of component models based on MCC maximization provided the best predictive performance. PMID:27271158

  14. An Algorithm to Identify Target-Selective Ligands - A Case Study of 5-HT7/5-HT1A Receptor Selectivity.

    Directory of Open Access Journals (Sweden)

    Rafał Kurczab

    Full Text Available A computational procedure to search for selective ligands for structurally related protein targets was developed and verified for serotonergic 5-HT7/5-HT1A receptor ligands. Starting from a set of compounds with annotated activity at both targets (grouped into four classes according to their activity: selective toward each target, not-selective and not-selective but active and with an additional set of decoys (prepared using DUD methodology, the SVM (Support Vector Machines models were constructed using a selective subset as positive examples and four remaining classes as negative training examples. Based on these four component models, the consensus classifier was then constructed using a data fusion approach. The combination of two approaches of data representation (molecular fingerprints vs. structural interaction fingerprints, different training set sizes and selection of the best SVM component models for consensus model generation, were evaluated to determine the optimal settings for the developed algorithm. The results showed that consensus models with molecular fingerprints, a larger training set and the selection of component models based on MCC maximization provided the best predictive performance.

  15. An in vivo pharmacological evaluation of pardoprunox (SLV308)--a novel combined dopamine D(2)/D(3) receptor partial agonist and 5-HT(1A) receptor agonist with efficacy in experimental models of Parkinson's disease.

    Science.gov (United States)

    Jones, C A; Johnston, L C; Jackson, M J; Smith, L A; van Scharrenburg, G; Rose, S; Jenner, P G; McCreary, A C

    2010-08-01

    Partial D(2/3) dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D(2/3) receptor partial agonist and full 5-HT(1A) receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED=0.03mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED=0.03mg/kg; po) and decreased motor disability (MED=0.03mg/kg; po). The effects of pardoprunox were reversed by the D(2) antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induced 5-HT(1A) receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po) and these were reversed by the 5-HT(1A) receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D(2) receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT(1A) agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.

  16. 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model.

    Science.gov (United States)

    Wang, Chao-Chuan; Lin, Hui-Ching; Chan, Yun-Han; Gean, Po-Wu; Yang, Yen Kung; Chen, Po See

    2013-10-01

    Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addition, studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomography and computed tomography co-registration following injection of (123)I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio)-5-iodophenylamine((123)I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.

  17. A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function

    Directory of Open Access Journals (Sweden)

    L.E. Gonzalez

    2003-02-01

    Full Text Available Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A receptor agonist (8-hydroxy-2-(di-n-propylaminotetralin, 8-OH-DPAT has resulted in high DPAT-sensitive (HDS and low DPAT-sensitive (LDS lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS in the prefrontal cortex (mean ± SEM, pg/20 µl, was 3.0 ± 0.4 for LDS, 3.8 ± 0.3 for HDS and 6.4 ± 0.6 for RDS; F(2,59 = 5.8, P<0.005. The administration of (±-fenfluramine (10 mg/kg induced a greater increase in hippocampal 5-HT levels in HDS rats (500% as compared with LDS (248% or RDS (243% rats (P<0.0001. There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900% in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line.

  18. Two C-methyl derivatives of [C-11]WAY-100635 - Effects of an amido alpha-methyl group on metabolism and brain 5-HT1A receptor radioligand behavior in monkey

    NARCIS (Netherlands)

    McCarron, JA; Marchais-Oberwinkler, S; Pike, VW; Tarkiainen, J; Halldin, C; Sovago, J; Gulyas, BZ; Wikstrom, HV; Farde, L; Marchais-Overwinkler, S

    2005-01-01

    Purpose: [carbonyl-C-11]N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl)cyclohexanecarboxamide ([carbonyl-C-11]WAY-100635) is an effective radioligand for imaging brain 5-HT1A receptors with positron emission tomography (PET). However, this radioligand has some drawbacks for deriving

  19. Solid-Supported Synthesis and 5-HT7 /5-HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5-dihydro-1,2,4-triazine-6-(1H)-one.

    Science.gov (United States)

    Grychowska, Katarzyna; Masurier, Nicolas; Verdié, Pascal; Satała, Grzegorz; Bojarski, Andrzej J; Martinez, Jean; Pawłowski, Maciej; Subra, Gilles; Zajdel, Paweł

    2015-10-01

    A series of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6(1H)-ones was designed and synthesized according to the new solid-supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc-protected glycine. The library representatives showed different levels of affinity for 5-HT7 and 5-HT1A receptors; compounds 13, 14 and 18-20 were classified as dual 5-HT7 /5-HT1A receptors ligands. The structure-affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.

  20. Linoleic acid derivative DCP-LA ameliorates stress-induced depression-related behavior by promoting cell surface 5-HT1A receptor translocation, stimulating serotonin release, and inactivating GSK-3β.

    Science.gov (United States)

    Kanno, Takeshi; Tanaka, Akito; Nishizaki, Tomoyuki

    2015-04-01

    Impairment of serotonergic neurotransmission is the major factor responsible for depression and glycogen synthase kinase 3β (GSK-3β) participates in serotonergic transmission-mediated signaling networks relevant to mental illnesses. In the forced-swim test to assess depression-like behavior, the immobility time for mice with restraint stress was significantly longer than that for nonstressed control mice. Postsynaptic cell surface localization of 5-HT1A receptor, but not 5-HT2A receptor, in the hypothalamus for mice with restraint stress was significantly reduced as compared with that for control mice, which highly correlated to prolonged immobility time, i.e., depression-like behavior. The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) restored restraint stress-induced reduction of cell surface 5-HT1A receptor and improved depression-like behavior in mice with restraint stress. Moreover, DCP-LA stimulated serotonin release from hypothalamic slices and cancelled restraint stress-induced reduction of GSK-3β phosphorylation at Ser9. Taken together, the results of the present study indicate that DCP-LA could ameliorate depression-like behavior by promoting translocation of 5-HT1A receptor to the plasma membrane on postsynaptic cells, stimulating serotonin release, and inactivating GSK-3β.

  1. Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Towards the therapeutics of cognitive impairment of schizophrenia

    Directory of Open Access Journals (Sweden)

    Takashi eUehara

    2014-09-01

    Full Text Available Rationale Augmentation therapy with serotonin-1A (5-HT1A receptor partial agonists has been suggested to improve cognitive deficits in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production.Objectives and methods The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days of tandospirone (0.05 and 5 mg/kg on brain energy metabolism, as represented by extracellular lactate concentration (eLAC in the medial prefrontal cortex (mPFC of young adult rats..Results Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot shock stress (FS. Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment.Conclusions These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism based on brain energy metabolism by which 5-HT1A agonism improve cognitive impairment in schizophrenia and related disorders.

  2. Central PGE2 exhibits anxiolytic-like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5-HT1A, dopamine D1 and GABAA receptors.

    Science.gov (United States)

    Suzuki, Chihiro; Miyamoto, Chihiro; Furuyashiki, Tomoyuki; Narumiya, Shuh; Ohinata, Kousaku

    2011-07-21

    We found that centrally administered prostaglandin (PG) E(2) exhibited anxiolytic-like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP(1) and EP(4) receptors, among four receptor subtypes for PGE(2), mimicked the anxiolytic-like activity of PGE(2). The anxiolytic-like activity of PGE(2) was blocked by an EP(1) or EP(4) antagonist, as well as in EP(4) but not EP(1) knockout mice. Central activation of either EP(1) or EP(4) receptors resulted in anxiolytic-like activity. The PGE(2)-induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT(1A), dopamine D(1) and GABA(A) receptors. Taken together, PGE(2) exhibits anxiolytic-like activity via EP(1) and EP(4) receptors, with downstream involvement of 5-HT(1A), D(1) and GABA(A) receptor systems. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  3. The replacement of the 2-methoxy substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine improves the selectivity for 5-HT1A receptor over α1-adrenoceptor and D2-like receptor subtypes.

    Science.gov (United States)

    Del Bello, Fabio; Bonifazi, Alessandro; Giannella, Mario; Giorgioni, Gianfabio; Piergentili, Alessandro; Petrelli, Riccardo; Cifani, Carlo; Micioni Di Bonaventura, Maria Vittoria; Keck, Thomas M; Mazzolari, Angelica; Vistoli, Giulio; Cilia, Antonio; Poggesi, Elena; Matucci, Rosanna; Quaglia, Wilma

    2017-01-05

    N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1A receptor and α1d-adrenoceptor (α1d-AR) ligand. Analogues 5-10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1A receptor and improve selectivity over α1-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1A and α1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1A receptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1A selectivity profile and the highest potency at 5-HT1A receptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1A receptor is involved.

  4. New arylpiperazinylalkyl derivatives of 8-alkoxy-purine-2,6-dione and dihydro[1,3]oxazolo[2,3-f]purinedione targeting the serotonin 5-HT1A /5-HT2A /5-HT7 and dopamine D2 receptors.

    Science.gov (United States)

    Chłoń-Rzepa, Grażyna; Zagórska, Agnieszka; Bucki, Adam; Kołaczkowski, Marcin; Pawłowski, Maciej; Satała, Grzegorz; Bojarski, Andrzej J; Partyka, Anna; Wesołowska, Anna; Pękala, Elżbieta; Słoczyńska, Karolina

    2015-04-01

    To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 ) and dopamine (D2 ) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A /5-HT7 /D2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver.

  5. Locomotor-activated neurons of the cat. I. Serotonergic innervation and co-localization of 5-HT7, 5-HT2A, and 5-HT1A receptors in the thoraco-lumbar spinal cord.

    Science.gov (United States)

    Noga, Brian R; Johnson, Dawn M G; Riesgo, Mirta I; Pinzon, Alberto

    2009-09-01

    Monoamines are strong modulators and/or activators of spinal locomotor networks. Thus monoaminergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the serotonergic innervation of locomotor-activated neurons within the thoraco-lumbar spinal cord following induction of hindlimb locomotion. This was determined by immunohistochemical co-localization of serotonin (5-HT) fibers or 5-HT(7)/5-HT2A/5-HT1A receptors with cells expressing the activity-dependent marker c-fos. Experiments were performed on paralyzed, decerebrate cats in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. Abundant c-fos immunoreactive cells were observed in laminae VII and VIII throughout the thoraco-lumbar segments of locomotor animals. Control sections from the same segments showed significantly fewer labeled neurons, mostly within the dorsal horn. Multiple serotonergic boutons were found in close apposition to the majority (80-100%) of locomotor cells, which were most abundant in lumbar segments L3-7. 5-HT7 receptor immunoreactivity was observed on cells across the thoraco-lumbar segments (T7-L7), in a dorsoventral gradient. Most locomotor-activated cells co-localized with 5-HT7, 5-HT2A, and 5-HT1A receptors, with largest numbers in laminae VII and VIII. Co-localization of c-fos and 5-HT7 receptor was highest in the L5-L7 segments (>90%) and decreased rostrally (to approximately 50%) due to the absence of receptors on cells within the intermediolateral nucleus. In contrast, 60-80 and 35-80% of c-fos immunoreactive cells stained positive for 5-HT2A and 5-HT1A receptors, respectively, with no rostrocaudal gradient. These results indicate that serotonergic modulation of locomotion likely involves 5-HT(7)/5-HT2A/5-HT1A receptors located on the soma and proximal dendrites of serotonergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments.

  6. Parametric mapping of 5HT1A receptor sites in the human brain with the Hypotime method: theory and normal values

    DEFF Research Database (Denmark)

    Møller, Mette; Rodell, Anders; Gjedde, Albert

    2009-01-01

    analysis. METHODS: A total of 19 healthy volunteers (age range, 23-73 y) underwent PET to test the Hypotime application of the chemical microsphere properties of (11)C-WAY to identify regions of binding and nonbinding on the exclusive basis of the rate of washout of (11)C-WAY. RESULTS: The results...... of the Hypotime method were compared with the simplified but multilinearized reference tissue method (MLSRTM). The distribution of receptor BP(ND) obtained with Hypotime was consistent with previous autoradiography of postmortem brain tissue, with the highest values of BP(ND) recorded in the medial temporal lobe...... and decline of receptor availability with age. The values in the basal ganglia and cerebellum were negligible. The MLSRTM, in contrast, yielded lower BP(ND) in all regions and only weakly revealed the decline with age. CONCLUSION: The simple and computationally efficient Hypotime method gave reliable values...

  7. 5-HT1A receptor blockade reverses GABA(A) receptor alpha(3) subunit-mediated anxiolytic effects on stress-induced hyperthermia

    NARCIS (Netherlands)

    Vinkers, Christiaan H.; van Oorschot, Ruud; Korte, S. Mechiel; Olivier, Berend; Groenink, Lucianne

    2010-01-01

    Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the anxiolyt

  8. Activation of septal 5-HT1A receptors alters spatial memory encoding, interferes with consolidation, but does not affect retrieval in rats subjected to a water-maze task.

    Science.gov (United States)

    Koenig, Julie; Cosquer, Brigitte; Cassel, Jean-Christophe

    2008-01-01

    Using Long-Evans rats tested in a water maze, this study assessed the role of 5-HT1A/5-HT7 receptors of the medial septum in encoding, consolidation, and retrieval of spatial information. The testing protocol (acquisition: daily four-trial sessions over three consecutive days; retention: probe trial on day 4) was first validated by showing that intraseptal infusions of lidocaine (LIDO; 40 microg/0.5 microL) disrupted acquisition and retrieval of the task. 8-OH-DPAT (4 microg/0.5 microL) infused before each acquisition session prevented learning/retention of the platform location, an effect attenuated by pretreatment with the 5-HT1A receptor antagonist WAY 100635. With the 5-HT7 antagonist SB 269970, the 8-OH-DPAT-induced acquisition deficit seemed attenuated, but there was no subsequent retention. When infused immediately, 1, 4, or 6 h after each acquisition session, 8-OH-DPAT did not hinder consolidation. When the infusions were performed 2 h postacquisition, however, consolidation was disrupted. Finally, when infused before a probe trial after drug-free acquisition, 8-OH-DPAT had no effect, suggesting no interference with retrieval processes. We also established that 8-OH-DPAT had no effects when the platform was visible, and altered neither home-cage activity nor anxiety-related behavior (elevated plus-maze). Altogether, these results show that 5-HT1A receptors in the septal region contribute both to declarative-like information encoding and subsequently, within a given postacquisition time window, to its consolidation. They do not participate in the retrieval of recently learned declarative-like information. These observations suggest that 5-HT1A receptors of the medial septum contribute to a serotonin-mediated mechanism involved in the encoding and consolidation, not the retrieval of spatial hippocampal-dependent knowledge. These results might have some relevance to approaches aimed at modifying serotonergic functions in the brain for the treatment of

  9. Tratamiento quirúrgico de la obesidad mórbida. Caracterización de los receptores 5HT1A gastrointestinales en obesidad mórbida

    OpenAIRE

    2010-01-01

    Estudios recientes muestran relación entre obesidad y síntomas gastrointestinales. Objetivos: 1. Determinar las características generales y la función gastrointestinal de pacientes obesos mórbidos sometidos a cirugía bariátrica. 2. Caracterizar los receptores serotoninérgicos 5-HT1A de fibra muscular lisa gastrointestinal (FMLGI) de los pacientes anteriores comparándolos con un control de pacientes sometidos a resección gastrointestinal sin sintomatología. Material y métodos: ...

  10. Retraction: Borroto-Escuela et al., The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity.

    Science.gov (United States)

    2013-07-10

    The Journal of Neuroscience has received a report describing an investigation by the Karolinska Institutet, which found substantial data misrepresentation in the article "The Existence of FGFR1-5-HT1A Receptor Heterocomplexes in Midbrain 5-HT Neurons of the Rat: Relevance for Neuroplasticity" by Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Mileidys Pérez-Alea, Manuel Narvaez, Alexander O. Tarakanov, Giuseppa Mudó , Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, and Kjell Fuxe, which appeared on pages 6295-6303 of the May 2, 2012 issue. Because the results cannot be considered reliable, the editors of The Journal are retracting the paper.

  11. The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae).

    Science.gov (United States)

    Twardowschy, André; Castiblanco-Urbina, Maria Angélica; Uribe-Mariño, Andres; Biagioni, Audrey Francisco; Salgado-Rohner, Carlos José; Crippa, José Alexandre de Souza; Coimbra, Norberto Cysne

    2013-12-01

    The potential anxiolytic and antipanic properties of cannabidiol have been shown; however, its mechanism of action seems to recruit other receptors than those involved in the endocannabinoid-mediated system. It was recently shown that the model of panic-like behaviors elicited by the encounters between mice and snakes is a good tool to investigate innate fear-related responses, and cannabidiol causes a panicolytic-like effect in this model. The aim of the present study was to investigate the 5-hydroxytryptamine (5-HT) co-participation in the panicolytic-like effects of cannabidiol on the innate fear-related behaviors evoked by a prey versus predator interaction-based paradigm. Male Swiss mice were treated with intraperitoneal (i.p.) administrations of cannabidiol (3 mg/kg, i.p.) and its vehicle and the effects of the peripheral pre-treatment with increasing doses of the 5-HT1A receptor antagonist WAY-100635 (0.1, 0.3 and 0.9 mg/kg, i.p.) on instinctive fear-induced responses evoked by the presence of a wild snake were evaluated. The present results showed that the panicolytic-like effects of cannabidiol were blocked by the pre-treatment with WAY-100635 at different doses. These findings demonstrate that cannabidiol modulates the defensive behaviors evoked by the presence of threatening stimuli, and the effects of cannabidiol are at least partially dependent on the recruitment of 5-HT1A receptors.

  12. Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

    Science.gov (United States)

    Tadros, Mariane G; Mohamed, Mohamed R; Youssef, Amal M; Sabry, Gilane M; Sabry, Nagwa A; Khalifa, Amani E

    2009-05-16

    Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

  13. Distribution of serotonin 5-HT1A-binding sites in the brainstem and the hypothalamus, and their roles in 5-HT-induced sleep and ingestive behaviors in rock pigeons (Columba livia).

    Science.gov (United States)

    Dos Santos, Tiago Souza; Krüger, Jéssica; Melleu, Fernando Falkenburger; Herold, Christina; Zilles, Karl; Poli, Anicleto; Güntürkün, Onur; Marino-Neto, José

    2015-12-15

    Serotonin 1A receptors (5-HT1ARs), which are widely distributed in the mammalian brain, participate in cognitive and emotional functions. In birds, 5-HT1ARs are expressed in prosencephalic areas involved in visual and cognitive functions. Diverse evidence supports 5-HT1AR-mediated 5-HT-induced ingestive and sleep behaviors in birds. Here, we describe the distribution of 5-HT1ARs in the hypothalamus and brainstem of birds, analyze their potential roles in sleep and ingestive behaviors, and attempt to determine the involvement of auto-/hetero-5-HT1ARs in these behaviors. In 6 pigeons, the anatomical distribution of [(3)H]8-OH-DPAT binding in the rostral brainstem and hypothalamus was examined. Ingestive/sleep behaviors were recorded (1h) in 16 pigeons pretreated with MM77 (a heterosynaptic 5-HT1AR antagonist; 23 or 69 nmol) for 20 min, followed by intracerebroventricular ICV injection of 5-HT (N:8; 150 nmol), 8-OH-DPAT (DPAT, a 5-HT1A,7R agonist, 30 nmol N:8) or vehicle. 5-HT- and DPAT-induced sleep and ingestive behaviors, brainstem 5-HT neuronal density and brain 5-HT content were examined in 12 pigeons, pretreated by ICV with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (N:6/group). The distribution of brainstem and diencephalic c-Fos immunoreactivity after ICV injection of 5-HT, DPAT or vehicle (N:5/group) into birds provided with or denied access to water is also described. 5-HT1ARs are concentrated in the brainstem 5-HTergic areas and throughout the periventricular hypothalamus, preoptic nuclei and circumventricular organs. 5-HT and DPAT produced a complex c-Fos expression pattern in the 5-HT1AR-enriched preoptic hypothalamus and the circumventricular organs, which are related to drinking and sleep regulation, but modestly affected c-Fos expression in 5-HTergic neurons. The 5-HT-induced ingestivebehaviors and the 5-HT- and DPAT-induced sleep behaviors were reduced by MM77 pretreatment. 5,7-DHT increased sleep per se, decreased tryptophan

  14. Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist.

    Science.gov (United States)

    Picard, M; Morisset, S; Cloix, J F; Bizot, J C; Guerin, M; Beneteau, V; Guillaumet, G; Hevor, T K

    2010-09-01

    A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area

  15. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

    OpenAIRE

    Stiedl, Oliver; Pappa, Elpiniki; Konradsson-Geuken, Åsa; Ögren, Sven Ove

    2015-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with th...

  16. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

    OpenAIRE

    Oliver eStiedl; Elpiniki ePappa; Åsa eKonradsson-Geuken; Sven Ove eÖgren

    2015-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the...

  17. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

    Directory of Open Access Journals (Sweden)

    Oliver eStiedl

    2015-08-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR subtypes, the 5-HT1AR and 5-HT7R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes.

  18. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory.

    Science.gov (United States)

    Stiedl, Oliver; Pappa, Elpiniki; Konradsson-Geuken, Åsa; Ögren, Sven Ove

    2015-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA) are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes.

  19. Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias;

    2014-01-01

    with .55°C ranging between .1-1.4°C. CONCLUSIONS: 5-hydroxytryptamine receptor 1A (5HT1A) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT1A agonists may be introduced to reduce body temperatures rapidly and prepare patients for further...

  20. Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils.

    Science.gov (United States)

    Cheeta, S; Tucci, S; Sandhu, J; Williams, A R; Rupniak, N M; File, S E

    2001-10-12

    The gerbil social interaction test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK(1)) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in social interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased social interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in social interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in social interaction. The other drugs tested were without effect on locomotor activity. The present findings suggest that the gerbil social interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK(1) receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.

  1. Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists.

    Science.gov (United States)

    Franchini, Silvia; Manasieva, Leda Ivanova; Sorbi, Claudia; Battisti, Umberto M; Fossa, Paola; Cichero, Elena; Denora, Nunzio; Iacobazzi, Rosa Maria; Cilia, Antonio; Pirona, Lorenza; Ronsisvalle, Simone; Aricò, Giuseppina; Brasili, Livio

    2017-01-05

    Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

  2. The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor.

    Science.gov (United States)

    Amigó, J; Díaz, A; Pilar-Cuéllar, F; Vidal, R; Martín, A; Compan, V; Pazos, A; Castro, E

    2016-12-01

    Preclinical studies support a critical role of 5-HT4 receptors (5-HT4Rs) in depression and anxiety, but their influence in depression- and anxiety-like behaviours and the effects of antidepressants remain partly unknown. We evaluated 5-HT4R knockout (KO) mice in different anxiety and depression paradigms and mRNA expression of some neuroplasticity markers (BDNF, trkB and Arc) and the functionality of 5-HT1AR. Moreover, the implication of 5-HT4Rs in the behavioural and molecular effects of chronically administered fluoxetine was assessed in naïve and olfactory bulbectomized mice (OBX) of both genotypes. 5-HT4R KO mice displayed few specific behavioural impairments including reduced central activity in the open-field (anxiety), and decreased sucrose consumption and nesting behaviour (anhedonia). In these mice, we measured increased levels of BDNF and Arc mRNA and reduced levels of trkB mRNA in the hippocampus, and a desensitization of 5-HT1A autoreceptors. Chronic administration of fluoxetine elicited similar behavioural effects in WT and 5-HT4R KO mice on anxiety-and depression-related tests. Following OBX, locomotor hyperactivity and anxiety were similar in both genotypes. Interestingly, chronic fluoxetine failed to reverse this OBX-induced syndrome in 5-HT4R KO mice, a response associated with differential effects in hippocampal neuroplasticity biomarkers. Fluoxetine reduced hippocampal Arc and BDNF mRNA expressions in WT but not 5-HT4R KO mice subjected to OBX. These results demonstrate that the absence of 5-HT4Rs triggers adaptive changes that could maintain emotional states, and that the behavioural and molecular effects of fluoxetine under pathological depression appear to be critically dependent on 5-HT4Rs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory.

    Science.gov (United States)

    Meneses, Alfredo

    2007-11-22

    In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.

  4. The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors.

    Science.gov (United States)

    Riga, Maurizio S; Bortolozzi, Analia; Campa, Letizia; Artigas, Francesc; Celada, Pau

    2016-02-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. LOCALIZATION OF 5-HT1A RECEPTOR SUBTYPE IN THE RAT NERVOUS SYSTEM%大鼠神经系统内5-羟色胺1A受体亚型的定位分布

    Institute of Scientific and Technical Information of China (English)

    武胜昔; 王亚云; 王文; 李云庆

    2002-01-01

    Immunocytochemical staining technique by using specific antibody against 5-HT1A receptor subtype (5-HT1AR) wasused to observe the distribution of 5-HT1AR immunoreactivity in the rat nervous system. The highest level of 5-HT1AR im-munoreactivity was observed in piriform cortex, septum, ventraldorsal thalamic nucleus, reticular thalamic nucleus, basolateralamygdaloid nucleus, Purkinje cell layer, red nucleus, facial nucleus and nucleus of the trapezoid body. Considerably weaker im-munoreactivity was detected in hippocampus, frontal cortex, mediodorsal thalamic nucleus, interpeduncular nucleus, mesen-cephalic trigeminal nucleus, dorsal raphe nucleus, spinal trigeminal nucleus, the superficial layers of the spinal dorsal horn, dor-sal root and trigeminal nerve ganglia, Very weak immunoreactivity was found in the olfactory bulb, caudate putamen,globus pal-lidus, nucleus diagonal band, bed nucleus stria terminalis, habenular nucleus, substantia nigra and superior olive. The presentresults indicate that 5-HT1AR immunoreactive structures are widely distributed in the rat nervous system and might play impor-tant role in mediating the multiple effects of 5-HT in the nervous system.%应用免疫组织化学技术观察了大鼠神经系统内5-羟色胺1A受体亚型(5-HTIAR)免疫阳性结构的分布.结果显示:5-HT1AR免疫阳性结构主要分布于梨状皮质、隔核、丘脑腹后核、丘脑网状核、杏仁基外侧核、Purkinje细胞层、红核、面神经核、斜方体核等;在海马、额叶皮质、丘脑背内侧核、脚间核、三叉神经中脑核、中缝背核、三叉神经脊束核、脊髓背角浅层、背根神经节和三叉神经等结构内有中等强度的分布;在嗅球、尾壳核、苍白球、斜角带核、终纹床核、缰核、黑质、上橄榄等部位有弱的分布.本文的结果提示5-HT1AR阳性结构广泛地分布在大鼠神经系统,它们可能介导5-HT在神经系统中的多种生理功能.

  6. Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression.

    Science.gov (United States)

    Able, Jessica A; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K

    2014-03-01

    Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats.

  7. Desensitization of 5-HT(1A) autoreceptors induced by neonatal DSP-4 treatment.

    Science.gov (United States)

    Dabrowska, Joanna; Nowak, Przemysław; Brus, Ryszard

    2007-01-15

    To examine the effect of noradrenergic lesion on the reactivity of central 5-HT(1A) receptors, DSP-4 (50 mg/kg) was administered neonatally 30 min after zimelidine (10 mg/kg) administration. 5-HT(1A) autoreceptors are involved in the regulation of serotonin (5-HT) synthesis. In HPLC assay R-(+)-8-OH-DPAT (0.03 mg/kg) significantly decreased 5-HT synthesis rate in striatum, hypothalamus and frontal cortex of control, whilst nonsignificantly in DSP-4-lesioned adult rats (10-12 weeks old). To determine which type of receptor, pre- or postsynaptically located, is involved in the attenuated response to 5-HT(1A) receptors' agonist, behavioral tests were conducted. R-(+)-8-OH-DPAT (0.015 mg/kg) caused hyperphagia of control rats, but did not change feeding of DSP-4 treated rats. R-(+)-8-OH-DPAT (0.1 mg/kg) induced hypothermia and "5-HT(1A) syndrome" in both control and DSP-4-lesioned animals. The nature of this phenomenon is attributable to the presynaptic adaptive mechanism and suggests the desensitization of 5-HT(1A) autoreceptors of rats with neonatal lesion of the central noradrenergic system.

  8. Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT(1A/2A) and 5-HT(7) receptor ligands.

    Science.gov (United States)

    Lewgowd, Wieslawa; Bojarski, Andrzej J; Szczesio, Malgorzata; Olczak, Andrzej; Glowka, Marek L; Mordalski, Stefan; Stanczak, Andrzej

    2011-08-01

    A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT(1A) receptor, and moderate-to-low affinity for 5-HT(2A) and 5-HT(7) receptors. X-ray analysis, two-dimensional NMR, conformational studies and docking into the 5-HT(1A) receptor model were conducted to investigate conformational preferences of selected 5-HT(1A) receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation.

  9. Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181

    Science.gov (United States)

    Hillegaart, Viveka; Ahlenius, Sven

    1998-01-01

    Ejaculatory problems and anorgasmia are well-known side-effects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5-HT1A and 5-HT1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5-HT receptor subtypes.The 5-HT1A receptor agonist 8-OH-DPAT (0.25–4.00 μmol kg−1 s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the new selective 5-HT1A receptor antagonist (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299) (1.0 μmol kg−1 s.c.). NAD-299 by itself (0.75–3.00 μmol kg−1 s.c.) did not affect the male rat ejaculatory behaviour.The 5-HT1B receptor agonist anpirtoline (0.25–4.00 μmol kg−1 s.c.) produced a dose-dependent inhibition of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the 5-HT1B receptor antagonist isamoltane (16 μmol kg−1 s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorpholino methansulphonate (NAS-181) (16 μmol kg−1 s.c.). Isamoltane (1.0–16.0 μmol kg−1 s.c.) and NAD-181 (1.0–16.0 μmol kg−1 s.c.) had no, or weakly facilitatory effects on the male rat ejaculatory behaviour. The non-selective 5-HT1 receptor antagonist (−)-pindolol (8 μmol kg−1 s.c.), did not antagonize the inhibition produced by anpirtoline.The present results demonstrate opposite effects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5-HT1A and 5-HT1B receptors, respectively, suggesting that the SSRI-induced inhibition of male ejaculatory dysfunction is due to 5-HT1B receptor stimulation. PMID:9886765

  10. Mutational analysis of the promoter and the coding region of the 5-HT1A gene

    Energy Technology Data Exchange (ETDEWEB)

    Erdmann, J.; Noethen, M.M.; Shimron-Abarbanell, D. [Univ. of Bonn (Germany)] [and others

    1994-09-01

    Disturbances of serotonergic pathways have been implicated in many neuropsychiatric disorders. Serotonin (5HT) receptors can be subdivided into at least three major families (5HT1, 5HT2, and 5HT3). Five human 5HT1 receptor subtypes have been cloned, namely 1A, 1D{alpha}, 1D{beta}, 1E, and 1F. Of these, the 5HT1A receptor is the best characterized subtype. In the present study we sought to identify genetic variation in the 5HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetics of neuropsychiatric diseases. The coding region and the 5{prime} promoter region of the 5HT1A gene from 159 unrelated subjects (45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette`s syndrome, as well as 25 controls) were analyzed using SSCA. SSCA revealed the presence of two mutations both located in the coding region of the 5HT1A receptor gene. The first mutation is a rare silent C{r_arrow}T substitution at nucleotide position 549. The second mutation is characterized by a base pair substitution (A{r_arrow}G) at the first position of codon 28 and results in an amino acid exchange (Ile{r_arrow}Val). Since Val28 was found only in a single schizophrenic patient and in none of the other patients or controls, we decided to extend our samples and to use a restriction assay for screening a further 74 schizophrenic, 95 bipolar affective, and 49 patients with Tourette`s syndrome, as well as 185 controls, for the presence of the mutation. In total, the mutation was found in 2 schizophrenic patients, in 3 bipolars, in 1 Tourette patient, and in 5 controls. To our knowledge the Ile-28-Val substitution reported here is the first natural occuring molecular variant which has been identified for a serotonin receptor so far.

  11. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

    Science.gov (United States)

    Pokorny, Thomas; Preller, Katrin H; Kraehenmann, Rainer; Vollenweider, Franz X

    2016-04-01

    The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (ppsilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.

  12. 5-HT1A receptors are involved in the modulation of discharge activities of biphasic expiratory neurons and inspiratory neurons%5-HT1A受体对双相呼气和吸气神经元电活动的调制

    Institute of Scientific and Technical Information of China (English)

    秦峥; 王晓锋; 郭谦; 吴中海

    2007-01-01

    目的 探讨5-HT1A受体对延髓脑片双相呼气神经元和吸气神经元电活动的影响.方法 在新生大鼠延髓脑片上同步记录舌下神经根和双相呼气神经元/吸气神经元单位的放电活动,并在灌流的改良Kreb'S液中先后加以5-HT1A受体的特异性激动剂(+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide(8-OH-DPAT)和特异性拮抗剂多次甲基多苯基多异氰酸酯[4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride](PMPPI)观察对神经元单位放电的影响.结果 给予5-HT1A受体激动剂8-OH-DPAT后,双相呼气神经元/吸气神经元的呼吸周期和呼气时程明显延长,积分幅度降低,单位放电峰频率显著性降低;给予特异性拮抗剂PMPPI后,对呼吸周期,呼气时程的作用相反,而积分幅度和单位放电峰频率无明显变化.结论 5-HT1A受体可能通过影响双相呼气神经元的电活动参与了呼吸时相的转换,同时也可能介导了吸气神经元的抑制性突触输入.%Objective To determine whether 5-HT1A receptors could modulate the discharge activities of biphasic expiratory neurons(BE-neurons)and inspiratory neurons (I-neurons).Methods Brainstem slices from newborn SD rats(0~3d)were made according to the method of Suzue,et al.These preparations included the medial region of the nucleus retrofacialis (mNRF)with the hypoglossal nerve rootlets retained.Respiratory rhythmical discharge activities (RRDA)of BE-neurons/I-neurons in mNRF and activities of the hypoglossal nerve(Ⅻ nerve)were simultaneously recorded by using extracellular microelectrodes and suction electrode,respectively.The effects of 5-HT1A receptors on the respiratory rhythm were investigated by application of 5-HT1A receptor specific agonist 8-OH-DPAT and its specific antagonist PMPPI in the perfusion solution.Results 8-OHDPAT induced a significant increase in the respiratory cycles(RC)and the expiratory time (TE) as well as a decrease

  13. Influence of 5-HT1A agonist on the feeding behavior of Coturnix japonica (Galliformes: Aves

    Directory of Open Access Journals (Sweden)

    L. C. Reis

    Full Text Available In this study, we investigate the effect of serotonin receptor 5-HT1A stimulation on the feeding behavior of quails (Coturnix japonica. The administration of 5-HT1A agonist, 8-OH-DPAT (0.05 to 5.0 mg/Kg dose-dependently inhibited the food intake in normally fed quails. Greater inhibition was attained with 5.0 mg/kg (0.93 ± 0.21 g vs. 5.83 ± 0.25 g, P < 0.05, 2 h after food offer. A comparable response was obtained from previously fasted quails. At end of 2 h, a higher dose of 8-OH-DPAT induced more intense hypophagy (1.59 ± 0.41 g vs. 6.85 ± 1.04 g, P < 0.0001. Previous treatment with the antagonist 5-HT1A/beta-adrenergic, propranolol, failed to block the inhibitory action of 8-OH-DPAT, but instead, intensified it (controls, 5.22 ± 1.09 g; 8-OH-DPAT, 1.41 ± 0.19 g; propranolol + 8-OH-DPAT, 0.44 ± 0.25 g, P < 0.01, for all comparisons. The administration of an isolated higher dose of propranolol induced a hypophagic action (controls, 4.5 ± 0.8 g vs. propranolol, 2.0 ± 0.2 g, P < 0.01. Current outcomes suggest a possible role of 5-HT1A receptor on the feeding behavior of quails, as opposed to mammals. On the other hand, the intensified hypophagy induced by previous administration of propranolol raises the hypothesis of a beta-adrenergic excitatory mechanism that controls the feeding behavior of quails.

  14. Distribution and effects of 5-HT1A receptors in distal cerebral spinal fluid-contacting neurons in rat brain parenchyma in neuropathic pain%大鼠脑实质内远位触液神经元中5-HT1A受体的分布及其在神经病理性痛中的表达

    Institute of Scientific and Technical Information of China (English)

    蒋文旭; 张励才

    2008-01-01

    The present study aimed to explore the effects of 5-HT1A receptors in the distal cerebral spinal fluid-contacting neurons(CSF-CNs) in rat brain parenchyma in neuropathic pain. The model of neuropathic pain with chronic constriction injury (CCI) of thesciatic nerve was made in Sprague-Dawley rats. The behavioral studies of animal were scored and the paw withdrawal latency (PWL)and paw withdrawal threshold (PWT) were measured. The distribution and expression of 5-HT1A receptors were observed in the distalCSF-CNs in brain parenchyma with double labeling of cholera toxin subunit B with horseradish peroxidase (CB-HRP) and 5-HT1A receptors with immunhistochemistry. The relationship between 5-HT1A receptors in distal CSF-CNs and neuropathic pain wasanalyzed. The results were as follows. On days 1, 3, 7, 14 of neuropathic pain, the PWL was 19.37±2.74, 12.04±1.77, 8.74±1.15 and12.31±1.94, respectively; the PWT was 18.58±3.62, 13.05±1.81, 6.66±1.43 and 11.55±2.01, respectively. CB-HRP-labeled neuronsof two clusters were always found in definite region but not in other area in brain parenchyma. The number of neurons double-labeledwith CB-HRP/5-HT1A receptors in each group was 276.14±36.00, 161.72±28.41,108.64±6.81, and 139.76±44.64, which was about95%, 60%, 40% and 55% of all CB-HRP-iabeled neurons in the four courses of neuropathic pain, respectively. It is suggested that thedistal CSF-CNs are always located in a special region in rat brain parenchyma and most of them have 5-HT1A receptors. A negativecorrelation is found between the expression of 5-HT1A receptors and neuropathic pain.%本文旨在探讨大鼠脑实质内远位触液神经元中5-HT1A受体的分布及其在神经病理性痛中的作用.慢性结扎损伤坐骨神经建立大鼠神经病理性痛模型,分别以缩足潜伏期(paw withdrawal latency,PWL)和缩足阈值(paw withdrawal threshold,PWT)对大鼠热痛敏和机械触诱发痛反应进行评分,以可靠CB-HRP(cholera toxin subunit B

  15. Rat dams exposed repeatedly to a daily brief separation from the pups exhibit increased maternal behavior, decreased anxiety and altered levels of receptors for estrogens (ERα, ERβ), oxytocin and serotonin (5-HT1A) in their brain.

    Science.gov (United States)

    Stamatakis, Antonios; Kalpachidou, Theodora; Raftogianni, Androniki; Zografou, Efstratia; Tzanou, Athanasia; Pondiki, Stavroula; Stylianopoulou, Fotini

    2015-02-01

    In the present study we investigated the neurobiological mechanisms underlying expression of maternal behavior. Increased maternal behavior was experimentally induced by a brief 15-min separation between the mother and the pups during postnatal days 1 to 22. On postnatal days (PND) 12 and 22, we determined in experimental and control dams levels of anxiety in the elevated plus maze (EPM) as well as the levels of receptors for estrogens (ERα, ERβ), oxytocin (OTR) and serotonin (5-HT1AR) in areas of the limbic system (prefrontal cortex-PFC, hippocampus, lateral septum-SL, medial preoptic area-MPOA, shell of nucleus accumbens-nAc-Sh, central-CeA and basolateral-BLA amygdala), involved in the regulation of maternal behavior. Experimental dams, which showed increased maternal behavior towards their offspring, displayed reduced anxiety in the EPM on both PND12 and PND22. These behavioral differences could be attributed to neurochemical alterations in their brain: On both PND12 and PND22, experimental mothers had higher levels of ERα and OTRs in the PFC, hippocampus, CeA, SL, MPOA and nAc-Sh. The experimental manipulation-induced increase in ERβ levels was less widespread, being localized in PFC, the hippocampal CA2 area, MPOA and nAc-Sh. In addition, 5-HT1ARs were reduced in the PFC, hippocampus, CeA, MPOA and nAc-Sh of the experimental mothers. Our results show that the experience of the daily repeated brief separation from the pups results in increased brain ERs and OTRs, as well as decreased 5-HT1ARs in the dam's brain; these neurochemical changes could underlie the observed increase in maternal behavior and the reduction of anxiety.

  16. Screening of medicinal plants from Suriname for 5-HT(1A) ligands: Bioactive isoquinoline alkaloids from the fruit of Annona muricata.

    Science.gov (United States)

    Hasrat, J A; Pieters, L; De Backer, J P; Vauquelin, G; Vlietinck, A J

    1997-06-01

    Plants from Suriname (South-America) and several Annona species, including A. muricata, A. ckerimolia, A. montana and A. glabra were screened for 5-HT(1A) receptor binding activity by ligand-binding-studies (LBS). Crude extracts of all Annona species and from Hibiscus bifurcatus, Irlbarchia purpurascens and Scoparia dulcis showed high activity. The isoquinoline alkaloids asimilobine (1), nornuciferine (2), and annonaine (3) were isolated as the active principles from the fruit of Annona muricata. These results may partially explain the use of Hibiscus bifurcatus and Annona muricata in traditional medicine in Suriname.

  17. Orbitofrontal Cortex 5-HT1A Receptor Modulate Glutamate and GABA in Depression Induced by Chronic Unpredictable Mild Stress%应激性抑郁样行为发生中眶额叶5-HT1A受体对谷氨酸和γ-氨基丁酸的调节

    Institute of Scientific and Technical Information of China (English)

    李江娜; 安书成; 李珍

    2015-01-01

    Stress response and depression have a crucial impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. Currently, the monoaminergic systems, especially serotonergic systems, have received the most attention in the research of depression. Accumulating evidence suggests that the glutamatergic and GABAergic system play an important role in the neurobiology and treatment of this disease. Multiple studies have shown that serotonin (5-HT) could modulate the neurotransmission of glutamic acid (Glu) and gamma-aminobutyric acid (GABA). The orbitofrontal cortex (OFC), which is involved in the pathophysiology and treatment of depression, plays a critical role in the control of higher brain functions and it mainly receives a dense 5-HT innervation from the dorsal raphe nucleus. There exist some 5-HT1A receptors on glutamatergic neurons and GABAergic neurons in the OFC. The purpose of this research was to elucidate the modulatory action of 5-HT1A receptor on the functions of Glu and GABA, which are the principal neurotransmitters mediating excitatory and inhibitory signals in the OFC respectively, in a well-established animal model of depression induced by chronic unpredictable mild stress (CUMS). We used CUMS in rat to mimic the core symptoms in human. Using the pharmacology approaches by microinjecting of 5-HT1A receptor agonist 8-OH-DPAT and its antagonist WAY100635 to the OFC, we detected behavioral changes by using behavior tests including sucrose preference test, open field test and tail suspension test. In addition, high-performance liquid chromatography (HPLC) was used to detect the level of neurotransmitters such as 5-HT, Glu and GABA in the OFC, respectively. CUMS group showed a variety of behavioral characteristics of depression, including a significant reduction in the sucrose preference, and locomotion, rearing and grooming in the open field test, and a significant increase in

  18. Effect of chronic rapid eye movement sleep deprivation on cognition and protein expression of brain 5-HT1A receptor in rats%慢性睡眠剥夺对大鼠学习记忆功能及不同脑区5-羟色胺1A受体蛋白表达的影响

    Institute of Scientific and Technical Information of China (English)

    荣霏; 程滨; 温晓飒; 马文领

    2012-01-01

    Objective To investigate the effect of chronic rapid eye movement (REM) sleep deprivation on learning and memory function and the changes of 5-HT1A receptor protein expression in hippocampus, prefrontal cortex and hypothalamus in rats. Methods Adult male Sprague-Dawley rats were randomly divided into chronic REM sleep deprivation (CSD, n = 15), big platform treatment control (TC, n = 12) and blank control (BC, n = 4) groups after screening experiment. The sleep deprivation model was established by modified multiple platform method. Learning and memory functions were detected by Morris water maze and open field test before and after sleep deprivation. The effects of chronic REM sleep deprivation on 5-HT1A receptor protein expression in the hippocampus, prefrontal cortex and hypothalamus were analyzed by Western blotting analysis. Results Compared with BC and TC groups, the weight of the rats in CSD group was significantly decreased 3 days after sleep deprivation (all P0.05). Motion speed of the central region in CSD rats was significantly slower than that in TC rats 21 days after CSD (P<0.05). Compared with BC and TC groups, the protein expression of 5-HT1A receptor in the 3 encephalic regions significantly increased in CSD group 21 days after CSD (P<0. 05), especially in the hypothalamus (P<0. 01). Conclusion Chronic REM sleep deprivation can impair the learning and memory. 5-HT1A receptor may be involved in modulating the dysfunction.%目的 观察慢性快速眼动相(REM)睡眠剥夺对大鼠学习记忆能力以及海马、前额皮质、下丘脑5-羟色胺1A(5-HT1A)受体蛋白表达变化的影响.方法 成年雄性Sprague-Dawley大鼠经过筛选后随机分为空白对照组(BC组,4只)、大平台对照组(TC组,12只)和慢性睡眠剥夺(CSD)组(15只).采用改良多平台水环境方法建立大鼠慢性REM睡眠剥夺模型,利用Morris水迷宫、自主活动箱检测CSD后大鼠学习记忆功能变化,Western印迹法分析CSD对大鼠海

  19. Antidepressant-like effects of YL-0919, a novel dual-acting antidepressant with 5-HT1A receptor agonist and serotonin reuptake inhibitor%5-HT1A受体激动和5-HT重摄取抑制双靶标新药YL-0919抗抑郁作用的药效学评价

    Institute of Scientific and Technical Information of China (English)

    陈红霞; 徐晓丹; 薛瑞; 袁莉; 杨日芳; 李云峰

    2011-01-01

    目的 评价兼有5-HT1A受体激动和5-HT重摄取抑制双靶标化合物YL-0919的抗抑郁作用,并在靶标水平探讨其作用机制.方法和结果 在小鼠悬尾和小鼠强迫游泳实验中,YL-0919(1.25,2.5,5 mg/kg,ig)能够显著地缩短小鼠悬尾不动时间和游泳不动时间,5-HT1A受体拮抗剂WAY100635(0.3 mg/kg,sc)能够完全拮抗YL-0919(2.5 mg/kg,ig)在小鼠悬尾实验中的抗抑郁作用;在药物诱发抑郁模型上,YL-0919增强5-羟色氨酸(5-hydroxytryptophan,5-HTP,120 mg/kg,ip)诱导的小鼠甩头行为,但不能拮抗高剂量阿扑吗啡(16 mg/kg,sc)诱导的降温作用;YL-0919在抗抑郁有效剂量范围内对小鼠的自主活动性无显著性影响.结论 新型双靶标新药YL-0919具有明确的抗抑郁作用,此作用与激动5-HT1A受体,增强5-HT系统的功能有关.%Objective To investigate the antidepressant-like effect and possible mechanism of YL-0919, a novel dual-acting antidepressant with 5-HT1A receptor agonist and serotonin reuptake inhibitor. Methods and Results In the tail suspension test and forced swimming test in mice, YL-0919( 1. 25, 2. 5 and 5 mg/kg, ig )significantly decreased the immobility time. 5-HT1A receptor antagonist ( WAY100635 , 0. 3 mg/kg, sc ) could completely prevent the antidepressant-like effect in the tail suspension test. In the 5-hydroxytryptophan ( 5-HTP,120 mg/kg, ip ) potentiation test, YL-0919 significantly increased the symptom of head-twitches induced by 5-HTP. However, YL-0919 had no significant effect on the apomorphine (16 mg/kg,sc )induced hypothermia or the locomotor activity in mice. Conclusion YL-0919 produces reliable antidpres-sant-like effect, which may be attributed to the activation of 5-HT1A receptor and the potentiation of 5-HT system.

  20. No change in [¹¹C]CUMI-101 binding to 5-HT(1A) receptors after intravenous citalopram in human

    DEFF Research Database (Denmark)

    Pinborg, Lars H; Feng, Ling; Haahr, Mette E

    2012-01-01

    Med Biol 38:273-277; Kumar et al. [2006] J Med Chem 49:125-134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243-249). We studied six healthy individuals. Two PET-scans were performed on the same day in each...... individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference...

  1. Disruption of 5-HT1A function in adolescence but not early adulthood leads to sustained increases of anxiety.

    Science.gov (United States)

    Garcia-Garcia, A L; Meng, Q; Richardson-Jones, J; Dranovsky, A; Leonardo, E D

    2016-05-03

    Current evidence suggests that anxiety disorders have developmental origins. Early insults to the circuits that sub-serve emotional regulation are thought to cause disease later in life. Evidence from studies in mice demonstrate that the serotonergic system in general, and serotonin 1A (5-HT1A) receptors in particular, are critical during the early postnatal period for the normal development of circuits that subserve anxious behavior. However, little is known about the role of serotonin signaling through 5-HT1A receptors between the emergence of normal anxiety behavior after weaning, and the mature adult phenotype. Here, we use both transgenic and pharmacological approaches in male mice, to identify a sensitive period for 5-HT1A function in the stabilization of circuits mediating anxious behavior during adolescence. Using a transgenic approach we show that suppression of 5-HT1A receptor expression beginning in early adolescence results in an anxiety-like phenotype in the open field test. We further demonstrate that treatment with the 5-HT1A antagonist WAY 100,635 between postnatal day (P)35 and P50, but not at later timepoints, results in altered anxiety in ethologically based conflict tests like the open field test and elevated plus maze. This change in anxiety behavior occurs without impacting behavior in the more depression-related sucrose preference test or forced swim test. The treatment with WAY 100,635 does not affect adult 5-HT1A expression levels, but leads to increased expression of the serotonin transporter in the raphe, along with enhanced serotonin levels in both the prefrontal cortex and raphe that correlate with the behavioral changes observed in adult mice. This work demonstrates that signaling through 5-HT1A receptors during adolescence (a time when pathological anxiety emerges), but not early adulthood, is critical in regulating anxiety setpoints. These data suggest the possibility that brief interventions in the serotonergic system during

  2. Augmentative effect of tetrandrine on pentobarbital hypnosis mediated by 5-HT1A and 5-HT2A/2C receptors in mice%5-HT1A和5-HT2A/2C受体在粉防己碱增强戊巴比妥钠睡眠中的介导作用

    Institute of Scientific and Technical Information of China (English)

    杜楠; 王黎恩; 师晓荣; 崔翔宇; 崔素颖; 张帆; 张永鹤

    2008-01-01

    前期研究表明粉防己碱增强戊巴比妥钠诱导的催眠作用与5-HT系统相关.本研究采用戊巴比妥钠(45 mg/kg,协)诱导的小鼠翻正反射消失和恢复实验方法,对粉防己碱与不同5-HT受体在增强戊巴比妥钠诱导睡眠中的相互作用进行了探讨.结果表明粉防己碱分别与选择性5-HT1A受体拮抗剂p-MPPI(1 mg/kg,i.p.),选择性5-HT2A/2C受体拮抗剂ketanserin(1.5mg/kg,i.p.)合用可以显著增强戊巴比妥钠诱导的催眠作用.选择性5-HT1A受体激动剂8-OH-DPAT(0.1 mg/kg,s.c.)或5-HT2A/2C受体激动剂DOI(0.2 mg/kg.i.p.)能够显著减少戊巴比妥钠诱导的小鼠睡眠时间,而粉防己碱(60 mg/kg,i.p.)可以显著拮抗这种睡眠抑制作用.此结果提示,粉防己碱增强戊巴比妥钠诱导的催眠作用可能与5-HT1A受体和5-HT2A/2C受体有关.%It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to sero-tonergic system. The present study was undertaken to investigate the interaction of tetrandrine and different 5-HT receptors on pentobarbital-induced sleep by using the loss-of-righting reflex method. The results showed that augmentative effect of tetrandrine on pentobarbital hypnosis in mice were potentiated by the p-MPPI (5-HT1A receptor antagonist) (1 mg/kg, i.p.) and ketanserin (5-HT2A/2C receptor antagonist) (1.5 mg/kg, i.p.), respectively. Pretreatment with either 8-OH-DPAT (5-HT1A receptor agonist)(0.1 mg/kg, s.c.) or DOI (5-HT2A/2C receptor agonist) (0.2 mg/kg, i.p.) significantly decreased pentobarbital-induced sleep time,and tetrandrine (60 mg/kg, i.g.) significantly reversed this effect. These results suggest that both the 5-HTtA and 5-HT2A/2C subfamily may be involved in the potentiating mechanism of tetrandrine's effects on pentobarbital hypnosis.

  3. Evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system.

    Science.gov (United States)

    Borroto-Escuela, Dasiel O; Narvaez, Manuel; Pérez-Alea, Mileidys; Tarakanov, Alexander O; Jiménez-Beristain, Antonio; Mudó, Giuseppa; Agnati, Luigi F; Ciruela, Francisco; Belluardo, Natale; Fuxe, Kjell

    2015-01-02

    The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague-Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Similar results were reached upon coactivation by agonists in HEK293T cells using the Fluorescent Resonance Energy Transfer (FRET) technique resulting in increased FRETmax and reduced FRET50 values. The heteroreceptor complex formation was dependent on TMV of the 5-HT1A receptor since it was blocked by incubation with TMV but not with TMII. Taken together, the 5-HT1A autoreceptors by being recruited into a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells may develop a novel function, namely a trophic role in many midbrain 5-HT neuron systems originating from the dorsal and medianus raphe nuclei.

  4. 5-HT1A autoreceptor modulation of locomotor activity induced by nitric oxide in the rat dorsal raphe nucleus

    Directory of Open Access Journals (Sweden)

    L.B. Gualda

    2011-04-01

    Full Text Available The dorsal raphe nucleus (DRN is the origin of ascending serotonergic projections and is considered to be an important component of the brain circuit that mediates anxiety- and depression-related behaviors. A large fraction of DRN serotonin-positive neurons contain nitric oxide (NO. Disruption of NO-mediated neurotransmission in the DRN by NO synthase inhibitors produces anxiolytic- and antidepressant-like effects in rats and also induces nonspecific interference with locomotor activity. We investigated the involvement of the 5-HT1A autoreceptor in the locomotor effects induced by NO in the DRN of male Wistar rats (280-310 g, N = 9-10 per group. The NO donor 3-morpholinosylnomine hydrochloride (SIN-1, 150, and 300 nmol and the NO scavenger S-3-carboxy-4-hydroxyphenylglycine (carboxy-PTIO, 0.1-3.0 nmol were injected into the DRN of rats immediately before they were exposed to the open field for 10 min. To evaluate the involvement of the 5-HT1A receptor and the N-methyl-D-aspartate (NMDA glutamate receptor in the locomotor effects of NO, animals were pretreated with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylaminotetralin (8-OH-DPAT, 8 nmol, the 5-HT1A receptor antagonist N-(2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635, 0.37 nmol, and the NMDA receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 nmol, followed by microinjection of SIN-1 into the DRN. SIN-1 increased the distance traveled (mean ± SEM in the open-field test (4431 ± 306.1 cm; F7,63 = 2.44, P = 0.028 and this effect was blocked by previous 8-OH-DPAT (2885 ± 490.4 cm or AP7 (3335 ± 283.5 cm administration (P < 0.05, Duncan test. These results indicate that 5-HT1A receptor activation and/or facilitation of glutamate neurotransmission can modulate the locomotor effects induced by NO in the DRN.

  5. 17β-estradiol-induced regulation of the novel 5-HT1A-related transcription factors NUDR and Freud-1 in SH SY5Y cells.

    Science.gov (United States)

    Adeosun, Samuel O; Albert, Paul R; Austin, Mark C; Iyo, Abiye H

    2012-05-01

    Nuclear deformed epidermal autoregulatory factor-1 (NUDR/Deaf-1) and five prime repressor element under dual repression (Freud-1) are novel transcriptional regulators of the 5-HT(1A) receptor, a receptor that has been implicated in the pathophysiology of various psychiatric illnesses. The antidepressant effect of 17β-Estradiol (17βE(2)) is purported to involve the downregulation of this receptor. We investigated the possible role of NUDR and Freud-1 in 17βE(2)-induced downregulation of the 5-HT(1A) receptor in the neuroblastoma cell line SH SY5Y. Cells were treated with 10 nM of 17βE(2) for 3 or 48 h, followed by a 24-h withdrawal period. Proteins were isolated and analyzed by western blotting. 17βE(2) treatment increased NUDR immunoreactivity while Freud-1 and the 5-HT(1A) receptor showed significant decreases. Upon withdrawal of 17βE(2), protein expression returned to control levels, except for NUDR, which remained significantly elevated in the 3-h treatment. Taken together, these data support a non-genomic downregulation of 5-HT(1A) receptor protein by 17βE(2), which does not involve NUDR and Freud-1. Rather, changes in both transcription factors seem to be compensatory/homeostatic responses to changes in 5-HT(1A) receptor induced by 17βE(2). These observations further highlight the importance of NUDR and Freud-1 in regulating 5-HT(1A) receptor expression.

  6. Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 Antagonists in Animal Models

    Science.gov (United States)

    Pytka, Karolina; Partyka, Anna; Jastrzębska-Więsek, Magdalena; Siwek, Agata; Głuch-Lutwin, Monika; Mordyl, Barbara; Kazek, Grzegorz; Rapacz, Anna; Olczyk, Adrian; Gałuszka, Adam; Błachuta, Marian; Waszkielewicz, Anna; Marona, Henryk; Sapa, Jacek; Filipek, Barbara; Wesołowska, Anna

    2015-01-01

    The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds. PMID:26554929

  7. 5-羟色胺1A受体激动剂改善脊髓损伤大鼠排尿功能障碍的实验研究%Improving the voding dysfunction by a 5-HT1A receptor agonist in rats with chronic spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    曹海兵; 吴刚; 程曙杰; 谷宝军

    2011-01-01

    目的 研究5-羟色胺-1A(5-HTlA)受体激动剂对慢性脊髓损伤(spinal cord injury,SCI)大鼠排尿障碍的改善作用. 方法 雌性SD大鼠14只,体质量175 ~ 200 g.随机分为2组:实验组7只显微镜下大鼠T10棘突水平行脊髓离断建立脊髓损伤模型,正常对照组7只.8周后乌拉坦(1.3 g/kg)麻醉下,2组大鼠颈静脉和膀胱内置管,连接压力感受器,记录膀胱最大容量、残余尿量、排尿量和尿道外括约肌的肌电活动.静脉注入5-HTI A/7受体激动剂8-羟基-丙胺-四氢萘(8-OH-DPAT,0.03 ~1.00 mg/kg),得出剂量—效应曲线后再给予5HTIA受体抑制剂WAY-100635 (0.3g/kg).观察比较2组大鼠用药前后尿动力学指标的变化. 结果 随着8-OH-DPAT剂量增加,SCI大鼠膀胱容量从(33.2 ±8.3)ml降至(22.8±2.4) ml,排尿量从(0.14±0.08)ml增至(0.38 ±0.09) ml,残余尿量从(3.68±1.36)ml降至(1.84±0.21)ml,而膀胱最高压力从(27.1±3.6)mm Hg(1 mm Hg=0.133 kPa)降至(22.8±2.4) mm Hg,用药前后差异均有统计学意义(P<0.05).对照组大鼠用药前后排尿情况变化差异无统计学意义.肌电图显示8-OH-DPAT引起SCI大鼠尿道外括约肌强直收缩中出现阶段性的松弛,正常对照组大鼠作用无明显改变. 结论 8-OH-DPAT可以剂量依赖性地部分恢复SCI大鼠的尿道外括约肌协调性松弛,从而降低膀胱容量,增加排尿量,减少残尿量,增加排尿效率,改善排尿障碍.%Objective To investigate the effect of 5-hydroxytryptamine serotonin receptor-1A (5-HT1 A) agonists on micturition dysfunction in rats with chronic spinal cord injury (SCI).Methods Female SD rats weighing 175 -200 g were used.Seven of the rats were modified for a spinal cord injury model (transsection at T10).Eight weeks later,control rats and SCI rats were tested.Rats were anesthetized with urethane ( 1.3 g/kg ).A polyethylene (PE) -50 catheter was placed in the left jugular vein for intravenous drug administration.A PE-90 catheter was

  8. Blonanserin reverses the phencyclidine (PCP)-induced impairment in novel object recognition (NOR) in rats: role of indirect 5-HT(1A) partial agonism.

    Science.gov (United States)

    Horiguchi, M; Meltzer, H Y

    2013-06-15

    Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2 mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3 mg/kg) and the 5-HT1A partial agonist, tandospirone (0.2 mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6 mg/kg), a 5-HT1A antagonist, and blonanserin (1 mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6 mg/kg) blocked the ameliorating effect of risperidone (0.1 mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Decision time and perseveration of adolescent rats in the T-maze are affected differentially by buspirone and independent of 5-HT-1A expression.

    Science.gov (United States)

    Rhoads, Dennis E; Grimes, Nicole; Kaushal, Sunaina; Mallari, Janine; Orlando, Krystal

    2012-07-01

    Disruption of spontaneous alternation behavior (SAB) by the serotonin 1A (5-HT-1A) receptor agonist, 8-hydroxy-dipropylaminotetraline (8-OH-DPAT), results in repetitive behaviors that have been used to model the perseveration and indecisiveness of human obsessive-compulsive disorder (OCD). In the present study, we compared the effects of buspirone to those of 8-OH-DPAT in two strains of adolescent rats and analyzed repetitive choices of arms of the maze and prolonged apparent decision time due to induction of vicarious trial and error (VTE) behavior. In adolescent Sprague-Dawley (SD) rats, 8-OH-DPAT induced repetitive choices of arms of the maze (perseveration) and increased the apparent decision time. Buspirone induced VTE behavior and increased apparent decision time without perseveration. This distinct effect of buspirone was seen in SD adolescents but not in Long-Evans (LE) adolescents which appeared to be insensitive to buspirone. Lack of responsiveness to buspirone was dependent on the developmental stage because buspirone induced VTE behavior and prolonged decision time in LE adults. Western blotting of brain 5-HT-1A receptors showed expression of receptor protein in adolescent LE brain was comparable to that of adolescent SD and adult LE. The 5-HT-1A antagonist WAY 100365 blocked the effect 8-OH-DPAT on repetitive choice of arms but not the effect of buspirone on VTE behavior. We conclude that the adolescent LE rat has normal levels of 5-HT-1A receptor and that the effect of buspirone on VTE behavior is not mediated by the 5-HT-1A receptor. The LE strain may provide a useful system for further study of the adolescent brain and potential genetic differences in induction of repetitive behaviors.

  10. The selective 5-HT1A receptor antagonist WAY-100635 inhibits neuronal activity of the ventromedial prefrontal cortex in a rodent model of Parkinson' s disease%选择性5-HT1A受体拮抗剂WAY-100635抑制帕金森病模型大鼠腹内侧前额叶皮质的神经活动

    Institute of Scientific and Technical Information of China (English)

    曹健; 刘健; 张巧俊; 王涛; 王爽; 韩玲娜; 李强

    2007-01-01

    目的 腹内侧前额叶皮质在随意运动的起始和控制、情感以及认知中具有重要作用.然而,黑质-纹状体通路变性后腹内侧前额叶皮质的神经活动和5-HT1A受体的作用仍不清楚.本研究观察了6-羟基多巴胺(6-hydroxydopamine,6-OHDA)损毁黑质致密部(substantia nigra pars compacta,SNc)后大鼠腹内侧前额叶皮质神经活动的变化和体循环给予选择性5-HT1A受体拮抗剂WAY-100635后神经元活动的改变.方法 采用在体玻璃微电极细胞外记录方法,记录正常大鼠和SNc单侧损毁大鼠的腹内侧前额叶皮质神经元的活动.结果 6-OHDA损毁SNc大鼠的腹内侧前额叶皮质神经元放电频率显著增加,放电形式没有明显改变.体循环给予WAY-100635(0.1 mg/kg,i.v.)不改变正常大鼠腹内侧前额叶皮质神经元的平均放电频率和放电形式,而显著降低了SNc损毁大鼠前额叶皮质神经元的平均放电频率.结论 黑质-纹状体通路的变性可导致腹内侧前额叶皮质神经活动增强,5-HT1A受体拮抗剂WAY-100635可以抑制这种活动增强,提示可能存在腹内侧前额叶皮质5-HT1A受体功能失调.%Objective The ventral part of the medial prefrontal cortex (mPFC) plays an important role in initiation and control of voluntary movement, mood and cognition. However, after the degeneration of the nigrostriatal pathway, the neuronal activity of the ventral mPFC and the role of serotonin1A (5-hydroxytryptamine, 5-HT1A) receptors in the firing of the neurons are still unknown. The present study is to investigate the change of neuronal activity in the ventral mPFC and the effect of systemic administration of the selective 5-HT1A receptor antagonist WAY- 100635 on the activity of the neurons in normal and 6-hydroxydopamine (6-OHDA)-lesioned rats. Methods Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesiond rats in vivo

  11. The C(-1019G 5-HT1A promoter polymorphism and personality traits: no evidence for significant association in alcoholic patients

    Directory of Open Access Journals (Sweden)

    Zill P

    2006-02-01

    Full Text Available Abstract The 5HT1A receptor is one of at least 14 different receptors for serotonin which has a role in moderating several brain functions and may be involved in the aetiology of several psychiatric disorders. The C(-1019G 5-HT1A promoter polymorphism was reported to be associated with major depression, depression-related personality traits and suicidal behavior in various samples. The G(-1019 allele carriers are prone to depressive personality traits and suicidal behavior, because serotonergic neurotransmission is reduced. The aim of this study is to replicate previous findings in a sample of 185 Alcohol-dependent individuals. Personality traits were evaluated using the NEO FFI and TCI. History of suicidal behavior was assessed by a standardized semistructured interview (SSAGA. No significant differences across C(-1019G 5-HT1A genotype groups were found for TCI temperament and character traits and for NEO FFI personality scales. No association was detected between this genetic variant and history of suicide attempts. These results neither support a role of C(-1019G 5-HT1A promoter polymorphism in the disposition of personality traits like harm avoidance or neuroticism, nor confirm previous research reporting an involvement of the G allele in suicidal behavior in alcoholics. Significant associations, however, were detected between Babor's Type B with number of suicide attempts in history, high neuroticism and harm avoidance scores in alcoholics.

  12. Association between the 5-HT1A receptor gene C (-1019)G polymorphism and geriatric depression and Alzheimer′s disease with depressive symptoms%5-羟色胺1A受体C(-1019)G基因多态性与老年抑郁症和伴有抑郁症状的阿尔茨海默病的关联研究

    Institute of Scientific and Technical Information of China (English)

    饶冬萍; 陈建华; 温全球; 黄杏笑; 沐楠; 陈建平; 徐世超; 韩海英; 刘文滔

    2014-01-01

    目的:探讨中国汉族人群中5-羟色胺(5-hydroxytryptamine,5-HT)1A受体C(-1019)G基因多态性与老年抑郁症和伴有抑郁症状的阿尔茨海默病(Alzheimer′s disease, AD)的关系。方法:采用病例对照研究方法,以106例老年抑郁症(老年抑郁症组)、72例伴有抑郁症状的AD患者(AD组)和150例正常老年人(正常对照组)为研究对象,用聚合酶链反应-限制性片段长度多态性技术检测5-HT1AC(-1019)G多态性。结果:老年抑郁症组5-HT1A(-1019)C/G基因型(39.6%)、G/G基因型频率(24.5%)、G等位基因频率(44.3%)均高于正常对照组(分别为35.3%、13.3%、31.0%),差异有统计学意义(字2分别为7.9549、9.5157,均P<0.05)。伴有抑郁症状的AD组5-HT1A(-1019)G等位基因频率(41.0%)高于正常对照组(31.0%),差异有统计学意义(字2=4.2879,P<0.05),基因型分布频率差异无统计学意义(字2=3.6506,P>0.05)。老年抑郁症组5-HT1A (-1019)G等位基因及各基因型分布频率与AD组的差异均无统计学意义(字2值分别为0.3656、0.3957,均P>0.05)。结论:5-HT1A受体C(-1019)G基因多态性可能在老年抑郁症及伴有抑郁症状的AD患者的发病中起一定作用,G等位基因可能是其风险因子之一。%Objective To investigate the relationship between the 5-hydroxytryptamine (5-HT)1A receptor gene C(-1019)G polymorphism and geriatric depression and Alzheimer′s disease (AD) with depressive symptoms in Han Chinese. Methods The case control study was used in the study among 106 patients with geriatric depression, 72 AD patients with depressive symptoms and 150 healthy old individuals in China. The C(-1019)G polymorphism of 5-HT1A was analyzed with the technique of polymerase chain reaction-restriction fragment length polymorphism. Results The frequencies of 5

  13. 5-HT1A receptor agonist 8-OH-DPAT improves motor complications in Parkinson's disease%5-羟色胺1A受体激动剂8-OH-DPAT改善帕金森病运动并发症的实验研究

    Institute of Scientific and Technical Information of China (English)

    巴茂文; 刘振国; 孔敏; 马国诏; 陈生弟; 陆国强

    2007-01-01

    目的 探讨5-羟色胺1A(5-HT1A)受体激动剂8-OH-DPAT对左旋多巴诱发的运动并发症的细胞学与行为学效应.方法 通过6-羟基多巴胺立体定向注射至大鼠前脑内侧前脑束建立帕金森病(Parkinson disease,PD)动物模型.对模型成功的PD大鼠进行两套实验:第1套实验中3组PD大鼠接受每日2次左旋多巴甲酯(50 mg/kg加12.5 mg/kg苄丝肼)腹腔注射,持续22 d.在第23天左旋多巴注射前,3组PD大鼠先分别接受8-OH-DPAT、8-OH-DPAT+5-羟色胺1A(5-HT1A)受体阻断剂WAY-100635(0.1 mg/kg)及溶剂对照注射;第2套实验中2组PD大鼠每日2次分别接受左旋多巴/苄丝肼+8-OH-DPAT与左旋多巴/苄丝肼+溶剂,持续22 d.评估旋转时间、关期发生频率情况;采用蛋白印迹法检测纹状体区谷氨酸受体1(GluR1)亚细胞分布及GluR1的845位丝氨酸(GluR1Ser845)磷酸化的表达情况.结果 8-OH-DPAT逆转了左旋多巴所诱导的PD大鼠旋转时间的缩短,延长约27.8%±6.1%;并使关期发生频率减少约7.2%±1.7%.5-HT1A受体阻断剂WAY-100635与8-OH-DPAT联合应用则消除了8-OH-DPAT的效应,提示所观察到的8-OH-DPAT的效应是通过5-HT1A受体起作用的.此外,8-OH-DPAT能调节与运动并发症密切相关的GluR1的亚细胞分布,且使GluR1Ser845的磷酸化水平降低约22.1%±3.5%.结论 激动5-HT1A受体的药物可能是治疗及预防PD运动并发症有益的疗法.

  14. 何首乌的抗抑郁作用及其对海马5HT1A受体表达和神经细胞发生的影响%Anti-depression effect of Heshouwu (Radix Polygoni Muotiflori) and its influences on expression of hippocampus 5HT1A receptor and neurogenesis

    Institute of Scientific and Technical Information of China (English)

    畅洪昇; 鲁艺; 王伟明; 李丽娜; 孙文燕; 王伟; 王庆国

    2012-01-01

    Objective To study the anti-depression effect and mechanism of Heshouwu {Radix Polygoni Muotiflori), a medicinal with the actions of nourishing blood and tonifying liver. Methods The rat and mouse models of depression were established by using bounding combining chronic unpredictable mild stress. The anti-depression effect of Heshouwu was evaluated through open field test and sucrose preference degree detection. The expression of 5HT1A was analyzed by using RT-PCR technique. New neurons were labeled through the intraperitoneal injection of Brdu, and neurogenesis in brain tissue was detected by applying ELISA. Results Heshouwu (2 g/kg) improved the horizontal movement and sucrose preference degree (P <0. 05), and increased the expression of hippocampus 5HT1A mRNA in chronic stress rats. Heshouwu (2. 85 g/kg) increased the content of brain Brdu in chronic stress mice (P <0.01). All above effects of Heshouwu were similar to those of fluoxetine. Conclusion Heshouwu can relieve the depression behaviors of chronic stress animals, and the mechanism may be related to that it can improve 5HT neuron transmission and axoneuron proliferation. The therapy of nourishing blood and tonifying liver and related medicinal and formulas is important in the treatment of depression.%目的 研究养血补肝药物何首乌的抗抑郁作用和机制.方法 采用束缚联合慢性不可预知温和应激大鼠、小鼠抑郁模型,通过敞箱行为和蔗糖水偏嗜度测试评价何首乌的抗抑郁药效作用.通过RT-PCR技术分析海马5HT1A基因表达,通过腹腔注射溴脱氧核苷尿嘧啶(Brdu)标记新生神经细胞,并以酶联免疫(ELISA)检测分析脑组织神经细胞发生.结果 何首乌(2 g/kg)增加了慢性应激大鼠的水平运动、蔗糖水偏嗜度(P<0.05),以及海马5HT1AmRNA表达(P<0.01).何首乌(2.85 g/kg)增加了慢性应激小鼠脑组织中Brdu含量(P<0.01),以上作用与氟西汀相似.结论 何首乌可以改善慢性应激动物

  15. Effect of prenatal stress on memory, nicotine withdrawal and 5HT1A expression in raphe nuclei of adult rats.

    Science.gov (United States)

    Said, N; Lakehayli, S; El Khachibi, M; El Ouahli, M; Nadifi, S; Hakkou, F; Tazi, A

    2015-06-01

    Maternal distress has often been associated with cognitive deficiencies and drug abuse in rats. This study examined these behavioral effects in offspring of mothers stressed during gestation. To this end, pregnant dams were subjected to daily electric foot shocks during the last 10 days of pregnancy. We measured litter parameters and body weights of the descendants after weaning (21 days) and at adulthood (80 days). Afterwards, prenatally stressed and control rats' performances in the novel object recognition test were compared in order to evaluate their memory while others underwent the Water consumption test to assess the nicotine withdrawal intensity after perinatal manipulations. Meanwhile, another set of rats were sacrificed and 5HT1A receptors' mRNA expression was measured in the raphe nuclei by quantitative Real Time PCR. We noticed no significant influence of maternal stress on litter size and body weight right after weaning. However, control rats were heavier than the stressed rats in adulthood. The results also showed a significant decrease in the recognition score in rats stressed in utero compared to the controls. Moreover, a heightened anxiety symptom was observed in the prenatally stressed offspring following nicotine withdrawal. Additionally, the Real Time PCR method revealed that prenatal stress induced a significant decrease in 5HT1A receptors' levels in the raphe nuclei. Nicotine had a similar effect on these receptors' expression in both nicotine-treated control and prenatally stressed groups. Taken together, these findings suggest that the cognitive functions and drug dependence can be triggered by early adverse events in rats.

  16. Role of Hippocampal 5-HT1A Receptor and Its Modulation to NMDA Receptor and AMPA Receptor in Depression Induced by Chronic Unpredictable Mild Stress%应激性抑郁样行为发生中海马5-羟色胺1A受体的作用及其对NMDA受体和AMPA受体的调节

    Institute of Scientific and Technical Information of China (English)

    问黎敏; 安书成; 刘慧

    2012-01-01

    为探讨慢性不可预见性温和应激(chronic unpredictable mild stress,CUMS)诱发抑郁样行为发生中海马5-羟色胺1A受体(5-hydroxytryptamine receptor 1A,5-HT1AR)表达与作用,及其对谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受体和α-氨基羟甲基异恶唑丙酸(α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid,AMPA)受体的影响.通过建立CUMS动物模型,给应激抑郁模型大鼠海马微量注射5-HT1A受体激动剂、给正常大鼠海马微量注射5-HT1A受体拮抗剂,测量大鼠体重变化率,并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测,运用Western blot和ELISA方法检测大鼠海马组织中5-HT1AR和NMDAR和AMPAR的关键亚基的表达以及磷酸化水平.结果显示,与对照组相比,CUMS组大鼠表现出抑郁样行为,海马5-HT1AR、AMPA受体的GluR2/3亚基表达及磷酸化明显降低,NMDA受体的NR1和NR2B亚基表达及磷酸化显著增加;正常大鼠海马微量注射5-HT1A受体拮抗剂WAY100635,动物行为学表现及AMPA受体、NMDA受体表达及磷酸化水平均与CUMS组相同;注射5-HT1A受体激动剂8-OH-DPAT能逆转应激诱导的上述改变.以上结果表明,CUMS诱发抑郁榉行为与海马5-HT1AR表达下降,AMPAR表达量及磷酸化水平降低,NMDAR表达量及磷酸化水平升高有关.5-HT通过5-HT1AR产生抗抑郁作用.5-HT1AR激动剂抗抑郁作用与降低NMDAR表达量及磷酸化水平,提高AMPAR表达量及磷酸化水平密切相关.%Stressors markedly influence central neurochemical and hormonal processes and thus play a pivotal role in the occurrence of depressive illnesses. As the center for stress response and the potential target for stressfulprovocation, the hippocampus is becoming a focus in depression research. Although a large number of behavioral paradigms have been proposed as animal models of depression, only a few are considered potentially useful research tools with

  17. An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.

    Science.gov (United States)

    Becker, Oren M; Dhanoa, Dale S; Marantz, Yael; Chen, Dongli; Shacham, Sharon; Cheruku, Srinivasa; Heifetz, Alexander; Mohanty, Pradyumna; Fichman, Merav; Sharadendu, Anurag; Nudelman, Raphael; Kauffman, Michael; Noiman, Silvia

    2006-06-01

    We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.

  18. DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats.

    Science.gov (United States)

    Kato, Taro; Matsumoto, Yuji; Yamamoto, Masanori; Matsumoto, Kenji; Baba, Satoko; Nakamichi, Keiko; Matsuda, Harumi; Nishimuta, Haruka; Yabuuchi, Kazuki

    2015-06-01

    Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the K i values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg(-1), dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.

  19. Prolonged reversal of the phencyclidine-induced impairment in novel object recognition by a serotonin (5-HT)1A-dependent mechanism.

    Science.gov (United States)

    Horiguchi, Masakuni; Miyauchi, Masanori; Neugebauer, Nichole M; Oyamada, Yoshihiro; Meltzer, Herbert Y

    2016-03-15

    Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15-21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

  20. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET.

    Science.gov (United States)

    Jovanovic, Hristina; Lundberg, Johan; Karlsson, Per; Cerin, Asta; Saijo, Tomoyuki; Varrone, Andrea; Halldin, Christer; Nordström, Anna-Lena

    2008-02-01

    Women and men differ in serotonin associated psychiatric conditions, such as depression, anxiety and suicide. Despite this, very few studies focus on sex differences in the serotonin system. Of the biomarkers in the serotonin system, serotonin(1A) (5-HT(1A)) receptor is implicated in depression, and anxiety and serotonin transporter (5-HTT) is a target for selective serotonin reuptake inhibitors, psychotropic drugs used in the treatment of these disorders. The objective of the present study was to study sex related differences in the 5-HT(1A) receptor and 5-HTT binding potentials (BP(ND)s) in healthy humans, in vivo. Positron emission tomography and selective radioligands [(11)C]WAY100635 and [(11)C]MADAM were used to evaluate binding potentials for 5-HT(1A) receptors (14 women and 14 men) and 5-HTT (8 women and 10 men). The binding potentials were estimated both on the level of anatomical regions and voxel wise, derived by the simplified reference tissue model and wavelet/Logan plot parametric image techniques respectively. Compared to men, women had significantly higher 5-HT(1A) receptor and lower 5-HTT binding potentials in a wide array of cortical and subcortical brain regions. In women, there was a positive correlation between 5-HT(1A) receptor and 5-HTT binding potentials for the region of hippocampus. Sex differences in 5-HT(1A) receptor and 5-HTT BP(ND) may reflect biological distinctions in the serotonin system contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety. The result of the present study may help in understanding sex differences in drug treatment responses to drugs affecting the serotonin system.

  1. THE RELATIONSHIP BETWEEN 5-HTERGIC TERMINALS AND THE VESTIBULO-PARABRACHIAL NUCLEUS PROJECTION NEURONS EXPRESSING 5-HT1A RECEPTOR IN THE VESTIBULAR NUCLEAR COMPLEX%大鼠前庭神经核复合体内5-HT能终末与表达5-HT1A受体的前庭-臂旁核投射神经元之间的联系

    Institute of Scientific and Technical Information of China (English)

    秦灵芝; 张富兴; 李金莲; 李云庆

    2007-01-01

    目的 观察大鼠前庭神经核复合体(VNC)内5-羟色胺(5-HT)样阳性终末与表达5-HT1A受体(5-HT1A R)的前庭-臂旁核投射神经元之间的联系.方法 运用逆行束路追踪和免疫荧光组织化学染色相结合的双重标记技术,在激光共焦显微镜下观察.结果 将四甲基罗达明(TMR)注入臂旁核后,在双侧VNC的各个核团内均可观察到许多TMR逆标神经元,但以同侧为主.免疫荧光组织化学染色结果显示,在前庭内侧核(MVe)、前庭下核(SpVe)、前庭上核(SuVe)、前庭外侧核(LVe)、X核以及Y核的一些区域内,许多神经元表达5-HT1A R样免疫阳性,并可观察到大量5-HT样阳性纤维和终末.激光共焦显微镜下可进一步观察到一些TMR逆标神经元同时呈5-HT1A R样免疫阳性,且有部分5-HT样阳性终末与TMR/5-HT1A R双标神经元的胞体或树突形成密切接触.结论 提示5-HT可能通过5-HT1A R对前庭神经核复合体-臂旁核间的信息传递发挥调控作用.

  2. Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

    Science.gov (United States)

    Rossi, Dania V; Burke, Teresa F; Hensler, Julie G

    2008-03-31

    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

  3. Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET

    Science.gov (United States)

    Lanzenberger, R; Baldinger, P; Hahn, A; Ungersboeck, J; Mitterhauser, M; Winkler, D; Micskei, Z; Stein, P; Karanikas, G; Wadsak, W; Kasper, S; Frey, R

    2013-01-01

    Electroconvulsive therapy (ECT) is a potent therapy in severe treatment-refractory depression. Although commonly applied in psychiatric clinical routine since decades, the exact neurobiological mechanism regarding its efficacy remains unclear. Results from preclinical and clinical studies emphasize a crucial involvement of the serotonin-1A receptor (5-HT1A) in the mode of action of antidepressant treatment. This includes associations between treatment response and changes in 5-HT1A function and density by antidepressants. Further, alterations of the 5-HT1A receptor are consistently reported in depression. To elucidate the effect of ECT on 5-HT1A receptor binding, 12 subjects with severe treatment-resistant major depression underwent three positron emission tomography (PET) measurements using the highly selective radioligand [carbonyl-11C]WAY100635, twice before (test–retest variability) and once after 10.08±2.35 ECT sessions. Ten patients (∼83%) were responders to ECT. The voxel-wise comparison of the 5-HT1A receptor binding (BPND) before and after ECT revealed a widespread reduction in cortical and subcortical regions (P<0.05 corrected), except for the occipital cortex and the cerebellum. Strongest reductions were found in regions consistently reported to be altered in major depression and involved in emotion regulation, such as the subgenual part of the anterior cingulate cortex (−27.5%), the orbitofrontal cortex (−30.1%), the amygdala (−31.8%), the hippocampus (−30.6%) and the insula (−28.9%). No significant change was found in the raphe nuclei. There was no significant difference in receptor binding in any region comparing the first two PET scans conducted before ECT. This PET study proposes a global involvement of the postsynaptic 5-HT1A receptor binding in the effect of ECT. PMID:22751491

  4. The association between romantic relationship status and 5-HT1A gene in young adults.

    Science.gov (United States)

    Liu, Jinting; Gong, Pingyuan; Zhou, Xiaolin

    2014-11-20

    What factors determine whether or not a young adult will fall in love? Sociological surveys and psychological studies have shown that non-genetic factors, such as socioeconomic status, external appearance, and personality attributes, are crucial components in romantic relationship formation. Here we demonstrate that genetic variants also contribute to romantic relationship formation. As love-related behaviors are associated with serotonin levels in the brain, this study investigated to what extent a polymorphism (C-1019G, rs6295) of 5-HT1A gene is related to relationship status in 579 Chinese Han people. We found that 50.4% of individuals with the CC genotype and 39.0% with CG/GG genotype were in romantic relationship. Logistic regression analysis indicated that the C-1019G polymorphism was significantly associated with the odds of being single both before and after controlling for socioeconomic status, external appearance, religious beliefs, parenting style, and depressive symptoms. These findings provide, for the first time, direct evidence for the genetic contribution to romantic relationship formation.

  5. Envolvimento de receptores 5-HT1A no comportamento defensivo induzido por estimulação elétrica da substãncia cinzenta periaquedutal dorsal de ratos com experiência prévia a eventos estressantes

    OpenAIRE

    Ana Carolina Garcia Broiz

    2007-01-01

    O comportamento emocional tem sido considerado fundamental para a sobrevivência dos animais, sendo o medo uma se suas mais primitivas e importantes formas. A substância cinzenta periaquedutal dorsal (SCPD) tem-se destacado como uma estrutura importante na organização das respostas defensivas. Estudos usando estimulação elétrica e química da SCPD e microinjeções de drogas agonistas e antagonistas de receptores serotoninérgicos mostraram uma mediação serotoninérgica através dos subtipos de rece...

  6. 5-HT1A-like receptor activation inhibits abstinence-induced methamphetamine withdrawal in planarians

    OpenAIRE

    Rawls, Scott M.; Shah, Hardik; Ayoub, George; Raffa, Robert B.

    2010-01-01

    No pharmacological therapy is approved to treat methamphetamine physical dependence, but it has been hypothesized that serotonin (5-HT)-enhancing drugs might limit the severity of withdrawal symptoms. To test this hypothesis, we used a planarian model of physical dependence that quantifies withdrawal as a reduction in planarian movement. Planarians exposed to methamphetamine (10 µM) for 60 min, and then placed (tested) into drug-free water for 5 min, displayed less movement (i.e., withdrawal)...

  7. Tolerability, pharmacokinetics, and neuroendocrine effects of PRX-00023, a novel 5-HT1A agonist, in healthy subjects.

    Science.gov (United States)

    Iyer, Ganesh R; Reinhard, John F; Oshana, Scott; Kauffman, Michael; Donahue, Stephen

    2007-07-01

    PRX-00023 is a novel, nonazapirone 5-HT1A agonist in clinical development for treatment of affective disorders. The objectives of the initial clinical phase I studies (a single ascending dose study and multiple dose-ascending and high-dose titration studies) were to measure the pharmacokinetics, pharmacodynamic (neuroendocrine) effects, and tolerability of PRX-00023 in healthy subjects. The studies evaluated 10-mg to 150-mg doses of PRX-00023 in up to 112 healthy male and female subjects aged 18 to 54 years. Single and multiple oral doses of PRX-00023 were found to be safe and well tolerated in healthy subjects. PRX-00023 was absorbed relatively rapidly, with a tmax of 0.5 to 2 hours, and eliminated with a half-life of approximately 12 hours. PRX-00023 treatment transiently increased blood prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 5-HT1A agonist.

  8. Neither in vivo MRI nor behavioural assessment indicate therapeutic efficacy for a novel 5HT1A agonist in rat models of ischaemic stroke

    Directory of Open Access Journals (Sweden)

    Modo Michel M

    2009-07-01

    Full Text Available Abstract Background 5HT1A agonists have previously been shown to promote recovery in animal models of stroke using ex vivo outcome measures which have raised the hopes for a potential clinical implementation. The purpose of this study was to evaluate the potential neuroprotective properties of a novel 5HT1A agonist DU123015 in 2 different models of transient focal ischaemic stroke of varying severities using both in vivo neuroimaging and behavioural techniques as primary outcome measures. For these studies, the NMDA receptor antagonist MK-801 was also utilized as a positive control to further assess the effectiveness of the stroke models and techniques used. Results In contrast to MK-801, no significant therapeutic effect of DU123015 on lesion volume in either the distal MCAo or intraluminal thread model of stroke was found. MK-801 significantly reduced lesion volume in both models; the mild distal MCAo condition (60 min ischaemia and the intraluminal thread model, although it had no significant impact upon the lesion size in the severe distal MCAo condition (120 min ischaemia. These therapeutic effects on lesion size were mirrored on a behavioural test for sensory neglect and neurological deficit score in the intraluminal thread model. Conclusion This study highlights the need for a thorough experimental design to test novel neuroprotective compounds in experimental stroke investigations incorporating: a positive reference compound, different models of focal ischaemia, varying the duration of ischaemia, and objective in vivo assessments within a single study. This procedure will help us to minimise the translation of less efficacious compounds.

  9. Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression.

    Science.gov (United States)

    Hadjighassem, Mahmoud R; Austin, Mark C; Szewczyk, Bernadeta; Daigle, Mireille; Stockmeier, Craig A; Albert, Paul R

    2009-08-01

    Altered expression of serotonin-1A (5-HT1A) receptors, both presynaptic in the raphe nuclei and post-synaptic in limbic and cortical target areas, has been implicated in mood disorders such as major depression and anxiety. Within the 5-HT1A receptor gene, a powerful dual repressor element (DRE) is regulated by two protein complexes: Freud-1/CC2D1A and a second, unknown repressor. Here we identify human Freud-2/CC2D1B, a Freud-1 homologue, as the second repressor. Freud-2 distribution was examined with Northern and Western blot, reverse transcriptase polymerase chain reaction, and immunohistochemistry/immunofluorescence; Freud-2 function was examined by electrophoretic mobility shift, reporter assay, and Western blot. Freud-2 RNA was widely distributed in brain and peripheral tissues. Freud-2 protein was enriched in the nuclear fraction of human prefrontal cortex and hippocampus but was weakly expressed in the dorsal raphe nucleus. Freud-2 immunostaining was co-localized with 5-HT1A receptors, neuronal and glial markers. In prefrontal cortex, Freud-2 was expressed at similar levels in control and depressed male subjects. Recombinant hFreud-2 protein bound specifically to 5' or 3' human DRE adjacent to the Freud-1 site. Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells. Furthermore, small interfering RNA knockdown of endogenous hFreud-2 expression de-repressed 5-HT1A promoter activity and increased levels of 5-HT1A receptor protein in SK-N-SH cells. Human Freud-2 binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons.

  10. Serotonin 1A receptor binding and treatment response in late-life depression.

    Science.gov (United States)

    Meltzer, Carolyn Cidis; Price, Julie C; Mathis, Chester A; Butters, Meryl A; Ziolko, Scott K; Moses-Kolko, Eydie; Mazumdar, Sati; Mulsant, Benoit H; Houck, Patricia R; Lopresti, Brian J; Weissfeld, Lisa A; Reynolds, Charles F

    2004-12-01

    Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

  11. Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene.

    Science.gov (United States)

    Hadjighassem, Mahmoud R; Galaraga, Kimberly; Albert, Paul R

    2011-01-01

    The serotonin-1A (5-HT1A) receptor functions as a pre-synaptic autoreceptor in serotonin neurons that regulates their activity, and is also widely expressed on non-serotonergic neurons as a post-synaptic heteroreceptor to mediate serotonin action. The 5-HT1A receptor gene is strongly repressed by a dual repressor element (DRE), which is recognized by two proteins: Freud-1/CC2D1A and another unknown protein. Here we identify mouse Freud-2/CC2D1B as the second repressor of the 5-HT1A-DRE. Freud-2 shares 50% amino acid identity with Freud-1, and contains conserved structural domains. Mouse Freud-2 bound specifically to the rat 5-HT1A-DRE adjacent to, and partially overlapping, the Freud-1 binding site. By supershift assay using nuclear extracts from L6 myoblasts, Freud-2-DRE complexes were distinguished from Freud-1-DRE complexes. Freud-2 mRNA and protein were detected throughout mouse brain and peripheral tissues. Freud-2 repressed 5-HT1A promoter-reporter constructs in a DRE-dependent manner in non-neuronal (L6) or 5-HT1A-expressing neuronal (NG108-15, RN46A) cell models. In NG108-15 cells, knockdown of Freud-2 using a specific short-interfering RNA reduced endogenous Freud-2 protein levels and decreased Freud-2 bound to the 5-HT1A-DRE as detected by chromatin immunoprecipitation assay, but increased 5-HT1A promoter activity and 5-HT1A protein levels. Taken together, these data show that Freud-2 is the second component that, with Freud-1, mediates dual repression of the 5-HT1A receptor gene at the DRE. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  12. Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

    Science.gov (United States)

    Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

    2014-03-01

    Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. © 2013 International Society for Neurochemistry.

  13. Systemic treatment with a 5HT1a agonist induces anti-oxidant protection and preserves the retina from mitochondrial oxidative stress.

    Science.gov (United States)

    Biswal, Manas R; Ahmed, Chulbul M; Ildefonso, Cristhian J; Han, Pingyang; Li, Hong; Jivanji, Hiral; Mao, Haoyu; Lewin, Alfred S

    2015-11-01

    Chronic oxidative stress contributes to age related diseases including age related macular degeneration (AMD). Earlier work showed that the 5-hydroxy-tryptamine 1a (5HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) protects retinal pigment epithelium (RPE) cells from hydrogen peroxide treatment and mouse retinas from oxidative insults including light injury. In our current experiments, RPE derived cells subjected to mitochondrial oxidative stress were protected from cell death by the up-regulation of anti-oxidant enzymes and of the metal ion chaperone metallothionein. Differentiated RPE cells were resistant to oxidative stress, and the expression of genes for protective proteins was highly increased by oxidative stress plus drug treatment. In mice treated with 8-OH-DPAT, the same genes (MT1, HO1, NqO1, Cat, Sod1) were induced in the neural retina, but the drug did not affect the expression of Sod2, the gene for manganese superoxide dismutase. We used a mouse strain deleted for Sod2 in the RPE to accelerate age-related oxidative stress in the retina and to test the impact of 8-OH-DPAT on the photoreceptor and RPE degeneration developed in these mice. Treatment of mice with daily injections of the drug led to increased electroretinogram (ERG) amplitudes in dark-adapted mice and to a slight improvement in visual acuity. Most strikingly, in mice treated with a high dose of the drug (5 mg/kg) the structure of the RPE and Bruch's membrane and the normal architecture of photoreceptor outer segments were preserved. These results suggest that systemic treatment with this class of drugs may be useful in preventing geographic atrophy, the advanced form of dry AMD, which is characterized by RPE degeneration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin.

    Science.gov (United States)

    Carter, Olivia L; Pettigrew, John D; Hasler, Felix; Wallis, Guy M; Liu, Guang B; Hell, Daniel; Vollenweider, Franz X

    2005-06-01

    Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)1A and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose (115 microg/kg) and high-dose (250 microg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration (the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC (altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem

  15. Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Homberg, Judith R; De Boer, Sietse F; Raasø, Halfdan S; Olivier, Jocelien D A; Verheul, Mark; Ronken, Eric; Cools, Alexander R; Ellenbroek, Bart A; Schoffelmeer, Anton N M; Vanderschuren, Louk J M J; De Vries, Taco J; Cuppen, Edwin

    2008-01-01

    RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout

  16. Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats.

    NARCIS (Netherlands)

    Homberg, J.R.; Boer, SF De; Raaso, H.S.; Olivier, J.D.A.; Verheul, M.; Ronken, E.; Cools, A.R.; Ellenbroek, B.A.; Schoffelmeer, A.N.; Schuren, L.J. van der; Vries, TJ De; Cuppen, E.

    2008-01-01

    RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout

  17. Peripheral 5-HT 1A and 5-HT 7 Serotonergic Receptors Modulate Parasympathetic Neurotransmission in Long-Term Diabetic Rats

    OpenAIRE

    Beatriz Restrepo; María Luisa Martín; Luis San Román; Asunción Morán

    2010-01-01

    We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT), effect reproduced by 5-carboxamidotryptamine maleate (5-CT), a 5-HT1/7 agonist. The enhancement of the bradycardia at l...

  18. Larger adaptive response of 5-HT1A autoreceptors to chronic fluoxetine in a mouse model of depression than in healthy mice

    Institute of Scientific and Technical Information of China (English)

    N.FROGER; E.PALAZZO; T.RENOIR; M.MELFORT; N.BARDEN; M.HAMON; L.LANFUMEY

    2004-01-01

    Vulnerability to major depressive disorders, in particular depression, is often associated with both hypoactivity of the central serotoninergic (5-HT) system and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Extensive studies in normal healthy rodents showed that chronic treatment with SSRI antidepressants produced a marked functional desensitization of somatodendritic 5-HT1A autoreceptors, and this adaptive change has been claimed to play a key role in the therapeutic action of

  19. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    concentrations of 5-HT in seven distinct brain structures from one hemisphere: frontal and occipital cortex, striatum, hippocampus, cerebellum, rostral, and caudal brain stem, were determined. The other hemisphere was processed for receptor autoradiography. Treatments with 50 mg/kg and 100 mg/kg pCPA caused...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT₄ receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  20. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    concentrations of 5-HT in seven distinct brain structures from one hemisphere: frontal and occipital cortex, striatum, hippocampus, cerebellum, rostral, and caudal brain stem, were determined. The other hemisphere was processed for receptor autoradiography. Treatments with 50 mg/kg and 100 mg/kg pCPA caused...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT4 receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  1. Effect of the 5-HT(1A) partial agonist buspirone on regional brain electrical activity in man: a functional neuroimaging study using low-resolution electromagnetic tomography (LORETA).

    Science.gov (United States)

    Anderer, P; Saletu, B; Pascual-Marqui, R D

    2000-12-04

    In a double-blind, placebo-controlled study, the effects of 20 mg buspirone - a 5-HT(1A) partial agonist - on regional electrical generators within the human brain were investigated utilizing three-dimensional EEG tomography. Nineteen-channel vigilance-controlled EEG recordings were carried out in 20 healthy subjects before and 1, 2, 4, 6 and 8 h after drug intake. Low-resolution electromagnetic tomography (LORETA; Key Institute for Brain-Mind Research, software: http://www.keyinst.unizh.ch) was computed from spectrally analyzed EEG data, and differences between drug- and placebo-induced changes were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux human brain atlas available as a digitized MRI (McConnell Brain Imaging Centre: http://www.bic.mni.mcgill.ca). At the pharmacodynamic peak (1st hour), buspirone increased theta and decreased fast alpha and beta sources. Areas of theta increase were mainly the left temporo-occipito-parietal and left prefrontal cortices, which is consistent with PET studies on buspirone-induced decreases in regional cerebral blood flow and fenfluramine-induced serotonin activation demonstrated by changes in regional cerebral glucose metabolism. In later hours (8th hour) with lower buspirone plasma levels, delta, theta, slow alpha and fast beta decreased, predominantly in the prefrontal and anterior limbic lobe. Whereas the results of the 1st hour speak for a slight CNS sedation (more in the sense of relaxation), those obtained in the 8th hour indicate activation. Thus, LORETA may provide useful and direct information on drug-induced changes in central nervous system function in man.

  2. SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test.

    Science.gov (United States)

    Starr, Kathryn R; Price, Gary W; Watson, Jeannette M; Atkinson, Peter J; Arban, Roberto; Melotto, Sergio; Dawson, Lee A; Hagan, Jim J; Upton, Neil; Duxon, Mark S

    2007-10-01

    Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

  3. Dynamic alterations of serotonergic metabolism and receptors during social isolation of low- and high-active mice.

    Science.gov (United States)

    Rilke, O; Freier, D; Jähkel, M; Oehler, J

    1998-04-01

    Alterations induced by social isolation (1 day to 18 weeks) in low- and high-active mice (LAM and HAM) were studied in respect to serotonin metabolism, [3H]-8-OH-DPAT binding of presynaptic (midbrain), postsynaptic (hippocampus) 5-HT1A receptors and [3H]-ketanserin binding of cortical 5-HT2A receptors. Individual housing of mice was associated with reduction of serotonin metabolism, depending on isolation time and brain structure. Whereas a transient decrease in the striatum and cortex was detected between 1 week and 6 weeks, reduction of cerebellar and hippocampal serotonin metabolism was found later (12-18 weeks). Serotonergic systems of HAM were found to be more reactive to environmental disturbances, and their serotonin metabolism was more affected by social isolation. Isolation-induced upregulation of cortical 5-HT2A receptors was measured only in HAM. Densities of postsynaptic 5-HT1A receptors in the hippocampus did differ either in grouped or isolated mice. However, there were significant differences in hippocampal 5-HT1A receptor affinity, especially between 1 day and 3 weeks. Transient downregulation of presynaptic 5-HT1A receptors in the midbrain was found in isolated mice between 3 and 6 weeks. These results are discussed in terms of interactions between serotonergic alterations and isolation-induced aggression.

  4. Biological and Environmental Factors Impacting Risk of Cognitive Decline:Imaging ß-amyloid plaques, Tau Neurofibrillary Tangles and the 5HT1A Receptor

    OpenAIRE

    Martin-Harris, Laurel

    2015-01-01

    Diseases of aging, such as Alzheimer’s, occur at the hands of many cumulative risk factors occurring over a lifetime. As with virtually all non-mendelian diseases, genetics and environment play essential and synergistic roles in disease development. Disentangling the relative contributions of risk factors will aide future prevention in youth to reduce an individual’s risk later in life. The same risk factors may also serve as biomarkers signaling brain changes in advance of disease state. Onc...

  5. Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway

    OpenAIRE

    Wang, Yan-Juan; Ren, Qing-Guo; Gong, Wei-Gang; Wu, Di; Tang, Xiang; Li, Xiao-Li; Wu, Fang-Fang; Bai, Feng; Xu, Lin; Zhang, Zhi-Jun

    2016-01-01

    Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-β (Aβ)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aβ1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aβ1–42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3β pathway, and t...

  6. A linear combination of pharmacophore hypotheses as a new tool in search of new active compounds--an application for 5-HT1A receptor ligands.

    Directory of Open Access Journals (Sweden)

    Dawid Warszycki

    Full Text Available This study explores a new approach to pharmacophore screening involving the use of an optimized linear combination of models instead of a single hypothesis. The implementation and evaluation of the developed methodology are performed for a complete known chemical space of 5-HT1AR ligands (3616 active compounds with K i < 100 nM acquired from the ChEMBL database. Clusters generated from three different methods were the basis for the individual pharmacophore hypotheses, which were assembled into optimal combinations to maximize the different coefficients, namely, MCC, accuracy and recall, to measure the screening performance. Various factors that influence filtering efficiency, including clustering methods, the composition of test sets (random, the most diverse and cluster population-dependent and hit mode (the compound must fit at least one or two models from a final combination were investigated. This method outmatched both single hypothesis and random linear combination approaches.

  7. THE EFFECT OF SEROTONIN 5-HT1A, 5-HT2 RECEPTOR LIGANDS, KETOPROFEN AND THEIR COMBINATION IN MODELS OF INDUCED PAIN IN MICE.

    Science.gov (United States)

    Zygmunt, Małgorzata; Chłoń-Rzepa, Grażyna; Sapa, Jacek

    2015-01-01

    The present study was carried out to investigate the effects of the 7-(3-chlorophenyl)piperazinylalkyl derivatives of 8-alkoxypurine-2,6-dione (compounds 1-4) in two animal models of induced pain and to compare their effects with ketoprofen and with their combination. All experiments were performed on albino mice. Mice were evaluated for their responsiveness to noxious stimuli using: the hot-plate test and the phenylbenzo-quinone-induced writhing test. All compounds showed analgesic activity only in the writhing test. The analgesic activities of compounds 3 and 4 were similar to ketoprofen. The compounds slightly increased the analgesic effect of ketoprofen when used in combination in the visceral type of pain. The possible mechanisms of the antinociceptive effect of these compounds are thought to involve the activation of analgesic effect mediated by the serotonergic pathways or combination of this mechanism with other important mediators playing a role in pain modulation.

  8. The Relevance of the Functional 5-HT1A Receptor Polymorphism for Attention and Working Memory Processes during Mental Rotation of Characters

    Science.gov (United States)

    Beste, Christian; Heil, Martin; Domschke, Katharina; Konrad, Carsten

    2010-01-01

    Numerous lines of research indicate that attentional processes, working memory and saccadic processes are highly interrelated. In the current study, we examine the relation between these processes with respect to their cognitive-neurophysiological and neurobiological background by means of event-related potentials (ERPs) in a sample of N = 72…

  9. 5-HT1A and 5-HT1B receptor agonists and aggression : A pharmacological challenge of the serotonin deficiency hypothesis

    NARCIS (Netherlands)

    de Boer, Sietse F.; Koolhaas, Jaap M.

    2005-01-01

    More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the p

  10. Establishment of Radiolabelling Method for the Development of Neurodegenerative Disease Imaging Agent Using 5-HT{sub 1A} Subtype of Receptor Anatagonist

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Sun Ju; Choi, Sang Mu; Kim, On Hee; Hong, Young Don; Park, Kyung Bae [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2005-07-01

    The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain. And it is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy and diagnosis of diseases. Serotonin is synthesized from the amino acid L-tryptophan by sequential hydroxylation and decarboxylation. It is stored in presynaptic vesicles and released from nerve terminals during neuronal firing. One of the best-characterised binding sites for serotonin is the 5-HT1A receptor. This is mainly due to the relatively early discovery of a selective ligand, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) for this subpopulation. Thus, many researchers have tried to develop a radioligand capable of assessing in vivo changes in 5-HT1A receptors in depressed subjects, people with anxiety disorders, patients with Alzheimer's disease and schizophrenics. In present study, we studied the radioligands which would play a role in visualization and quantification of this important neuroreceptor for single-photon emission tomography (SPET)

  11. Receptor binding profiles and quantitative structure-affinity relationships of some 5-substituted-N,N-diallyltryptamines.

    Science.gov (United States)

    Cozzi, Nicholas V; Daley, Paul F

    2016-02-01

    N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12-20mg range, while the unsubstituted compound DALT had few discernible effects in the 42-80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10-80 nM range for serotonin 5-HT1A and 5-HT2B receptors, while the affinity of DALT itself at 5-HT1A receptors was slightly lower at 100 nM. Among the 5-HT2 subtypes, the weakest affinity was at 5-HT2A receptors, spanning 250-730 nM. Five of the DALT compounds had affinity in the 50-400 nM range for serotonin 5-HT1D, 5-HT6, and 5-HT7 receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT1B, 5-HT1E, and 5-HT5A subtypes and little or no affinity for the 5-HT3 subtype. These compounds also had generally nanomolar affinities for adrenergic α2A, α2B, and α2C receptors, sigma receptors σ1 and σ2, histamine H1 receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure-affinity relationships existed, we evaluated

  12. On the existence and function of galanin receptor heteromers in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Kjell eFuxe

    2012-10-01

    Full Text Available Galanin receptor (GalR subtypes1-3 linked to central galanin neurons may form heteromers with each other and other types of G protein coupled receptors (GPCRs in the Central Nervous System (CNS. These heteromers may be one molecular mechanism for galanin peptides and their N-terminal fragments (gal 1-15 to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional and the cardiovascular networks. GalR-5-HT1A heteromers likely exist with antagonistic GalR-5-HT1A receptor-receptor interactions in the ascending midbrain raphe 5-HT neuron systems and their target regions. They represent a novel target for antidepressant drugs. Evidence is given for the existence of GalR1-5-HT1A heteromers in cellular models with transinhibition of the protomer signaling. A GalR1-GalR2 heteromer is proposed to be a galanin N-terminal fragment preferring receptor (1-15 in the CNS. Furthermore, a GalR1-GalR2-5-HT1A heterotrimer is postulated to explain why only galanin (1-15 but not galanin (1-29 can antagonistically modulate the 5-HT1A receptors in the dorsal hippocampus rich in gal fragment binding sites. The results underline a putative role of different types of GalR-5-HT1A heteroreceptor complexes in depression. GalR antagonists may also have therapeutic actions in depression by blocking the antagonistic GalR-NPYY1 receptor interactions in putative GalR-NPYY1 receptor heteromers in the CNS resulting in increases in NPYY1 transmission and antidepressant effects. In contrast the galanin fragment receptor (a postulated GalR1-GalR2 heteromer appears to be linked to the NPYY2 receptor enhancing the affinity of the NPYY2 binding sites in a putative GalR1-GalR2-NPYY2 heterotrimer. Finally, putative GalR-α2-adrenoreceptor heteromers with antagonistic receptor-receptor interactions may be a widespread mechanism in the CNS for integration of galanin and noradrenaline signals also of likely relevance for depression.

  13. Binding of lurasidone, a novel antipsychotic, to rat 5-HT7 receptor: analysis by [3H]SB-269970 autoradiography.

    Science.gov (United States)

    Horisawa, Tomoko; Ishiyama, Takeo; Ono, Michiko; Ishibashi, Tadashi; Taiji, Mutsuo

    2013-01-10

    Lurasidone is a novel antipsychotic agent with high affinity for dopamine D(2) and serotonin 5-HT(7), 5-HT(2A), and 5-HT(1A) receptors. We previously reported that in addition to its antipsychotic action, lurasidone shows beneficial effects on mood and cognition in rats, likely through 5-HT(7) receptor antagonistic actions. In this study, we evaluated binding of lurasidone to 5-HT(7) receptors in the rat brain by autoradiography using [(3)H]SB-269970, a specific radioligand for 5-HT(7) receptors. Brain slices were incubated with 4 nM [(3)H]SB-269970 at room temperature and exposed to imaging plates for 8 weeks before phosphorimager analysis. Using this method, we first investigated 5-HT(7) receptor distribution. We found that 5-HT(7) receptors are abundantly localized in brain limbic structures, including the lateral septum, thalamus, hypothalamus, hippocampus, and amygdala. On the other hand, its distribution was moderate in the cortex and low in the caudate putamen and cerebellum. Secondly, binding of lurasidone, a selective 5-HT(7) receptor antagonist SB-656104-A and an atypical antipsychotic olanzapine to this receptor was examined. Lurasidone, SB-656104-A (10–1000 nM), and olanzapine (100–10,000 nM) showed concentration-dependent inhibition of [(3)H]SB-269970 binding with IC(50) values of 90, 49, and 5200 nM, respectively. Similar inhibitory actions of these drugs were shown in in vitro [(3)H]SB-269970 binding to 5-HT(7) receptors expressed in Chinese hamster ovary cells. Since there was no marked species difference in rat and human 5-HT(7) receptor binding by lurasidone (K(i) = 1.55 and 2.10 nM, respectively), these findings suggest that binding to 5-HT(7) receptors might play some role in its beneficial pharmacological actions in schizophrenic patients.

  14. Serotonin receptors in suicide victims with major depression.

    Science.gov (United States)

    Stockmeier, C A; Dilley, G E; Shapiro, L A; Overholser, J C; Thompson, P A; Meltzer, H Y

    1997-02-01

    Serotonin1A (5-HT1A) and serotonin2A (5-HT2A) receptors in the brain have been implicated in the pathophysiology of suicide. Brain samples were collected at autopsy from suicide victims with a current episode of major depression and matched comparison subjects who died of natural or accidental causes. Retrospective psychiatric assessments were collected from knowledgeable informants for all suicide victims and most of the comparison subjects. Psychiatric diagnoses were determined according to DSM-III-R criteria. Any subjects with current psychoactive substance use disorders were excluded. Quantitative receptor autoradiography was used in serial sections of the right prefrontal cortex (area 10) and hippocampus to measure the binding of [3H]8-hydroxy-2-(di-n-propyl)-aminotetralin ([3H]8-OH-DPAT) to 5-HT1A receptors and [3H]ketanserin to 5-HT2A receptors. Analysis of covariance was used to compare control subjects and suicide victims with major depression. The age of subjects, the time from death to freezing the tissue (postmortem interval), and the storage time of tissues in the freezer were used as covariates in the analyses. There were no significant differences between suicide victims with major depression and comparison subjects in 5-HT1A or 5-HT2A receptors in area 10 of the right prefrontal cortex or the hippocampus. The current results suggest that the number of 5-HT1A and 5-HT2A receptors in the right prefrontal cortex (area 10) or hippocampus are not different in suicide victims with major depression.

  15. CARBOHYDRATE-CONTAINING COMPOUNDS WHICH BIND TO CARBOHYDRATE BINDING RECEPTORS

    DEFF Research Database (Denmark)

    1995-01-01

    Carbohydrate-containing compounds which contain saccharides or derivatives thereof and which bind to carbohydrate binding receptors are useful in pharmaceutical products for treatment of inflammatory diseases and other diseases.......Carbohydrate-containing compounds which contain saccharides or derivatives thereof and which bind to carbohydrate binding receptors are useful in pharmaceutical products for treatment of inflammatory diseases and other diseases....

  16. Selective 5-HT7 Receptor Activation May Enhance Synaptic Plasticity Through N-methyl-D-aspartate (NMDA) Receptor Activity in the Visual Cortex.

    Science.gov (United States)

    Xiang, Kangjian; Zhao, Xuefei; Li, Youjun; Zheng, Liang; Wang, Jue; Li, Yan-Hai

    2016-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist). A specific antagonist for the 5-HT7 receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HT1A receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HT7 receptors, but not 5-HT1A receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

  17. [18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge

    DEFF Research Database (Denmark)

    Pinborg, L. H.; Adams, K. H.; Yndsgaard, S;

    2004-01-01

    The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus...... subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline...... condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram...

  18. Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

    Science.gov (United States)

    Chilmonczyk, Zdzisław; Bojarski, Andrzej Jacek; Pilc, Andrzej; Sylte, Ingebrigt

    2015-01-01

    Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies. PMID:26262615

  19. Autoradiography reveals selective changes in serotonin binding in neocortex of patients with temporal lobe epilepsy.

    Science.gov (United States)

    Rocha, Luisa; Lorigados-Pedre, Lourdes; Orozco-Suárez, Sandra; Morales-Chacón, Lilia; Alonso-Vanegas, Mario; García-Maeso, Iván; Villeda-Hernández, Juana; Osorio-Rico, Laura; Estupiñán, Bárbara; Quintana, Christian

    2007-08-15

    The main goal of the present study was to evaluate binding to serotonin in the neocortex surrounding the epileptic focus of patients with mesial temporal lobe epilepsy (MTLE). Binding to 5-HT, 5-HT(1A), 5-HT(4), 5-HT(7) receptors and serotonin transporter (5-HTT) in T1-T2 gyri of 15 patients with MTLE and their correlations with clinical data, neuronal count and volume were determined. Autopsy material acquired from subjects without epilepsy (n=6) was used as control. The neocortex from MTLE patients demonstrated decreased cell count in layers III-IV (21%). No significant changes were detected on the neuronal volume. Autoradiography experiments showed the following results: reduced 5-HT and 5-HT(1A) binding in layers I-II (24% and 92%, respectively); enhanced 5-HT(4) binding in layers V-VI (32%); no significant changes in 5-HT(7) binding; reduced 5-HTT binding in all layers (I-II, 90.3%; III-IV, 90.3%, V-VI, 86.9%). Significant correlations were found between binding to 5-HT(4) and 5-HT(7) receptors and age of seizure onset, duration of epilepsy and duration of antiepileptic treatment. The present results support an impaired serotoninergic transmission in the neocortex surrounding the epileptic focus of patients with MTLE, a situation that could be involved in the initiation and propagation of seizure activity.

  20. Mivazerol, a novel compound with high specificity for alpha 2 adrenergic receptors: binding studies on different human and rat membrane preparations.

    Science.gov (United States)

    Noyer, M; de Laveleye, F; Vauquelin, G; Gobert, J; Wülfert, E

    1994-03-01

    Mivazerol, 3-[1(H-imidazol-4-yl)methyl]-2-hydroxybenzamide hydrochloride, a new potential anti-ischemic drug designed by UCB S.A. Pharma Sector, has been studied in binding experiments on adrenergic, dopaminergic, serotoninergic, muscarinic and idazoxan binding sites. Our results indicate that this compound displays high affinity and marked specificity for alpha 2 adrenoceptors. Mivazerol displaced the binding of the alpha 2 adrenoceptor antagonist [3H]RX 821002 to the alpha 2A adrenoceptors in human frontal cortex membranes with an apparent Ki value of 37 nM. The competition curve was shallow (nH = 0.55), suggesting that this compound acts as an alpha 2 adrenergic agonist. Mivazerol was also a potent competitor for [3H]RX 821002 binding to human platelet membranes (containing alpha 2A adrenoceptors) and rat kidney membranes (75% of the alpha 2 adrenoceptors of the alpha 2B subtype), indicating that this compound is not alpha 2 adrenoceptor subtype selective. Equilibrium dissociation constants for alpha 1 adrenoceptors (displacement of [3H]prazosin) and 5-HT1A receptors (displacement of [3H]rauwolscine) were respectively about 120 times (Ki = 4.4 microM) and 14 times (Ki = 530 nM) higher than that for the alpha 2 adrenoceptors. Equilibrium dissociation constants were approximately 1000 times higher for all other receptors tested in this study; namely beta 1 and beta 2 adrenoceptors, D1- and D2-dopamine receptors, M1-, M2- and M3-muscarinic receptors, 5-HT2 receptors and non-adrenergic idazoxan binding sites.

  1. Spacer conformation in biologically active molecules. Part 2. Structure and conformation of 4-[2-(diphenylmethylamino)ethyl]-1-(2-methoxyphenyl) piperazine and its diphenylmethoxy analog—potential 5-HT 1A receptor ligands

    Science.gov (United States)

    Karolak-Wojciechowska, J.; Fruziński, A.; Czylkowski, R.; Paluchowska, M. H.; Mokrosz, M. J.

    2003-09-01

    As a part of studies on biologically active molecule structures with aliphatic linking chain, the structures of 4-[2-diphenylmethylamino)ethyl]-1-(2-methoxyphenyl)piperazine dihydrochloride ( 1) and 4-[2-diphenylmethoxy)ethyl]-1-(2-methoxyphenyl)piperazine fumarate ( 2) have been reported. In both compounds, four atomic non-all-carbons linking chains (N)C-C-X-C are present. The conformation of that linking spacer depends on the nature of the X-atom. The preferred conformation for chain with XNH has been found to be fully extended while for that with XO—the bend one. It was confirmed by conformational calculations (strain energy distribution and random search) and crystallographic data, including statistics from CCDC.

  2. Modulació dels nuclis aminèrgics del mesèncefal pels receptors 5-HT1A i 5-HT2A corticals. Implicació dels antipsicòtics

    OpenAIRE

    2006-01-01

    L'esquizofrènia és una malaltia cerebral crònica, greu i incapacitant que afecta l'1% de la població i que s'expressa en forma de funcions mentals anormals i alteracions en el comportament. Només amb l'aparició dels primer fàrmacs antipsicòtics va millorar sensiblement la situació d'aquests malalts. Els antipsicòtics clàssics presenten efectes secundaris greus, mentre que els antipsicòtics atípics amb una eficàcia terapèutica igual o superior que els clàssics no indueixen aquest efecte advers...

  3. Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function.

    Science.gov (United States)

    Eshleman, Amy J; Forster, Michael J; Wolfrum, Katherine M; Johnson, Robert A; Janowsky, Aaron; Gatch, Michael B

    2014-03-01

    Psychoactive-substituted phenethylamines 2,5-dimethoxy-4-chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5-dimethoxy-4-ethylphenethylamine (2C-E); 2,5-dimethoxy-4-iodophenethylamine (2C-I); 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2); and 2,5-dimethoxy-4-chloroamphetamine (DOC) are used recreationally and may have deleterious side effects. This study compares the behavioral effects and the mechanisms of action of these substituted phenethylamines with those of hallucinogens and a stimulant. The effects of these compounds on mouse locomotor activity and in rats trained to discriminate dimethyltryptamine, (-)-DOM, (+)-LSD, (±)-MDMA, and S(+)-methamphetamine were assessed. Binding and functional activity of the phenethylamines at 5-HT1A, 5-HT2A, 5-HT2C receptors and monoamine transporters were assessed using cells heterologously expressing these proteins. The phenethylamines depressed mouse locomotor activity, although 2C-D and 2C-E stimulated activity at low doses. The phenethylamines except 2C-T-2 fully substituted for at least one hallucinogenic training compound, but none fully substituted for (+)-methamphetamine. At 5-HT1A receptors, only 2C-T-2 and 2C-I were partial-to-full very low potency agonists. In 5-HT2A arachidonic acid release assays, the phenethylamines were partial to full agonists except 2C-I which was an antagonist. All compounds were full agonists at 5-HT2A and 5-HT2C receptor inositol phosphate assays. Only 2C-I had moderate affinity for, and very low potency at, the serotonin transporter. The discriminative stimulus effects of 2C-C, 2C-D, 2C-E, 2C-I, and DOC were similar to those of several hallucinogens, but not methamphetamine. Additionally, the substituted phenethylamines were full agonists at 5-HT2A and 5-HT2C receptors, but for 2C-T-2, this was not sufficient to produce hallucinogen-like discriminative stimulus effects. Additionally, the 5-HT2A inositol phosphate pathway may be important in 2C

  4. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

    DEFF Research Database (Denmark)

    Borg, J; Cervenka, S; Kuja-Halkola, R

    2016-01-01

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about...... and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A...

  5. Argyreia nervosa (Burm. f.): receptor profiling of lysergic acid amide and other potential psychedelic LSD-like compounds by computational and binding assay approaches.

    Science.gov (United States)

    Paulke, Alexander; Kremer, Christian; Wunder, Cora; Achenbach, Janosch; Djahanschiri, Bardya; Elias, Anderson; Schwed, J Stefan; Hübner, Harald; Gmeiner, Peter; Proschak, Ewgenij; Toennes, Stefan W; Stark, Holger

    2013-07-09

    The convolvulacea Argyreia nervosa (Burm. f.) is well known as an important medical plant in the traditional Ayurvedic system of medicine and it is used in numerous diseases (e.g. nervousness, bronchitis, tuberculosis, arthritis, and diabetes). Additionally, in the Indian state of Assam and in other regions Argyreia nervosa is part of the traditional tribal medicine (e.g. the Santali people, the Lodhas, and others). In the western hemisphere, Argyreia nervosa has been brought in attention as so called "legal high". In this context, the seeds are used as source of the psychoactive ergotalkaloid lysergic acid amide (LSA), which is considered as the main active ingredient. As the chemical structure of LSA is very similar to that of lysergic acid diethylamide (LSD), the seeds of Argyreia nervosa (Burm. f.) are often considered as natural substitute of LSD. In the present study, LSA and LSD have been compared concerning their potential pharmacological profiles based on the receptor binding affinities since our recent human study with four volunteers on p.o. application of Argyreia nervosa seeds has led to some ambiguous effects. In an initial step computer-aided in silico prediction models on receptor binding were employed to screen for serotonin, norepinephrine, dopamine, muscarine, and histamine receptor subtypes as potential targets for LSA. In addition, this screening was extended to accompany ergotalkaloids of Argyreia nervosa (Burm. f.). In a verification step, selected LSA screening results were confirmed by in vitro binding assays with some extensions to LSD. In the in silico model LSA exhibited the highest affinity with a pKi of about 8.0 at α1A, and α1B. Clear affinity with pKi>7 was predicted for 5-HT1A, 5-HT1B, 5-HT1D, 5-HT6, 5-HT7, and D2. From these receptors the 5-HT1D subtype exhibited the highest pKi with 7.98 in the prediction model. From the other ergotalkaloids, agroclavine and festuclavine also seemed to be highly affine to the 5-HT1D-receptor

  6. 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception.

    Science.gov (United States)

    Biagioni, Audrey Franceschi; de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; da Silva, Juliana Almeida; dos Anjos-Garcia, Tayllon; Roncon, Camila Marroni; Corrado, Alexandre Pinto; Zangrossi, Hélio; Coimbra, Norberto Cysne

    2016-03-01

    The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH.

  7. Receptor binding profile of Otilonium bromide.

    Science.gov (United States)

    Evangelista, S; Giachetti, A; Chapelain, B; Neliat, G; Maggi, C A

    1998-08-01

    The interaction of Otilonium bromide (OB) with binding sites for 63 different receptors and ion channels in appropriate preparations has been investigated. Experiments were also performed in rat colon, the preferred tissue for OB 'in vivo' uptake after oral administration. Among the receptors investigated OB binds with sub microM affinity to muscarinic M1, M2, M4, M5 and PAF receptors and with microM affinity to the diltiazem binding site on L type Ca2+ channels. In the rat colon OB shows competitive interaction with the verapamil binding site on L type Ca2+ channels and with muscarinic M2 receptors with IC50 of 1020 and 1220 nM, respectively. These findings provide a molecular rationale to explain the spasmolytic action exerted by OB on intestinal smooth muscle. In particular, a combination of antimuscarinic and Ca2+ channel blocker properties seems to best account for the action of this compound.

  8. Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines.

    Science.gov (United States)

    Akama, Keith T; Thompson, Louisa I; Milner, Teresa A; McEwen, Bruce S

    2013-03-01

    The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.

  9. Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines*

    Science.gov (United States)

    Akama, Keith T.; Thompson, Louisa I.; Milner, Teresa A.; McEwen, Bruce S.

    2013-01-01

    The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity. PMID:23300088

  10. ABP: a novel AMPA receptor binding protein.

    Science.gov (United States)

    Srivastava, S; Ziff, E B

    1999-04-30

    We review the cloning of a novel AMPA receptor binding protein (ABP) that interacts with GluR2/3 and is homologous to GRIP. ABP is enriched in the PSD with GluR2 and is localized to the PSD by EM. ABP binds GluR2 via the C-terminal VXI motif through a Class I PDZ interaction. ABP and GRIP can also homo- and heteromultimerize. Thus, ABP and GRIP may be involved in AMPA receptor regulation and localization, by linking it to other cytoskeletal or signaling molecules. We suggest that the ABP/GRIP and PSD-95 families form distinct scaffolds that anchor, respectively, AMPA and NMDA receptors. We are currently investigating proteins that bind ABP and that may regulate the AMPA receptor.

  11. Enhanced human receptor binding by H5 haemagglutinins

    OpenAIRE

    Xiong, Xiaoli; Xiao, Haixia; Martin, Stephen R.; Coombs, Peter J.; Liu, Junfeng; Collins, Patrick J.; Vachieri, Sebastien G.; Walker, Philip A.; Lin, Yi Pu; McCauley, John W.; Gamblin, Steven J.; John J Skehel

    2014-01-01

    Mutant H5N1 influenza viruses have been isolated from humans that have increased human receptor avidity. We have compared the receptor binding properties of these mutants with those of wild-type viruses, and determined the structures of their haemagglutinins in complex with receptor analogues. Mutants from Vietnam bind tighter to human receptor by acquiring basic residues near the receptor binding site. They bind more weakly to avian receptor because they lack specific interactions between As...

  12. The Stimulus Effects of 8-OH-DPAT: Evidence for a 5-HT2A Receptor-Mediated Component

    OpenAIRE

    Reissig, C.J.; Eckler, J.R.; Rabin, R. A.; Rice, K. C.; Winter, J. C.

    2007-01-01

    A previous investigation in our laboratory found that the stimulus effects of the 5-HT2A agonist, LSD, are potentiated by 5-HT1A receptor agonists including the prototypic agonist, 8-OH-DPAT. Also suggestive of behaviorally relevant interactions between 5-HT1A and 5-HT2A receptors are behavioral analyses of locomotor activity, head twitch response, forepaw treading and production of the serotonin syndrome; in some instances effects are augmented, in other, diminished. These observations led u...

  13. Towards metabolically stable 5-HT7 receptor ligands: a study on 1-arylpiperazine derivatives and related isosters.

    Science.gov (United States)

    Lacivita, Enza; De Giorgio, Paola; Patarnello, Daniela; Niso, Mauro; Colabufo, Nicola A; Berardi, Francesco; Perrone, Roberto; Satala, Grzegorz; Duszynska, Beata; Bojarski, Andrzej J; Leopoldo, Marcello

    2013-10-01

    Serotonin 7 (5-hydroxytryptamine7 or 5-HT7) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Here, we report on the structural manipulation of the 5-HT7 receptor ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (1a) aimed at obtaining 5-HT7 receptor ligands endowed with good in vitro metabolic stability. A set of N-[3-methoxyphenyl)ethyl-substituted] 1-arylpiperazine, 4-arylpiperidine and 1-aryl-4-aminopiperidine was synthesized and tested in radioligand binding assays at human cloned 5-HT7 and 5-HT1A receptors. In vitro metabolic stability of the target compounds was assessed after incubation with rat hepatic S9 microsomal fraction. Among the new compounds, 1-(2-biphenyl)-4-[2-(3-methoxyphenyl)ethyl]piperazine (1d) and 4-(2-biphenyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine (2d) showed a good compromise between affinity at 5-HT7 receptor (K i = 7.5 nM and 13 nM, respectively) and in vitro metabolic stability (26 and 65 % recovery of parent compound, respectively) but were poorly selective over 5-HT1A receptor.

  14. Decreased response of interneurons in the medial prefrontal cortex to 5-HT₁A receptor activation in the rat 6-hydroxydopamine Parkinson model.

    Science.gov (United States)

    Zhang, Qiaojun; Wang, Shuang; Zhang, Lina; Zhang, Huan; Qiao, Hongfei; Niu, Xiaolin; Liu, Jian

    2014-08-01

    This study examined the response of interneurons in the medial prefrontal cortex (mPFC) to 5-HT1A receptor agonist 8-OH-DPAT and change in expression of 5-HT1A receptor on glutamate decarboxylase 67 (GAD67)-positive neurons in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc). Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT dose-dependently inhibited the firing rate of the interneurons at all doses tested in sham-operated rats. In 6-OHDA-lesioned rats, 8-OH-DPAT, at the same doses, also inhibited the firing rate of the interneurons, whereas the inhibition was significant only at a high cumulative dose. Furthermore, injection of 8-OH-DPAT into the mPFC inhibited the interneurons in sham-operated rats, while having no effect on firing rate of the interneurons in 6-OHDA-lesioned rats. In contrast to sham-operated rats, SNc lesion reduced the expression of 5-HT1A receptor on GAD67-positive neurons in the prelimbic cortex, a sub-region of the mPFC. Our results indicate that degeneration of the nigrostriatal pathway leads to decreased response of mPFC interneurons to 5-HT1A receptor activation, which attributes to the down-regulation of 5-HT1A receptor expression in these interneurons.

  15. DC-SIGN:Binding receptor for HCV?

    Institute of Scientific and Technical Information of China (English)

    Zhi-Hua Feng; Quan-Chu Wang; Qing-He Nie; Zhan-Sheng Jia; Yong-Xin Zhou

    2004-01-01

    DC-SIGN, a dendritic Cell-specific adhesion receptor and a type Ⅱ transmembrane mannose-binding C-type lectin, is very important in the function of DC, both in mediating naive T cell interactions through ICAM-3 and as a rolling receptor that mediates the DC-specific ICAM-2-dependent migration processes. It can be used by viral and bacterial pathogens including Human Immunodeficiency Virus (HIV), HCV, Ebola Virus, CMV and Mycobacterium tuberculosis to facilitate infection. Both DC-SIGN and DC-SIGNR can act either in cis,by concentrating virus on target cells, or in trans, by transmission of bound virus to a target cell expressing appropropriate entry receptors. Recent work showed that DC-SIGN are highaffinity binding receptors for HCV. Besides playing a role in entry into DC, HCV E2 interaction with DC-SIGN might also be detrimental for the interaction of DC with T cells during antigen presentation. The clinical strategies that target DCSIGN may be successful in restricting HCV dissemination and pathogenesis as well as directing the migration of DCs to manipulate appropriate immune responses in autoimmunity and tumorigenic situations.

  16. Expression of functional G protein-coupled receptors in photoreceptors of transgenic Xenopus laevis.

    Science.gov (United States)

    Zhang, Li; Salom, David; He, Jianhua; Okun, Alex; Ballesteros, Juan; Palczewski, Krzysztof; Li, Ning

    2005-11-08

    G protein-coupled receptors (GPCRs) constitute the largest superfamily of transmembrane signaling proteins; however, the only known GPCR crystal structure is that of rhodopsin. This disparity reflects the difficulty in generating purified GPCR samples of sufficient quantity and quality. Rhodopsin, the light receptor of retinal rod neurons, is produced in large amounts of homogeneous quality in the vertebrate retina. We used transgenic Xenopus laevis to convert these retina rod cells into bioreactors to successfully produce 20 model GPCRs. The receptors accumulated in rod outer segments and were homogeneously glycosylated. Ligand and [(35)S]GTPgammaS binding assays of the 5HT(1A) and EDG(1) GPCRs confirmed that they were properly folded and functional. 5HT(1A)R was highly purified by taking advantage of the rhodopsin C-terminal immunoaffinity tag common to all GPCR constructs. We have also developed an automated system that can generate hundreds of transgenic tadpoles per day. This expression approach could be extended to other animal model systems and become a general method for the production of large numbers of GPCRs and other membrane proteins for pharmacological and structural studies.

  17. Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

    Directory of Open Access Journals (Sweden)

    Zdzisław Chilmonczyk

    2015-08-01

    Full Text Available Serotonin (5-HT is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems, which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

  18. Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation

    Directory of Open Access Journals (Sweden)

    Nakayama H

    2014-02-01

    Full Text Available Hiroto Nakayama,1,* Sumiyo Umeda,2,* Masashi Nibuya,3 Takeshi Terao,4 Koichi Nisijima,5 Soichiro Nomura3 1Yamaguchi Prefecture Mental Health Medical Center, Yamaguchi, Japan; 2Department of Psychiatry, NTT West Osaka Hospital, Osaka, Japan; 3Department of Psychiatry, National Defense Medical College, Saitama, Japan; 4Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan; 5Department of Psychiatry, Jichi University School of Medicine, Tochigi, Japan  *These authors contributed equally to this work Abstract: We propose the possibility of 5-hydroxytryptamine (5-HT1A receptor involvement in mild serotonin toxicity. A 64-year-old woman who experienced hallucinations was treated with perospirone (8 mg/day. She also complained of depressed mood and was prescribed paroxetine (10 mg/day. She exhibited finger tremors, sweating, coarse shivering, hyperactive knee jerks, vomiting, diarrhea, tachycardia, and psychomotor agitation. After the discontinuation of paroxetine and perospirone, the symptoms disappeared. Another 81-year-old woman, who experienced delusions, was treated with perospirone (8 mg/day. Depressive symptoms appeared and paroxetine (10 mg/day was added. She exhibited tachycardia, finger tremors, anxiety, agitation, and hyperactive knee jerks. The symptoms disappeared after the cessation of paroxetine and perospirone. Recently, the effectiveness of coadministrating 5-HT1A agonistic psychotropics with selective serotonin reuptake inhibitors (SSRIs has been reported, and SSRIs with 5-HT1A agonistic activity have been newly approved in the treatment of depression. Perospirone is a serotonin–dopamine antagonist and agonistic on the 5-HT1A receptors. Animal studies have indicated that mild serotonin excess induces low body temperature through 5-HT1A, whereas severe serotonin excess induces high body temperature through 5-HT2A activation. Therefore, it could be hypothesized that mild serotonin excess induces side effects

  19. Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro

    Directory of Open Access Journals (Sweden)

    Robert eRoot-Bernstein

    2014-07-01

    Full Text Available Rationale: Insulin resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome and obesity. The mechanism by which insulin and estrogen interact is unknown. We hypothesize that estrogen binds directly to insulin and the insulin receptor producing insulin resistance.Objectives: To determine the binding constants of steroid hormones to insulin, the insulin receptor, and insulin-like peptides derived from the insulin receptor; and to investigate the effect of estrogens on the binding of insulin to its receptor.Methods: Ultraviolet spectroscopy, capillary electrophoresis and NMR demonstrated estrogen binding to insulin and its receptor. Horse-radish peroxidase-linked insulin was used in an ELISA-like procedure to measure the effect of estradiol on binding of insulin to its receptor. Measurements: Binding constants for estrogens to insulin and the insulin receptor were determined by concentration-dependent spectral shifts. The effect of estradiol on insulin-HRP binding to its receptor was determined by shifts in the insulin binding curve. Main Results: Estradiol bound to insulin with a Kd of 12 x 10-9 M and to the insulin receptor with a Kd of 24 x 10-9 M, while other hormones had significantly less affinity. 200 nM estradiol shifted the binding curve of insulin to its receptor 0.8 log units to the right. Conclusions: Estradiol concentrations in many hyperestrogenemic syndromes are sufficient to interfere with insulin binding to its receptor producing significant insulin resistance.

  20. Structural Analysis of Botulinum Neurotoxin Type G Receptor Binding

    Energy Technology Data Exchange (ETDEWEB)

    Schmitt, John; Karalewitz, Andrew; Benefield, Desire A.; Mushrush, Darren J.; Pruitt, Rory N.; Spiller, Benjamin W.; Barbieri, Joseph T.; Lacy, D. Borden (Vanderbilt); (MCW)

    2010-10-19

    Botulinum neurotoxin (BoNT) binds peripheral neurons at the neuromuscular junction through a dual-receptor mechanism that includes interactions with ganglioside and protein receptors. The receptor identities vary depending on BoNT serotype (A-G). BoNT/B and BoNT/G bind the luminal domains of synaptotagmin I and II, homologous synaptic vesicle proteins. We observe conditions under which BoNT/B binds both Syt isoforms, but BoNT/G binds only SytI. Both serotypes bind ganglioside G{sub T1b}. The BoNT/G receptor-binding domain crystal structure provides a context for examining these binding interactions and a platform for understanding the physiological relevance of different Syt receptor isoforms in vivo.

  1. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.

    Directory of Open Access Journals (Sweden)

    Jiangnan Luo

    Full Text Available A set of 14 insulin-producing cells (IPCs in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5. Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  2. Formyl peptide receptor chimeras define domains involved in ligand binding.

    Science.gov (United States)

    Perez, H D; Holmes, R; Vilander, L R; Adams, R R; Manzana, W; Jolley, D; Andrews, W H

    1993-02-05

    We have begun to study the structural requirements for the binding of formyl peptides to their specific receptors. As an initial approach, we constructed C5a-formyl peptide receptor chimeras. Unique (and identical) restriction sites were introduced within the transmembrane domains of these receptors that allowed for the exchange of specific areas. Four types of chimeric receptors were generated. 1) The C5a receptor was progressively substituted by the formyl peptide receptor. 2) The formyl peptide receptor was progressively substituted by the C5a receptor. 3) Specific domains of the C5a receptor were substituted by the corresponding domain of the formyl peptide receptor. 4) Specific domains of the formyl peptide receptor were replaced by the same corresponding domain of the C5a receptor. Wild type and chimeric receptors were transfected into COS 7 cells and their ability to bind formyl peptide determined, taking into account efficiency of transfection and expression of chimeric protein. Based on these results, a ligand binding model is presented in which the second, third, and fourth extracellular (and/or their transmembrane) domains together with the first transmembrane domain form a ligand binding pocket for formyl peptides. It is proposed that the amino-terminal domain plays a role by presumably providing a "lid" to the pocket. The carboxyl-terminal cytoplasmic tail appears to modulate ligand binding by regulating receptor affinity.

  3. New 1-arylindoles based serotonin 5-HT7 antagonists. Synthesis and binding evaluation studies.

    Science.gov (United States)

    Sagnes, Charlène; Fournet, Guy; Satala, Grzegorz; Bojarski, Andrzej J; Joseph, Benoît

    2014-03-21

    Based on 5-HT1A and 5-HT7 ligand MR25003 scaffold, a new series of 1-aryl indole analogues were prepared and evaluated against 5-HT7 receptors. Modulations of aryl moieties provided a large number of new indolic derivatives. Most of compounds tested have displayed 5-HT7 affinity in the nanomolar range. Among them, 1-(naphthyl)indole derivative 3p (Ki (5-HT7) = 4.5 nM) showed also a good selectivity over 5-HT1A, 5-HT2A and 5-HT6 receptors. This compound was pharmacology characterized as an antagonist.

  4. Exploiting Receptor Competition to Enhance Nanoparticle Binding Selectivity

    Science.gov (United States)

    Angioletti-Uberti, Stefano

    2017-02-01

    Nanoparticles functionalized with multiple ligands can be programed to bind biological targets depending on the receptors they express, providing a general mechanism exploited in various technologies, from selective drug delivery to biosensing. For binding to be highly selective, ligands should exclusively interact with specific targeted receptors, because the formation of bonds with other, untargeted ones would lead to nonspecific binding and potentially harmful behavior. This poses a particular problem for multivalent nanoparticles, because even very weak bonds can collectively lead to strong binding. A statistical mechanical model is used here to describe how competition between different receptors together with multivalent effects can be harnessed to design ligand-functionalized nanoparticles insensitive to the presence of untargeted receptors, preventing nonspecific binding.

  5. Dysregulation of Striatal Dopamine Receptor Binding in Suicide.

    Science.gov (United States)

    Fitzgerald, Megan L; Kassir, Suham A; Underwood, Mark D; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2017-03-01

    Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [(3)H]mazindol), D1 receptor ([(3)H]SCH23390), and D2 receptor ([(3)H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R(2)=0.31, pELA, there was no correlation between striatal DAT and D1 receptor binding (R(2)=0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R(2)=0.32, pELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R(2)=0.12, pELA or age.

  6. THE RECEPTOR BINDING AFFINITIES, ANTIPROGESTERONE AND ANTIGLUCOCORTICOID ACTIVITIES OF MIFEPRISTONE AND LILOPRISTONE

    Institute of Scientific and Technical Information of China (English)

    LIUYong-Qiang; WUXi-Rui

    1989-01-01

    With radioligand binding assays, the receptor binding affmities of mifepristone and lilopristone to the rabbit uterus cytosol progesterone receptor and the rat fiver cytosol glucocorticoid receptor have been measured. The relative binding affinities ( RBA ) of

  7. Properties of Opiate-Receptor Binding in Rat Brain

    Science.gov (United States)

    Pert, Candace B.; Snyder, Solomon H.

    1973-01-01

    [3H]Naloxone, a potent opiate antagonist, binds stereospecifically to opiate-receptor sites in rat-brain tissue. The binding is time, temperature, and pH dependent and saturable with respect to [3H]naloxone and tissue concentration. The [3H]naloxone-receptor complex formation is bimolecular with a dissociation constant of 20 nM. 15 Opiate agonists and antagonists compete for the same receptors, whose density is 30 pmol/g. Potencies of opiates and their antagonists in displacing [3H]naloxone binding parallel their pharmacological potencies. PMID:4525427

  8. Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task.

    Science.gov (United States)

    Meneses, Alfredo

    2004-12-06

    There is an important debate regarding the functional role of the 5-HT(1A) and 5-HT(7) receptor in memory systems. Hence, the objective of this paper is to investigate the function of serotonin (5-hydroxytryptamine, 5-HT) in memory consolidation, utilising an autoshaping Pavlovian/instrumental learning test. Specific antagonists at 5-HT(1A) (WAY 100635) and 5-HT(7) (SB-269970 or DR 4004) receptors administered i.p. or s.c.) after training, significantly decreased the improvement of performance produced by the 5-HT(1A/7) agonist 8-OH-DPAT to levels lower than controls'. These same antagonists attenuated the decreased level of performance produced by mCPP, although they decrease the performance levels after p-chloroamphetamine (PCA) lesion of the 5-HT system, which has no effect on its own on the conditioned response. Moreover, SB-269970 or DR 4004 reversed amnesia induced by scopolamine and dizocilpine. These data confirm a role for 5-HT(1A) and 5-HT(7) receptors in memory formation and support the hypothesis that serotonergic, cholinergic, and glutamatergic systems interact in cognitively impaired animals. These findings support a potential role for both 5-HT(1A) and 5-HT(7) receptors in the pathophysiology and/or treatment of schizophrenia, cognitive deficits and the mechanism of action of atypical antipsychotic drugs.

  9. Receptor-binding radiotracers: a class of potential radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Eckelman, W.C.; Reba, R.C.; Gibson, R.E.; Rzeszotarski, W.J.; Vieras, F.; Mazaitis, J.K.; Francis, B.

    1979-04-01

    To date no radiopharmaceutical is routinely used to study changes in receptor concentration. Frequently changes in receptor concentration, or the appearance of receptors in tumors, indicates a specific pathologic state. With a receptor-binding radiotracer, in vivo studies of these changes will be possible. A reversible bimolecular model and in vitro tests were used to determine equilibrium constants and maximal target-to-blood ratios for new derivatives. Theoretical calculations showed that derivatives binding to the estrogen receptor, the beta adrenoceptor, or the cholinergic receptor are capable of achieving satisfactory target-to-blood ratios. Using in vitro tests, the apparent affinity constant was determined for five iodinated estrogen derivatives and five derivatives of beta blockers. Results of the in vitro study with derivatives of beta blockers. Results of the in vitro study with derivatives of beta blockers, and in vivo displacement studies using propranolol, indicated that the high heart-to-blood ratios (5 to 20) obtained with the new derivatives were not the result of a specific interaction with the receptor. In this instance factors other than receptor binding control the in vivo distribution. The in vitro assay using estrogen receptors showed that of the five derivatives, iodohexestrol and 17-alpha-iodoethynylestradiol bind to the receptor with the highest affinity. In vivo studies confirmed these results; iodohexestrol gave a uterus-to-blood ratio of 10 in immature rats when plasma-protein binding was blocked. With a tritiated muscarinic cholinergic blocking agent, heart-to-blood ratios near the theoretical maximum were obtained. This compound most closely follows the mechanism described by the model. Use of the theoretical model in conjunction with in vitro assays can greatly aid in the design of this new class of receptor-binding radiopharmaceuticals.

  10. Study of binding glycyrrhetic acid to AT1 receptor

    Institute of Scientific and Technical Information of China (English)

    ZHANG; Fengyun; (张凤云); YUE; Baozhen; (岳保珍); HE; Shipeng; (贺师鹏)

    2003-01-01

    To analyze the binding of glycyrrhetic acid (GA) to angiotensin II type I (AT1) receptor and to explore the mechanisms underlying the binding, primary cell culture of rat vascular smooth muscle cell (VSMC), radioactive ligand-receptor binding assay, lascer confocal scanning microscope (LCSM), Northern blot, 3H-TdR incorporation DNA assay were used in this study. The results suggest that specific binding of GA to AT1 receptor (IC50 value was 35.0 μmol/L) increases intracellular [Ca2+]i of VSMC, activates transcription factor c-myc and promotes the proliferation of VSMC, therefore GA was probably an agonist of AT1 receptor, providing a new target for GA's pharmaceutical effects.

  11. Binding characteristics of the muscarinic receptor subtype in rabbit pancreas

    Energy Technology Data Exchange (ETDEWEB)

    van Zwam, A.J.; Willems, P.H.; Rodrigues de Miranda, J.F.; de Pont, J.J.; van Ginneken, C.A. (Catholic Univ. of Nijmegen (Netherlands))

    1990-01-01

    The muscarinic receptor in the rabbit pancreas was characterized with the use of the labeled ligand ({sup 3}H)-(-)-quinuclidinyl-benzylate (({sup 3}H)-(-)-QNB). Specific binding of ({sup 3}H)-(-)-QNB to pancreatic acini was found to be reversible and of high affinity, with an equilibrium dissociation constant (KD) of 68 pmol/l and a receptor density (RT) of 170 fmol/mg protein. Agonist binding behaviour was investigated by displacement of ({sup 3}H)-(-)-QNB binding by eight agonists like arecoline, arecadine-propargylester (APE) and carbachol, yielding only low affinity binding sites. The inhibition of ({sup 3}H)-(-)-QNB binding by the selective antagonists pirenzepine, hexahydrosiladifenidol (HHSiD) and (11-(2-(diethyl-amino)-methyl-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyr ido (2,3-b) (1,4) benzodiazepin-6-one (AF-DX 116) confirmed the M3 nature of the rabbit pancreatic receptor.

  12. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

    Science.gov (United States)

    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  13. Distribution of neurotransmitter receptors and zinc in the pigeon (Columba livia) hippocampal formation: A basis for further comparison with the mammalian hippocampus.

    Science.gov (United States)

    Herold, Christina; Bingman, Verner P; Ströckens, Felix; Letzner, Sara; Sauvage, Magdalena; Palomero-Gallagher, Nicola; Zilles, Karl; Güntürkün, Onur

    2014-08-01

    The avian hippocampal formation (HF) and mammalian hippocampus share a similar functional role in spatial cognition, but the underlying neuronal mechanisms allowing the functional similarity are incompletely understood. To understand better the organization of the avian HF and its transmitter receptors, we analyzed binding site densities for glutamatergic AMPA, NMDA, and kainate receptors; GABAA receptors; muscarinic M1 , M2 and nicotinic (nACh) acetylcholine receptors; noradrenergic α1 and α2 receptors; serotonergic 5-HT1A receptors; dopaminergic D1/5 receptors by using quantitative in vitro receptor autoradiography. Additionally, we performed a modified Timm staining procedure to label zinc. The regionally different receptor densities mapped well onto seven HF subdivisions previously described. Several differences in receptor expression highlighted distinct HF subdivisions. Notable examples include 1) high GABAA and α1 receptor expression, which rendered distinctive ventral subdivisions; 2) high α2 receptor expression, which rendered distinctive a dorsomedial subdivision; 3) distinct kainate, α2 , and muscarinic receptor densities that rendered distinctive the two dorsolateral subdivisions; and 4) a dorsomedial region characterized by high kainate receptor density. We further observed similarities in receptor binding densities between subdivisions of the avian and mammalian HF. Despite the similarities, we propose that 300 hundred million years of independent evolution has led to a mosaic of similarities and differences in the organization of the avian HF and mammalian hippocampus and that thinking about the avian HF in terms of the strict organization of the mammalian hippocampus is likely insufficient to understand the HF of birds.

  14. Risperidone treatment increases CB1 receptor binding in rat brain

    DEFF Research Database (Denmark)

    Secher, Anna; Husum, Henriette; Holst, Birgitte

    2010-01-01

    BACKGROUND/AIMS: Body weight gain is a common side effect of treatment with antipsychotics, but the mechanisms underlying this weight gain are unknown. Several factors may be involved in antipsychotic-induced body weight gain including the cannabinoid receptor 1 (CB(1)), the serotonin receptor 2C...... positively correlated with visceral fat mass. Risperidone treatment increased CB(1) receptor binding in the arcuate nucleus (40%), hippocampus (25-30%) and amygdala (35%) without concurrent alterations in the CB(1) receptor mRNA. Risperidone treatment increased adiponectin mRNA. CONCLUSION: The present study...... showed that risperidone treatment altered CB(1) receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB(1) receptor density in brain regions involved in appetite and regulation of metabolic function....

  15. Noncovalent Interactions within a Synthetic Receptor Can Reinforce Guest Binding

    NARCIS (Netherlands)

    Rodriguez-Docampo, Zaida; Pascu, Sofia I.; Kubik, Stefan; Otto, Sijbren

    2006-01-01

    Structural and thermodynamic data are presented on the binding properties of anion receptors containing two covalently linked cyclopeptide subunits that bind sulfate and iodide anions with micromolar affinity in aqueous solution. A synchrotron X-ray crystal structure of the sulfate complex of one

  16. Pneumocystis carinii glycoprotein A binds macrophage mannose receptors.

    OpenAIRE

    O'Riordan, D.M.; Standing, J E; Limper, A H

    1995-01-01

    Pneumocystis carinii causes life-threatening pneumonia in patients with impaired immunity. Recent studies suggest that alveolar macrophages interact with P. carinii through macrophage mannose receptors. However, the ligand(s) on P. carinii that is recognized by these receptors has not been fully defined. P. carinii contains a major mannose-rich surface antigen complex termed glycoprotein A (gpA). It was therefore hypothesized that gpA binds directly to macrophage mannose receptors and mediate...

  17. Binding of tropane alkaloids to nicotinic and muscarinic acetylcholine receptors.

    Science.gov (United States)

    Schmeller, T; Sporer, F; Sauerwein, M; Wink, M

    1995-07-01

    Fourteen tropane and related alkaloids were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. The biogenetic intermediates littorine, 6 beta-hydroxyhyoscyamine, 7 beta-hydroxyhyoscyamine exhibit similar affinities at the muscarinic receptor as scopolamine and atropine. The quarternary derivatives N-methylatropine and N-methylscopolamine show the highest binding with IC50 values of less than 100 pM and 300 pM, respectively. The tropane alkaloids (including cocaine) also bind to the nicotinic acetylcholine receptor, albeit with much lower affinities.

  18. Effect of desipramine on dopamine receptor binding in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Suhara, Tetsuya (National Institute of Radiological Sciences, Chiba (Japan) Jikei Univ., Tokyo (Japan)); Inoue, Osamu; Kobayasi, Kaoru (National Institute of Radiological Sciences, Chiba (Japan))

    1990-01-01

    Effect of desipramine on the in vivo binding of {sup 3}H-SCH23390 and {sup 3}H-N-methylspiperone ({sup 3}H-NMSP) in mouse striatum was studied. The ratio of radioactivity in the striatum to that in the cerebellum at 15 min after i.v. injection of {sup 3}H-SCH23390 or 45 min after injection of {sup 3}H-NMSP were used as indices of dopamine D1 or D2 receptor binding in vivo, respectively. In vivo binding of D1 and D2 receptors was decreased in a dose-dependent manner by acute treatment with desipramine (DMI). A saturation experiment suggested that the DMI-induced reduction in the binding was mainly due to the decrease in the affinity of both receptors. No direct interactions between the dopamine receptors and DMI were observed in vitro by the addition of 1 mM of DMI into striatal homogenate. Other antidepressants such as imipramine, clomipramine, maprotiline and mianserin also decreased the binding of dopamine D1 and D2 receptors. The results indicated an important role of dopamine receptors in the pharmacological effect of antidepressants.

  19. Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system.

    Science.gov (United States)

    Murotani, Tomotaka; Ishizuka, Tomoko; Isogawa, Yuka; Karashima, Michitaka; Yamatodani, Atsushi

    2011-01-01

    The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis. Single injection of risperidone (0.5mg/kg, i.p.) or aripiprazole (1mg/kg, i.p.), which have binding affinities to 5-HT(1A, 2A, 2B) and (2C) receptors decreased food intake in C57BL/6N mice with concomitant increase of hypothalamic histamine release. However, a selective D(2)-antagonist, haloperidol (0.5mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H(1) receptor-deficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT(2A)-antagonists, volinanserin (0.5, 1mg/kg, i.p.) and ketanserin (5, 10mg/kg, i.p.), significantly increased histamine release and 5-HT(2B/2C) -antagonist, SB206553 (2.5, 5mg/kg, i.p.), slightly increased it. On the contrary, 5-HT(1A) -selective antagonist, WAY100635 (1, 2mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT(2) receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT(2) receptors resulting in anorexia via the H(1) receptor.

  20. Relationship between activity of 5-HT1A receptor and glucocorticoid receptor in hippocampus in the single-prolonged stress rat%连续单一应激后大鼠海马5-HT1A受体活性与糖皮质激素受体表达的关系

    Institute of Scientific and Technical Information of China (English)

    徐爱军; 李元春; 赵艳霞

    2010-01-01

    目的:观察连续单一应激(SPS)大鼠海马糖皮质激素受体(GR)变化与5-HT1A受体的关系,探讨创伤后应激障碍的发病机制.方法:选用雄性成年Wistar大鼠45只,将大鼠随机分为对照组、模型组和阻断组,每组15只.模型组和阻断组给予SPS应激,其中阻断组大鼠在接受SPS前用55-HT1A受休阻断剂WAY100635预处理.采用免疫组织化学和免疫印迹技术测定海马GR水平,采用逆转录-聚合酶链式反应检测GR mRNA表达变化.结果:(1)免疫组织化学结果显示,模型组大鼠海马GR表达高于对照组(P<0.01),阻断组则低与模型组(P<0.05);(2)Western Blot结果显示,模型组大鼠海马GR相对表达高于对照组(P<0.01),阻断组低于模型组(P<0.01);(3)RT-PCR结果表明,与对照组比较,模型组大鼠海马GR mRNA表达增强(P<0.01);与模型组比较,阻断组表达量降低(P<0.05).结论:SPS海马GR表达变化与5-HT1A受体有关.

  1. Receptor Binding Ligands to Image Infection

    NARCIS (Netherlands)

    Chianelli, M.; Boerman, O. C.; Malviya, G.; Galli, F.; Oyen, W. J. G.; Signore, A.

    2008-01-01

    The current gold standard for imaging infection is radiolabeled white blood cells. For reasons of safety, simplicity and cost, it would be desirable to have a receptor-specific ligand that could be used for imaging infection and that would allow a differential diagnosis between sterile and septic in

  2. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  3. Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2.

    Science.gov (United States)

    Leopoldo, Marcello; Lacivita, Enza; Contino, Marialessandra; Colabufo, Nicola A; Berardi, Francesco; Perrone, Roberto

    2007-08-23

    Here we report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides 16-29 that were designed to elucidate both structure-affinity and -activity relationships for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compounds were determined. A series of substituents covering a wide range of electronic, steric, and polar properties was evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CH(CH3)2, N(CH3)2, CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (Ki = 0.13-1.1 nM, EC50 = 0.90-1.77 microM), showing selectivity over 5-HT1A, 5-HT2A, and D2 receptors.

  4. Radioiodination of chicken luteinizing hormone without affecting receptor binding potency

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, M.; Ishii, S. (Waseda Univ., Tokyo (Japan))

    1989-12-01

    By improving the currently used lactoperoxidase method, we were able to obtain radioiodinated chicken luteinizing hormone (LH) that shows high specific binding and low nonspecific binding to a crude plasma membrane fraction of testicular cells of the domestic fowl and the Japanese quail, and to the ovarian granulosa cells of the Japanese quail. The change we made from the original method consisted of (1) using chicken LH for radioiodination that was not only highly purified but also retained a high receptor binding potency; (2) controlling the level of incorporation of radioiodine into chicken LH molecules by employing a short reaction time and low temperature; and (3) fractionating radioiodinated chicken LH further by gel filtration using high-performance liquid chromatography. Specific radioactivity of the final {sup 125}I-labeled chicken LH preparation was 14 microCi/micrograms. When specific binding was 12-16%, nonspecific binding was as low as 2-4% in the gonadal receptors. {sup 125}I-Labeled chicken LH was displaced by chicken LH and ovine LH but not by chicken follicle-stimulating hormone. The equilibrium association constant of quail testicular receptor was 3.6 x 10(9) M-1. We concluded that chicken LH radioiodinated by the present method is useful for studies of avian LH receptors.

  5. Effect of increased serotonin levels on [F-18] MPPF binding in rat brain : Fenfluramine vs the combination of citalopram and ketanserin

    NARCIS (Netherlands)

    de Haes, JIU; Cremers, TIFH; Bosker, FJ; Postema, F; Timersma-Wegman, TD; den Boer, JA

    2005-01-01

    [F-18]MPPF is a selective serotonin-1A (5-HT1A) receptor antagonist and may be used to measure changes in the functional levels of serotonin (5-HT). The technique is based on the assumption that the injected radiolabeled ligand competes for the same receptor as the endogenous transmitter. Results fr

  6. Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding

    DEFF Research Database (Denmark)

    Hansen, Mathilde Johanne Kaas; Olsen, Johan Gotthardt; Bernichtein, Sophie;

    2011-01-01

    H than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ~6.8 making histidine residues obvious candidates for examination....... From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity...... and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure...

  7. Role of spinal 5-HT receptors in cutaneous hypersensitivity induced by REM sleep deprivation.

    Science.gov (United States)

    Wei, Hong; Ma, Ainiu; Wang, Yong-Xiang; Pertovaara, Antti

    2008-06-01

    Previous studies indicate that rapid eye movement (REM) sleep deprivation facilitates pain sensitivity. Since serotoninergic raphe neurons are involved both in regulation of sleep and descending pain modulation, we studied whether spinal 5-HT receptors have a role in sleep deprivation-induced facilitation of pain-related behavior. REM sleep deprivation of 48h was induced by the flower pot method in the rat. The pain modulatory influence of various serotoninergic compounds administered intrathecally was assessed by determining limb withdrawal response to monofilaments. REM sleep deprivation produced a marked hypersensitivity. Sleep deprivation-induced hypersensitivity and normal sensitivity in controls were reduced both by a 5-HT(1A) receptor antagonist (WAY-100635) and a 5-HT(2C) receptor antagonist (RS-102221). An antagonist of the 5-HT(3) receptor (LY-278584) failed to modulate hypersensitivity in sleep-deprived or control animals. Paradoxically, sensitivity in sleep-deprived and control animals was reduced not only by a 5-HT(1A) receptor antagonist but also by a 5-HT(1A) receptor agonist (8-OHDPAT). The results indicate that serotoninergic receptors in the spinal cord have a complex role in the control of sleep-deprivation induced cutaneous hypersensitivity as well as baseline sensitivity in control conditions. While endogenous serotonin acting on 5-HT(1A) and 5-HT(2C) receptors may facilitate mechanical sensitivity in animals with a sleep deprivation-induced hypersensitivity as well as in controls, increased activation of spinal 5-HT(1A) receptors by an exogenous agonist leads to suppression of mechanical sensitivity in both conditions. Spinal 5-HT(3) receptors do not contribute to cutaneous hypersensitivity induced by sleep deprivation.

  8. DC-SIGN:binding receptors for hepatitis C virus

    Institute of Scientific and Technical Information of China (English)

    王全楚; 冯志华; 聂青和; 周永兴

    2004-01-01

    Objective To review the recent developments in and research into binding receptors of hepatitis C virus (HCV) and especially the role of dendritic cell-specitic adhesion receptor (DC-SIGN) in HCV.Data sources Both Chinese- and English-languge literature was searched using MEDLINE (2000-2003) and the databank of Chinese-language literature (2000-2003).Study selection Relevant articles on DC-SIGN and HCV binding receptors in recent domestic and foreign literature were selected.Data extraction Data were mainly extracted from 40 articles which are listed in the references section of this review. Results DC-SIGN, a dendritic cell-specific adhesion receptor and a type Ⅱ transmembrane mannose-binding C-type lectin, is very important in the function of dendritic cells (DC), both in mediating na(I)ve T cell interactions through ICAM-3 and as a rolling receptor that mediates the DC-specific ICAM-2-dependent migration processes-It can be used by HCV and other viral and bacterial pathogens including human immunodeficiency virus (HIV), Ebola virus, CMV and Mycobacterium tuberculosis- to facilitate infection. Both DC-SIGN and DC-SIGNR can act either in cis, by concentrating virus on target cells, or in trans, by transmission of bound virus to a target cell expressing appropriate entry receptors. Recent report showed that DC-S IGN not only plays a role in entry into DC, HCV E2 interaction with DC-SIGN might also be detrimental to the interaction of DC with T cells during antigen presentation.Conclusions DC-SIGNs are high-affinity binding receptors for HCV.The clinical strategies that target DC-SIGN may be successful in restricting HCV dissemination and pathogenesis as well as directing the migration of DCs to manipulate appropriate immune responses in autoimmunity and tumorigenic situations.

  9. Autoradiographic Mapping of 5-HT(1B/1D) Binding Sites in the Rhesus Monkey Brain Using [carbonyl-C]zolmitriptan.

    Science.gov (United States)

    Lindhe, Orjan; Almqvist, Per; Kågedal, Matts; Gustafsson, Sven-Åke; Bergström, Mats; Nilsson, Dag; Antoni, Gunnar

    2011-01-01

    Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [(11)C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [(11)C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [(11)C]zolmitriptan as a radioligand. In saturation studies, [(11)C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95-5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT(1) receptor antagonists, [(11)C]zolmitriptan binding was blocked by selective 5-HT(1B) and 5-HT(1D) ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT(1A) receptor antagonist.

  10. Autoradiographic Mapping of 5-H T 1B/1D Binding Sites in the Rhesus Monkey Brain Using [carbonyl-11C]zolmitriptan

    Science.gov (United States)

    Lindhe, Örjan; Almqvist, Per; Kågedal, Matts; Gustafsson, Sven-Åke; Bergström, Mats; Nilsson, Dag; Antoni, Gunnar

    2011-01-01

    Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist. PMID:22013519

  11. Autoradiographic Mapping of 5-HT1B/1D Binding Sites in the Rhesus Monkey Brain Using [carbonyl-11C]zolmitriptan

    Directory of Open Access Journals (Sweden)

    Örjan Lindhe

    2011-01-01

    Full Text Available Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90% binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM. There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist.

  12. Estrogen treatment increases the levels of regulator of G protein signaling-Z1 in the hypothalamic paraventricular nucleus: possible role in desensitization of 5-hydroxytryptamine1A receptors.

    Science.gov (United States)

    Carrasco, G A; Barker, S A; Zhang, Y; Damjanoska, K J; Sullivan, N R; Garcia, F; D'souza, D N; Muma, N A; van De Kar, L D

    2004-01-01

    Desensitization of post-synaptic serotonin1A (5-HT1A) receptors may underlie the clinical improvement of neuropsychiatric disorders. In the hypothalamic paraventricular nucleus, Galphaz proteins mediate the 5-HT1A receptor-stimulated increases in hormone release. Regulator of G protein signaling-Z1 (RGSZ1) is a GTPase-activating protein selective for Galphaz proteins. RGSZ1 regulates the duration of interaction between Galphaz proteins and effector systems. The present investigation determined the levels of RGSZ1 in the hypothalamic paraventricular nucleus of rats subjected to four different treatment protocols that produce desensitization of 5-HT1A receptors. These protocols include: daily administration of beta estradiol 3-benzoate (estradiol) for 2 days; daily administration of fluoxetine for 3 and 14 days; daily administration of cocaine for 7 or 14 days; and acute administration of (+/-)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI; a 5-HT2A/2C receptor agonist). Estradiol treatment was the only protocol that increased the levels of RGSZ1 protein in the hypothalamic paraventricular nucleus in a dose-dependent manner (46%-132% over control). Interestingly, previous experiments indicate that only estradiol produces a decreased Emax of 5-HT1A receptor-stimulation of hormone release, whereas fluoxetine, cocaine and DOI produce a shift to the right (increased ED50). Thus, the desensitization of 5-HT1A receptors by estradiol might be attributable to increased levels of RGSZ1 protein. These findings may provide insight into the adaptation of 5-HT1A receptor signaling during pharmacotherapies of mood disorders in women and the well-established gender differences in the vulnerability to depression.

  13. Crystal structure of mouse coronavirus receptor-binding domain complexed with its murine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Guiqing; Sun, Dawei; Rajashankar, Kanagalaghatta R.; Qian, Zhaohui; Holmes, Kathryn V.; Li, Fang (Cornell); (UMM-MED); (Colorado)

    2011-09-28

    Coronaviruses have evolved diverse mechanisms to recognize different receptors for their cross-species transmission and host-range expansion. Mouse hepatitis coronavirus (MHV) uses the N-terminal domain (NTD) of its spike protein as its receptor-binding domain. Here we present the crystal structure of MHV NTD complexed with its receptor murine carcinoembryonic antigen-related cell adhesion molecule 1a (mCEACAM1a). Unexpectedly, MHV NTD contains a core structure that has the same {beta}-sandwich fold as human galectins (S-lectins) and additional structural motifs that bind to the N-terminal Ig-like domain of mCEACAM1a. Despite its galectin fold, MHV NTD does not bind sugars, but instead binds mCEACAM1a through exclusive protein-protein interactions. Critical contacts at the interface have been confirmed by mutagenesis, providing a structural basis for viral and host specificities of coronavirus/CEACAM1 interactions. Sugar-binding assays reveal that galectin-like NTDs of some coronaviruses such as human coronavirus OC43 and bovine coronavirus bind sugars. Structural analysis and mutagenesis localize the sugar-binding site in coronavirus NTDs to be above the {beta}-sandwich core. We propose that coronavirus NTDs originated from a host galectin and retained sugar-binding functions in some contemporary coronaviruses, but evolved new structural features in MHV for mCEACAM1a binding.

  14. 5-HT1A receptors are involved in the modulation of respiratory rhythmical discharge activity in the medulla oblongata slice preparation of neonatal rats%5-HT1A受体对新生大鼠离体延髓脑片呼吸节律性放电的调制

    Institute of Scientific and Technical Information of China (English)

    秦峥; 吴中海; 王晓锋

    2007-01-01

    本研究探讨5-HT1A受体在延髓基本节律性呼吸放电发生和调节中的作用.以改良Kreb's液恒温灌流新生Sprague-Dawley大鼠离体延髓脑片标本,稳定记录与之相连的舌下神经根的呼吸节律性放电活动(respiratory rhythmical discharge activity,RRDA)后,第一组在灌流液中分别单独给予5-HT1A受体的特异性激动剂8-羟四氢萘[(+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide,8-OHDPAT]和特异性拮抗剂多次甲基多苯基多异氰酸酯[4-iodo-N-[2-[4-methoxyphenyl]-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride,PMPPI];第二组分别先后给予8-OHDPAT和8-OHDPAT+PMPPI,观察舌下神经根RRDA的变化,探讨5-HT1A受体对其调节作用.结果显示,给予8-OHDPAT后,呼吸周期(respiratory cycle,RC)和呼气时程(expiratory time,TE)显著延长,放电的积分幅度(integral amplitude,IA)持续降低,吸气时程(inspiratory time,TI)无明显变化;给予PMPPI后RC、TI和TE明显缩短,舌下神经根IA无明显变化,且8-OHDPAT的作用可部分被PMPPI逆转.结果提示,5-HT1A受体参与了哺乳动物基本呼吸节律的产生和调节.

  15. Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

    Science.gov (United States)

    Peng, Xin; Wang, Qi; Mishra, Yogesh; Xu, Jinbin; Reichert, David E; Malik, Maninder; Taylor, Michelle; Luedtke, Robert R; Mach, Robert H

    2015-02-01

    A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.

  16. Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

    Directory of Open Access Journals (Sweden)

    Fabrizio Fierro

    2017-09-01

    Full Text Available Human G-protein coupled receptors (hGPCRs constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.

  17. De novo analysis of receptor binding affinity data of xanthine adenosine receptor antagonists.

    Science.gov (United States)

    Dalpiaz, A; Gardenghi, A; Borea, P A

    1995-03-01

    The receptor binding affinity data to adenosine A1 and A2 receptors of a wide series of xanthine derivatives have been analyzed by means of the Free-Wilson model. The analysis of the individual group contribution shows, for both A1 and A2 receptors, the primary importance of the presence of bulky substituents at position 8 for an optimum receptor binding. Moreover, considering the different aij contributions of bulky substituents at position 8 for affinity to A1 with respect to A2 receptors, this position appears to be the most important for the synthesis of highly A1 selective xanthine derivatives. Moreover the analysis of group contributions for other substitution positions of the xanthine moiety allows to state that suitable substitutions at positions 3 and 7 could confer some degree of A2 selectivity.

  18. Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics.

    Science.gov (United States)

    Sumiyoshi, Tomiki; Bubenikova-Valesova, Vera; Horacek, Jiri; Bert, Bettina

    2008-10-01

    Serotonin (5-HT) receptors have been suggested to play key roles in psychosis, cognition, and mood via influence on neurotransmitters, synaptic integrity, and neural plasticity. Specifically, genetic evidence indicates that 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor single-nucleotide polymorphisms (SNPs) are related to psychotic symptoms, cognitive disturbances, and treatment response in schizophrenia. Data from animal research suggest the role of 5-HT in cognition via its influence on dopaminergic, cholinergic, glutamatergic, and GABAergic function. This article provides up-to-date findings on the role of 5-HT receptors in endophenotypic variations in schizophrenia and the development of newer cognition-enhancing medications, based on basic science and clinical evidence. Imaging genetics studies on associations of polymorphisms of several 5-HT receptor subtypes with brain structure, function, and metabolism suggest a role for the prefrontal cortex and the parahippocampal gyrus in cognitive impairments of schizophrenia. Data from animal experiments to determine the effect of agonists/antagonists at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors on behavioral performance in animal models of schizophrenia based on the glutamatergic hypothesis provide useful information. For this purpose, standard as well as novel cognitive tasks provide a measure of memory/information processing and social interaction. In order to scrutinize mixed evidence for the ability of 5-HT(1A) agonists/antagonists to improve cognition, behavioral data in various paradigms from transgenic mice overexpressing 5-HT(1A) receptors provide valuable insights. Clinical trials reporting the advantage of 5-HT(1A) partial agonists add to efforts to shape pharmacologic perspectives concerning cognitive enhancement in schizophrenia by developing novel compounds acting on 5-HT receptors. Overall, these lines of evidence from translational research will facilitate the development of newer pharmacologic strategies

  19. Serotonin 1A receptors alter expression of movement representations.

    Science.gov (United States)

    Scullion, Kathleen; Boychuk, Jeffery A; Yamakawa, Glenn R; Rodych, Justin T G; Nakanishi, Stan T; Seto, Angela; Smith, Victoria M; McCarthy, Ryan W; Whelan, Patrick J; Antle, Michael C; Pittman, Quentin J; Teskey, G Campbell

    2013-03-13

    Serotonin has a myriad of central functions involving mood, appetite, sleep, and memory and while its release within the spinal cord is particularly important for generating movement, the corresponding role on cortical movement representations (motor maps) is unknown. Using adult rats we determined that pharmacological depletion of serotonin (5-HT) via intracerebroventricular administration of 5,7 dihydroxytryptamine resulted in altered movements of the forelimb in a skilled reaching task as well as higher movement thresholds and smaller maps derived using high-resolution intracortical microstimulation (ICMS). We ruled out the possibility that reduced spinal cord excitability could account for the serotonin depletion-induced changes as we observed an enhanced Hoffman reflex (H-reflex), indicating a hyperexcitable spinal cord. Motor maps derived in 5-HT1A receptor knock-out mice also showed higher movement thresholds and smaller maps compared with wild-type controls. Direct cortical application of the 5-HT1A/7 agonist 8-OH-DPAT lowered movement thresholds in vivo and increased map size in 5-HT-depleted rats. In rats, electrical stimulation of the dorsal raphe lowered movement thresholds and this effect could be blocked by direct cortical application of the 5-HT1A antagonist WAY-100135, indicating that serotonin is primarily acting through the 5-HT1A receptor. Next we developed a novel in vitro ICMS preparation that allowed us to track layer V pyramidal cell excitability. Bath application of WAY-100135 raised the ICMS current intensity to induce action potential firing whereas the agonist 8-OH-DPAT had the opposite effect. Together our results demonstrate that serotonin, acting through 5-HT1A receptors, plays an excitatory role in forelimb motor map expression.

  20. (/sup 3/H)dihydroergotamine as a high-affinity, slowly dissociating radioligand for 5-HT1B binding sites in rat brain membranes: evidence for guanine nucleotide regulation of agonist affinity states

    Energy Technology Data Exchange (ETDEWEB)

    Hamblin, M.W.; Ariani, K.; Adriaenssens, P.I.; Ciaranello, R.D.

    1987-12-01

    (/sup 3/H)Dihydroergotamine (DE) labels a population of binding sites in rat brain membranes with an affinity of approximately 70 pM in both hippocampus (maximal binding at saturation (Bmax) = 340 fmol/mg of protein) and cerebral cortex (Bmax = 250 fmol/mg of protein). Specific binding typically comprises about 97% of total binding at the Kd of the radioligand when nonspecific binding is determined in the presence of 100 nM unlabeled DE. Association kinetics at 37 degrees C are consistent with a uniform association rate constant for all sites labeled. Specific binding is completely reversible with addition of excess unlabeled DE, but dissociation does not proceed with simple first-order kinetics, suggesting the presence of more than one discrete binding site. Competition studies with selective drugs reveal alpha adrenergic, 5-HT1A and 5-HT1B components of (/sup 3/H)DE specific binding. When phentolamine (500 nM) is included to block alpha receptors and DPAT (100 nM) or spiroxatrine (500 nM) is included to block 5-HT1A receptors, specific binding is exclusively to sites with drug affinities characteristic of 5-HT1B receptors. Under these 5-HT1B-selective conditions, (/sup 3/H)DE binding is about 90% specific, with a Kd of about 50 to 60 pM and a Bmax of 96 fmol/mg of protein in hippocampus and 77 fmol/mg of protein in cortex. (/sup 3/H)DE binding to 5-HT1B sites is very slowly dissociable, with a T1/2 of greater than 2 h at 37 degrees C. 5-HT1B antagonists and DE itself yield competition curves at (/sup 3/H)DE-labeled 5-HT1B sites that are adequately fit assuming a single site in nonlinear regression analysis. Addition of 100 microM guanylyl 5'-imidodiphosphate appears to convert nearly all 5-HT1B sites to those having low affinity for agonists while having a much smaller effect on the binding of (/sup 3/H)DE.

  1. The effects of serotonin1A receptor on female mice body weight and food intake are associated with the differential expression of hypothalamic neuropeptides and the GABAA receptor.

    Science.gov (United States)

    Butt, Isma; Hong, Andrew; Di, Jing; Aracena, Sonia; Banerjee, Probal; Shen, Chang-Hui

    2014-10-01

    Both common eating disorders anorexia nervosa and bulimia nervosa are characteristically diseases of women. To characterize the role of the 5-HT1A receptor (5-HT1A-R) in these eating disorders in females, we investigated the effect of saline or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) treatment on feeding behavior and body weight in adult WT female mice and in adult 5-HT1A-R knockout (KO) female mice. Our results showed that KO female mice have lower food intake and body weight than WT female mice. Administration of 8-OH-DPAT decreased food intake but not body weight in WT female mice. Furthermore, qRT-PCR was employed to analyze the expression levels of neuropeptides, γ-aminobutyric acid A receptor subunit β (GABAA β subunits) and glutamic acid decarboxylase in the hypothalamic area. The results showed the difference in food intake between WT and KO mice was accompanied by differential expression of POMC, CART and GABAA β2, and the difference in body weight between WT and KO mice was associated with significantly different expression levels of CART and GABAA β2. As such, our data provide new insight into the role of 5-HT1A-R in both feeding behavior and the associated expression of neuropeptides and the GABAA receptor.

  2. Beta 2-adrenergic receptors on eosinophils. Binding and functional studies

    Energy Technology Data Exchange (ETDEWEB)

    Yukawa, T.; Ukena, D.; Kroegel, C.; Chanez, P.; Dent, G.; Chung, K.F.; Barnes, P.J. (National Heart and Lung Institute, Brompton Hospital, London (England))

    1990-06-01

    We have studied the binding characteristics and functional effects of beta-adrenoceptors on human and guinea pig eosinophils. We determined the binding of the beta-antagonist radioligand (125I)pindolol (IPIN) to intact eosinophils obtained from the peritoneal cavity of guinea pigs and from blood of patients with eosinophilia. Specific binding was saturable, and Scatchard analysis showed a single binding site with a dissociation constant (Kd) of 24.6 pM and maximal number of binding sites (Bmax) of 7,166 per cell. ICI 118,551, a beta 2-selective antagonist, inhibited IPIN binding with a Ki value of 0.28 nM and was approximately 5,000-fold more effective than the beta 1-selective antagonist, atenolol. Isoproterenol increased cAMP levels about 5.5-fold above basal levels (EC50 = 25 microM); albuterol, a beta 2-agonist, behaved as a partial agonist with a maximal stimulation of 80%. Binding to human eosinophils gave similar results with a Kd of 25.3 pM and a Bmax corresponding to 4,333 sites per cell. Incubation of both human and guinea pig eosinophils with opsonized zymosan (2 mg/ml) or with phorbol myristate acetate (PMA) (10(-8) and 10(-6) M) resulted in superoxide anion generation and the release of eosinophil peroxidase; albuterol (10(-7) to 10(-5) M) had no inhibitory effect on the release of these products. Thus, eosinophils from patients with eosinophilia and from the peritoneal cavity of guinea pigs possess beta-receptors of the beta 2-subtype that are coupled to adenylate cyclase; however, these receptors do not modulate oxidative metabolism or degranulation. The possible therapeutic consequences of these observations to asthma are discussed.

  3. Human biodistribution and dosimetry of ¹¹C-CUMI-101, an agonist radioligand for serotonin-1a receptors in brain.

    Directory of Open Access Journals (Sweden)

    Christina S Hines

    Full Text Available UNLABELLED: As a reported agonist, ¹¹C-CUMI-101 is believed to selectively bind the G-protein-coupled state of the serotonin-1A (5-HT(1A receptor, thereby providing a measure of the active subset of all 5-HT(1A receptors in brain. Although ¹¹C-CUMI-101 has been successfully used to quantify 5-HT(1A receptors in human and monkey brain, its radiation exposure has not previously been reported. The purpose of this study was to calculate the radiation exposure to organs of the body based on serial whole-body imaging with positron emission tomography (PET in human subjects. METHODS: Nine healthy volunteers were injected with 428±84 MBq (mean ± SD (11C-CUMI-101 and then imaged with a PET-only device for two hours from head to mid-thigh. Eleven source organs (brain, heart, liver, pancreas, stomach, spleen, lungs, kidneys, lumbar spine L1-5, thyroid, and urinary bladder were identified on whole body images and used to calculate radiation doses using the software program OLINDA/EXM 1.1. To confirm that we had correctly identified the pancreas, a tenth subject was imaged on a PET/CT device. RESULTS: Brain had high uptake (∼11% of injected activity (IA at 10 min. Although liver had the highest uptake (∼35% IA at 120 min, excretion of this activity was not visible in gall bladder or intestine during the scanning session. Organs which received the highest doses (microSv/MBq were pancreas (32.0, liver (18.4, and spleen (14.5. The effective dose of ¹¹C-CUMI-101 was 5.3±0.5 microSv/MBq. CONCLUSION: The peak brain uptake (∼11% IA of ¹¹C-CUMI-101 is the highest among more than twenty ¹¹C-labeled ligands reported in the literature and provides good counting statistics from relatively low injected activities. Similar to that of other ¹¹C-labeled ligands for brain imaging, the effective dose of ¹¹C-CUMI-101 is 5.3±0.5 microSv/MBq, a value that can now be used to estimate the radiation risks in future research studies.

  4. Membrane cholesterol oxidation in live cells enhances the function of serotonin1A receptors.

    Science.gov (United States)

    Jafurulla, Md; Nalli, Aswan; Chattopadhyay, Amitabha

    2017-03-01

    The serotonin1A (5-HT1A) receptor is an important neurotransmitter receptor that belongs to the G protein-coupled receptor (GPCR) family. It is implicated in a variety of cognitive and behavioral functions and serves as an important drug target for neuropsychiatric disorders such as anxiety and depression. Previous work from our laboratory has demonstrated that membrane cholesterol plays an important role in the function of the serotonin1A receptor. Our earlier results highlighted several structural features of cholesterol essential for receptor function. In order to explore the importance of the hydroxyl group of cholesterol in the function of the serotonin1A receptor, we utilized cholesterol oxidase to oxidize the hydroxyl group of cholesterol to keto group. Our results show that the oxidation of the hydroxyl group of cholesterol in live cells resulted in enhancement of agonist binding and G-protein coupling to the receptor with no appreciable change in overall membrane order. These results extend our understanding of the structural requirements of cholesterol for receptor function. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Binding Mode of Insulin Receptor and Agonist Peptide

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

  6. Mast cell expression of the serotonin1A receptor in guinea pig and human intestine.

    Science.gov (United States)

    Wang, Guo-Du; Wang, Xi-Yu; Zou, Fei; Qu, Meihua; Liu, Sumei; Fei, Guijun; Xia, Yun; Needleman, Bradley J; Mikami, Dean J; Wood, Jackie D

    2013-05-15

    Serotonin [5-hydroxytryptamine (5-HT)] is released from enterochromaffin cells in the mucosa of the small intestine. We tested a hypothesis that elevation of 5-HT in the environment of enteric mast cells might degranulate the mast cells and release mediators that become paracrine signals to the enteric nervous system, spinal afferents, and secretory glands. Western blotting, immunofluorescence, ELISA, and pharmacological analysis were used to study expression of 5-HT receptors by mast cells in the small intestine and action of 5-HT to degranulate the mast cells and release histamine in guinea pig small intestine and segments of human jejunum discarded during Roux-en-Y gastric bypass surgeries. Mast cells in human and guinea pig preparations expressed the 5-HT1A receptor. ELISA detected spontaneous release of histamine in guinea pig and human preparations. The selective 5-HT1A receptor agonist 8-hydroxy-PIPAT evoked release of histamine. A selective 5-HT1A receptor antagonist, WAY-100135, suppressed stimulation of histamine release by 5-HT or 8-hydroxy-PIPAT. Mast cell-stabilizing drugs, doxantrazole and cromolyn sodium, suppressed the release of histamine evoked by 5-HT or 8-hydroxy-PIPAT in guinea pig and human preparations. Our results support the hypothesis that serotonergic degranulation of enteric mast cells and release of preformed mediators, including histamine, are mediated by the 5-HT1A serotonergic receptor. Association of 5-HT with the pathophysiology of functional gastrointestinal disorders (e.g., irritable bowel syndrome) underlies a question of whether selective 5-HT1A receptor antagonists might have therapeutic application in disorders of this nature.

  7. The Receptor Binding Domain of Botulinum Neurotoxin Stereotype C Binds Phosphoinositides

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yanfeng; Varnum, Susan M.

    2012-03-01

    Botulinum neurotoxins (BoNTs) are the most toxic proteins known for humans and animals with an extremely low LD50 of {approx} 1 ng/kg. BoNTs generally require a protein and a ganglioside on the cell membrane surface for binding, which is known as a 'dual receptor' mechanism for host intoxication. Recent studies have suggested that in addition to gangliosides, other membrane lipids such as phosphoinositides may be involved in the interactions with the receptor binding domain (HCR) of BoNTs for better membrane penetration. Here, using two independent lipid-binding assays, we tested the interactions of BoNT/C-HCR with lipids in vitro. BoNT/C-HCR was found to bind negatively charged phospholipids, preferentially phosphoinositides. Additional interactions to phosphoinositides may help BoNT/C bind membrane more tightly and transduct signals for subsequent steps of intoxication. Our results provide new insights into the mechanisms of host cell membrane recognition by BoNTs.

  8. Development of Gamma-Emitting Receptor Binding Radiopharmace

    Energy Technology Data Exchange (ETDEWEB)

    Reba, Richard

    2003-02-20

    The long-term objective is to develop blood-brain barrier (BBB) permeable m2-selective (relative to m1, m3, and m4) receptor-binding radiotracers and utilize these radiotracers for quantifying receptor concentrations obtained from PET or SPECT images of human brain. In initial studies, we concluded that the lipophilicity and high affinity prevented (R,S)-I-QNB from reaching a flow-independent and receptor-dependent state in a reasonable time. Thus, it was clear that (R,S)-I-QNB should be modified. Therefore, during the last portion of this funded research, we proposed that more polar heterocycles should help accomplish that. Since reports of others concluded that radiobromination and radiofluorination of the unactivated phenyl ring is not feasible (Newkome et al,,1982), we, therefore, explored during this grant period a series of analogues of (R)-QNB in which one or both of the six-membered phenyl rings is replaced by a five-membered thienyl (Boulay et al., 1995), or furyl ring. The chemistry specific aims were to synthesize novel compounds designed to be m2-selective mAChR ligands capable of penetrating into the CNS, and develop methods for efficient radiolabeling of promising m2-selective muscarinic ligands. The pharmacology specific aims were to determine the affinity and subtype-selectivity of the novel compounds using competition binding studies with membranes from cells that express each of the five muscarinic receptor subtypes, to determine the ability of the promising non-radioactive compounds and radiolabeled novel compounds to cross the BBB, to determine the biodistribution, in-vivo pharmacokinetics, and in-vitm kinetics of promising m2-selective radioligands and to determine the distribution of receptors for the novel m2-selective radioligands using quantitative autoradiography of rat brain, and compare this distribution to the distribution of known m2-selective compounds.

  9. Receptor binding characteristics and cytotoxicity of insulin-methotrexate

    Institute of Scientific and Technical Information of China (English)

    Xiao-Hong Ou; An-Ren Kuang; Zheng-Lu Liang; Xian Peng; Yu-Guo Zhong

    2004-01-01

    AIM: To characterize the receptor binding affinity and cytotoxicity of insulin-methotrexate (MTX) for the potential utilization of insulin as carriers for carcinoma target drugs.METHODS: MTX was covalently linked to insulin. InsulinMTX conjugate was purified by Sephadex G-25 column and analyzed by high performance liquid chromatography.Hepatocellular carcinoma cell membrane fractions were isolated by sucrose density gradient centrifugation.Competitive displacement of 125I-insulin with insulin and insulin-MTX binding to insulin receptors were carried out.Cytoreductive effect of insulin-MTX on human hepatoma BEL7402 cells and human hepatocyte cell line HL7702 was evaluated using the MTT assay.RESULTS: Insulin-MTX competed as effectively as insulin with 125I-insulin for insulin receptors. The values of Kd for insulin-MTX and insulin were 93.82±19.32 nmol/L and 5.01±1.24 nmol/L, respectively. The value of Kd for insulinMTX was significantly increased in comparison with insulin (t=7.2532,n=4, P<0.005). Insulin-MTX inhibited the growth of human hepatoma cells (BEL7402) almost as potently as MTX. The inhibitory effect reached a peak on the 5 th day when the growth of cells was inhibited by 79% at a concentration of 5.0 μg/mL insulin-MTX. Treatment with 5.0 μg/mL of MTX and 5.0 μg/mL of insulin-MTX merely resulted in inhibition of HL7702 cells by 31.5% and 7.8%on the 5 th day.CONCLUSION: Insulin-MTX specifically recognizes insulin receptors and inhibits the growth of BEL7402 cells. These results suggest that insulin can be used as a carrier in receptor mediated carcinoma-targeting therapy.

  10. Interaction of chemokines with their receptors--from initial chemokine binding to receptor activating steps

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Rosenkilde, Mette Marie

    2014-01-01

    interactions possibly occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly......The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system's primary function in leukocyte migration, it has a central role in immune homeostasis...... and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity...

  11. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  12. Study on Synthesis and Binding Ability of a New Anion Receptor Containing NH Binding Sites

    Institute of Scientific and Technical Information of China (English)

    QIAO,Yan-Hong; LIN,Hai; LIN,Hua-Kuan

    2007-01-01

    A new colorimetric recognition receptor 1 based on the dual capability containing NH binding sites of selectively sensing anionic guest species has been synthesized. Compared with other halide anions, its UV/Vis absorption spectrum in dimethyl sulfoxide showed the response toward the presence of fluoride anion with high selectivity,and also displayed dramatic color changes from colorless to yellow in the presence of TBAF (5 × 10-5 mol/L). The similar UV/Vis absorption spectrum change also occurred when 1 was treated with AcO- while a little change with H2PO-4 and OH-. Receptor 1 has almost not affinity abilities to Cl-, Br- and I-. The binding ability of receptor 1to fluoride with high selectivity over other halides contributes to the anion size and the ability of forming hydrogen bonding. While the different ability of binding with geometrically triangular (AcO-), tetrahedral (H2PO-4 ) and linear (OH-) anions maybe result from their geometry configuration.

  13. Localization of CGRP receptor components and receptor binding sites in rhesus monkey brainstem

    DEFF Research Database (Denmark)

    Eftekhari, Sajedeh; Roberts, Rhonda; Chen, Tsing-Bau

    2016-01-01

    that several regions in the brainstem may be involved in CGRP signaling. Interestingly, we found receptor expression and antagonist binding in some areas that are not protected by the blood-brain barrier, which suggests that drugs inhibiting CGRP signaling may not be able to penetrate the central nervous...

  14. Structure of the homodimeric androgen receptor ligand-binding domain

    Science.gov (United States)

    Nadal, Marta; Prekovic, Stefan; Gallastegui, Nerea; Helsen, Christine; Abella, Montserrat; Zielinska, Karolina; Gay, Marina; Vilaseca, Marta; Taulès, Marta; Houtsmuller, Adriaan B.; van Royen, Martin E.; Claessens, Frank; Fuentes-Prior, Pablo; Estébanez-Perpiñá, Eva

    2017-01-01

    The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å2 large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo, and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor. PMID:28165461

  15. Treponema pallidum receptor binding proteins interact with fibronectin

    Energy Technology Data Exchange (ETDEWEB)

    Peterson, K.M.; Baseman, J.B.; Alderete, J.F.

    1983-06-01

    Analysis of plasma proteins avidly bound to T. pallidum surfaces revealed the ability of T. pallidum to acquire numerous host macromolecules. No acquisition was evident by the avirulent spirochete, T. phagedenis biotype Reiter. Western blotting technology using hyperimmune antifibronectin serum as a probe revealed the ability of virulent treponemes to avidly bind fibronectin from a complex medium such as plasma. The specificity of the tiplike adherence of motile T. pallidum to fibronectin-coated glass surfaces and to fibronectin on HEp-2 cells was reinforced by the observation that pretreatment of coverslips or cell monolayers with monospecific antiserum against fibronectin substantially reduced T. pallidum attachment. The stoichiometric binding of T. pallidum to fibronectin-coated coverslips and the inability of unlabeled or /sup 35/S-radiolabeled treponemes to interact with glass surfaces treated with other plasma proteins further established the specific nature of the interaction between virulent T. pallidum and fibronectin. The avid association between three outer envelope proteins of T. pallidum and fibronectin was also demonstrated. These treponemal surface proteins have been previously identified as putative receptor-binding proteins responsible for T. pallidum parasitism of host cells. The data suggest that surface fibronectin mediates tip-oriented attachment of T. pallidum to host cells via a receptor-ligand mechanism of recognition.

  16. Sialyloligosaccharide receptors of binding variants of polyoma virus.

    Science.gov (United States)

    Cahan, L D; Singh, R; Paulson, J C

    1983-10-30

    Hemagglutination and lytic infection of host cells by polyoma virus has been shown to require specific sialyloligosaccharide structures. The nature of the sialyloligosaccharide sequence recognized by three binding variants of polyoma virus, the large plaque (LP), small plaque (SP), and Py235 variants, was examined. Hemagglutination of native erythrocytes and erythrocytes derivatized with highly specific sialyltransferases to contain cell surface sialyloligosaccharides of defined sequence was compared for the three variants. In addition, soluble glycoprotein inhibitors of known sialyloligosaccharide structure were used to further elucidate the specificities of the three variants. There are important differences in the receptors for these variants. While all three appear to bind the structure NeuAc alpha 2,3Gal beta 1,3GalNAc the LP and Py235 variant bind the disialyl structure NeuAc alpha 2,3Gal beta 1,3(NeuAc alpha 2,6)GalNAc with much lower affinity than does the SP virus. It is suggested that polyoma virus adsorption to cells may depend on the cell surface content of at least three different sialyloligosaccharide sequences and the relative abilities of the virus variant to utilize them as receptor determinants.

  17. A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder.

    Directory of Open Access Journals (Sweden)

    Yosuke Nakatani

    Full Text Available Serotonin 1A (5-HT1A receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB. Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET imaging, and assessed the utility of a receptor occupancy (RO assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50 estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%. Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.

  18. The binding of pirenzepine to digitonin-solubilized muscarinic acetylcholine receptors from the rat myocardium.

    Science.gov (United States)

    Birdsall, N. J.; Hulme, E. C.; Keen, M.

    1986-01-01

    The binding of pirenzepine to digitonin-solubilized rat myocardial muscarinic acetylcholine receptors has been examined at 4 degrees C. Solubilization produced only small changes in the binding of N-methylscopolamine and atropine. In contrast to the low affinity binding of pirenzepine found to be present in in the membranes, high affinity binding was detected in the soluble preparation. In both preparations, pirenzepine binding was complex. High affinity pirenzepine binding (KD approximately 3 X 10(-8)M) to the soluble myocardial receptors could be monitored directly using [3H]-pirenzepine. [3H]-pirenzepine-labelled soluble myocardial receptors have a sedimentation coefficient of 11.1 s. This indicates that [3H]-pirenzepine binds predominantly to the uncoupled form of the receptor. However, [3H]-pirenzepine-agonist competition experiments indicated that the high affinity pirenzepine binding sites are capable of coupling with a guanosine 5'-triphosphate (GTP)-binding protein. Pirenzepine affinities for the soluble myocardial receptors were unaffected by their state of association with the GTP-binding proteins found in the heart. The equilibrium binding properties of the soluble cortical and myocardial receptors were very similar. However, the binding kinetics of the myocardial receptor were much slower. It appears that the membrane environment can affect the affinity of pirenzepine for the rat myocardial muscarinic receptor. Removal of the constraint by solubilization allows the expression of high affinity pirenzepine binding. PMID:3754173

  19. Menthol binding and inhibition of α7-nicotinic acetylcholine receptors.

    Science.gov (United States)

    Ashoor, Abrar; Nordman, Jacob C; Veltri, Daniel; Yang, Keun-Hang Susan; Al Kury, Lina; Shuba, Yaroslav; Mahgoub, Mohamed; Howarth, Frank C; Sadek, Bassem; Shehu, Amarda; Kabbani, Nadine; Oz, Murat

    2013-01-01

    Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+)-dependent Cl(-) channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free bathing solution containing Ba(2+). Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125)I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca(2+) transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.

  20. Menthol binding and inhibition of α7-nicotinic acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Abrar Ashoor

    Full Text Available Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+-dependent Cl(- channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+ chelator BAPTA and perfusion with Ca(2+-free bathing solution containing Ba(2+. Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca(2+ transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.

  1. Fluorescent Receptor Binding Assay for Detecting Ciguatoxins in Fish

    Science.gov (United States)

    Hardison, D. Ransom; Holland, William C.; McCall, Jennifer R.; Bourdelais, Andrea J.; Baden, Daniel G.; Darius, H. Taiana; Chinain, Mireille; Tester, Patricia A.; Shea, Damian; Flores Quintana, Harold A.; Morris, James A.; Litaker, R. Wayne

    2016-01-01

    Ciguatera fish poisoning is an illness suffered by > 50,000 people yearly after consumption of fish containing ciguatoxins (CTXs). One of the current methodologies to detect ciguatoxins in fish is a radiolabeled receptor binding assay (RBA(R)). However, the license requirements and regulations pertaining to radioisotope utilization can limit the applicability of the RBA(R) in certain labs. A fluorescence based receptor binding assay (RBA(F)) was developed to provide an alternative method of screening fish samples for CTXs in facilities not certified to use radioisotopes. The new assay is based on competition binding between CTXs and fluorescently labeled brevetoxin-2 (BODIPY®- PbTx-2) for voltage-gated sodium channel receptors at site 5 instead of a radiolabeled brevetoxin. Responses were linear in fish tissues spiked from 0.1 to 1.0 ppb with Pacific ciguatoxin-3C (P-CTX-3C) with a detection limit of 0.075 ppb. Carribean ciguatoxins were confirmed in Caribbean fish by LC-MS/MS analysis of the regional biomarker (C-CTX-1). Fish (N = 61) of six different species were screened using the RBA(F). Results for corresponding samples analyzed using the neuroblastoma cell-based assay (CBA-N2a) correlated well (R2 = 0.71) with those of the RBA(F), given the low levels of CTX present in positive fish. Data analyses also showed the resulting toxicity levels of P-CTX-3C equivalents determined by CBA-N2a were consistently lower than the RBA(F) affinities expressed as % binding equivalents, indicating that a given amount of toxin bound to the site 5 receptors translates into corresponding lower cytotoxicity. Consequently, the RBA(F), which takes approximately two hours to perform, provides a generous estimate relative to the widely used CBA-N2a which requires 2.5 days to complete. Other RBA(F) advantages include the long-term (> 5 years) stability of the BODIPY®- PbTx-2 and having similar results as the commonly used RBA(R). The RBA(F) is cost-effective, allows high sample

  2. Fluorescent Receptor Binding Assay for Detecting Ciguatoxins in Fish.

    Science.gov (United States)

    Hardison, D Ransom; Holland, William C; McCall, Jennifer R; Bourdelais, Andrea J; Baden, Daniel G; Darius, H Taiana; Chinain, Mireille; Tester, Patricia A; Shea, Damian; Quintana, Harold A Flores; Morris, James A; Litaker, R Wayne

    2016-01-01

    Ciguatera fish poisoning is an illness suffered by > 50,000 people yearly after consumption of fish containing ciguatoxins (CTXs). One of the current methodologies to detect ciguatoxins in fish is a radiolabeled receptor binding assay (RBA(R)). However, the license requirements and regulations pertaining to radioisotope utilization can limit the applicability of the RBA(R) in certain labs. A fluorescence based receptor binding assay (RBA(F)) was developed to provide an alternative method of screening fish samples for CTXs in facilities not certified to use radioisotopes. The new assay is based on competition binding between CTXs and fluorescently labeled brevetoxin-2 (BODIPY®-PbTx-2) for voltage-gated sodium channel receptors at site 5 instead of a radiolabeled brevetoxin. Responses were linear in fish tissues spiked from 0.1 to 1.0 ppb with Pacific ciguatoxin-3C (P-CTX-3C) with a detection limit of 0.075 ppb. Carribean ciguatoxins were confirmed in Caribbean fish by LC-MS/MS analysis of the regional biomarker (C-CTX-1). Fish (N = 61) of six different species were screened using the RBA(F). Results for corresponding samples analyzed using the neuroblastoma cell-based assay (CBA-N2a) correlated well (R2 = 0.71) with those of the RBA(F), given the low levels of CTX present in positive fish. Data analyses also showed the resulting toxicity levels of P-CTX-3C equivalents determined by CBA-N2a were consistently lower than the RBA(F) affinities expressed as % binding equivalents, indicating that a given amount of toxin bound to the site 5 receptors translates into corresponding lower cytotoxicity. Consequently, the RBA(F), which takes approximately two hours to perform, provides a generous estimate relative to the widely used CBA-N2a which requires 2.5 days to complete. Other RBA(F) advantages include the long-term (> 5 years) stability of the BODIPY®-PbTx-2 and having similar results as the commonly used RBA(R). The RBA(F) is cost-effective, allows high sample

  3. Muscarinic receptor binding and muscarinic receptor-mediated inhibition of adenylate cyclase in rat brain myelin

    Energy Technology Data Exchange (ETDEWEB)

    Larocca, J.N.; Ledeen, R.W.; Dvorkin, B.; Makman, M.H.

    1987-12-01

    High-affinity muscarinic cholinergic receptors were detected in myelin purified from rat brain stem with use of the radioligands /sup 3/H-N-methylscopolamine (/sup 3/H-NMS), /sup 3/H-quinuclidinyl benzilate (/sup 3/H-QNB), and /sup 3/H-pirenzepine. /sup 3/H-NMS binding was also present in myelin isolated from corpus callosum. In contrast, several other receptor types, including alpha 1- and alpha 2-adrenergic receptors, present in the starting brain stem, were not detected in myelin. Based on Bmax values from Scatchard analyses, /sup 3/H-pirenzepine, a putative M1 selective ligand, bound to about 25% of the sites in myelin labeled by /sup 3/H-NMS, a nonselective ligand that binds to both M1 and M2 receptor subtypes. Agonist affinity for /sup 3/H-NMS binding sites in myelin was markedly decreased by Gpp(NH)p, indicating that a major portion of these receptors may be linked to a second messenger system via a guanine-nucleotide regulatory protein. Purified myelin also contained adenylate cyclase activity; this activity was stimulated several fold by forskolin and to small but significant extents by prostaglandin E1 and the beta-adrenergic agonist isoproterenol. Myelin adenylate cyclase activity was inhibited by carbachol and other muscarinic agonists; this inhibition was blocked by the antagonist atropine. Levels in myelin of muscarinic receptors were 20-25% and those of forskolin-stimulated adenylate cyclase 10% of the values for total particulate fraction of whole brain stem. These levels in myelin are appreciably greater than would be predicted on the basis of contamination. Also, additional receptors and adenylate cyclase, added by mixing nonmyelin tissue with whole brain stem, were quantitatively removed during the purification procedure.

  4. THIP and isoguvacine are partial agonists of GABA-stimulated benzodiazepine receptor binding.

    Science.gov (United States)

    Karobath, M; Lippitsch, M

    1979-10-15

    The effects of THIP and isoguvacine on 3H-flunitrazepam binding to washed membranes prepared from the cerebral cortex of adult rats have been examined. THIP, which has only minimal stimulatory effects on benzodiazepine (BZ) receptor binding, has been found to inhibit the stimulation induced by small concentrations (2 microM) of exogenous GABA. While isoguvacine stimulates BZ receptor binding, although to a smaller extent than GABA, it also antagonizes the stimulation of BZ receptor binding induced by GABA. Thus THIP and isoguvacine exhibit the properties of a partial agonist of GABA-stimulated BZ receptor binding.

  5. Rescue of ligand binding of a mutant IGF-I receptor by complementation

    DEFF Research Database (Denmark)

    Chakravarty, Arjun Anders; Hinrichsen, Jane; Whittaker, Linda;

    2005-01-01

    The IGF-I receptor binds IGF-I with complex kinetics characterized by a curvilinear Scatchard plot, suggesting receptor heterogeneity and apparent negative cooperativity. To explore the molecular mechanisms underlying these properties, we have characterized the binding of a hybrid receptor formed...

  6. Hormone Binding to Recombinant Estrogen Receptors from Human, Alligator, Quail, Salamander, and Fathead Minnow

    Science.gov (United States)

    In this work, a 96-well plate estrogen receptor binding assay was developed to facilitate the direct comparison of chemical binding to full-length recombinant estrogen receptors across vertebrate classes. Receptors were generated in a baculovirus expression system. This approach ...

  7. Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif.

    Science.gov (United States)

    Jehle, Katja; Cato, Laura; Neeb, Antje; Muhle-Goll, Claudia; Jung, Nicole; Smith, Emmanuel W; Buzon, Victor; Carbó, Laia R; Estébanez-Perpiñá, Eva; Schmitz, Katja; Fruk, Ljiljana; Luy, Burkhard; Chen, Yu; Cox, Marc B; Bräse, Stefan; Brown, Myles; Cato, Andrew C B

    2014-03-28

    The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.

  8. Genetic, functional and molecular features of glucocorticoid receptor binding.

    Directory of Open Access Journals (Sweden)

    Francesca Luca

    Full Text Available Glucocorticoids (GCs are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR, which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI and 4 Tuscans (TSI lymphoblastoid cell lines (LCLs, we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.

  9. Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice

    DEFF Research Database (Denmark)

    Licht, Cecilie L; Kirkegaard, Lisbeth; Zueger, Maha;

    2010-01-01

    . The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen....... Among post hoc analyzed regions, there was a 14% decrease in 5-HT(4) receptor binding in the olfactory tubercles. The 5-HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus....... In comparison, GR(+/-) mice had increased 5-HT(4) receptor (11%) binding in the caudal caudate putamen and decreased 5-HTT binding in the frontal caudate putamen but no changes in dorsal and ventral hippocampus. Post hoc analysis showed increased 5-HT(4) receptor binding in the olfactory tubercles of GR...

  10. Estrogen receptor determination in endometrial carcinoma: ligand binding assay versus enzyme immunoassay

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J;

    1995-01-01

    We compared concentrations of cytosolic estrogen receptors (ERc) measured in 35 postmenopausal endometrial carcinomas by ligand binding method (LBA) (dextran-coated charcoal assay) and enzyme immunoassay (EIA). Correlations between ERc, nuclear estrogen receptors (ERn) determined by EIA...

  11. Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2C receptors in mice.

    Science.gov (United States)

    Gleason, S D; Shannon, H E

    1998-01-12

    1-(Meta-chloro)phenylpiperazine (m-CPP) is a 5-HT receptor agonist which has been purported to be relatively selective for the 5-HT2C receptor. In particular, the hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT2C receptors. m-CPP binds with high affinity to 5-HT1 as well as 5-HT2 receptors, thus effects of m-CPP on locomotor activity may be due to the physiologic summation of the actions of m-CPP at 5-HT1 as well as 5-HT2 receptors. The present study investigated the effects of m-CPP alone and in the presence of the 5-HT2 receptor antagonist 6-methyl-1-(-methyethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY53857), the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2pyridinyl)c yclohexanecarboxamide trihydrochloride (WAY 100,635), and the 5-HT(1B/1D) receptor antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-corbox ylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935) on locomotor activity. Administration of m-CPP alone (0.3-10 mg/kg) produced a dose-related decrease in locomotor activity. The 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) in combination with m-CPP produced a slight leftward shift of the dose-response curve of m-CPP. The 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg) in combination with m-CPP did not alter the m-CPP dose-response curve. The non-selective 5-HT2 receptor antagonist LY53857 (1.0 mg/kg) in combination with m-CPP unmasked a hyperlocomotion produced by m-CPP. Furthermore, the hyperlocomotion produced by m-CPP in the presence of LY53857 (1.0 mg/kg) was blocked by both the 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) and the 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg). The present results demonstrate that the hyperlocomotion seen with the combination of m-CPP and LY53857 is mediated by 5-HT1 receptors. Taken together the data indicate that m-CPP affects locomotor activity by the

  12. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A.

    Science.gov (United States)

    Kounnas, M Z; Morris, R E; Thompson, M R; FitzGerald, D J; Strickland, D K; Saelinger, C B

    1992-06-25

    The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2 MR/LRP) is a large cell-surface glycoprotein consisting of a 515-kDa and an 85-kDa polypeptide; this receptor is thought to be responsible for the binding and endocytosis of activated alpha 2-macroglobulin and apoE-enriched beta-very low density lipoprotein. A similar high molecular weight glycoprotein has been identified as a potential receptor for Pseudomonas exotoxin A (PE). We demonstrate that the alpha 2 MR/LRP and the PE-binding glycoprotein have a similar mobility upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis and are immunologically indistinguishable. Furthermore, affinity-purified alpha 2 MR/LRP binds specifically to PE but not to a mutant toxin defective in its ability to bind cells. The 39-kDa receptor-associated protein, which blocks binding of ligands to alpha 2 MR/LRP, also prevents binding and subsequent toxicity of PE for mouse fibroblasts. The concentration of receptor-associated protein that was required to reduce binding and toxicity to 50% was approximately 14 nM, a value virtually identical to the KD measured for the interaction of receptor-associated protein with the purified receptor. Overall, the studies strongly suggest that the alpha 2 MR/LRP is responsible for internalizing PE.

  13. Serotonin-1A receptors in the dorsal periaqueductal gray matter mediate the panicolytic-like effect of pindolol and paroxetine combination in the elevated T-maze.

    Science.gov (United States)

    Sela, Vânia Ramos; Biesdorf, Carla; Ramos, Diego Henrique; Zangrossi, Hélio; Graeff, Frederico Guilherme; Audi, Elisabeth Aparecida

    2011-05-01

    The β-adrenergic blocker and 5-HT(1A) receptor antagonist pindolol has been combined with selective serotonin reuptake inhibitors (SSRIs) in patients with depressive and anxiety disorders to shorten the onset of the clinical action and/or increase the proportion of responders. The results of a previous study have shown that pindolol potentiates the panicolytic effect of paroxetine in rats submitted to the elevated T-maze (ETM). Since reported evidence has implicated the 5-HT(1A) receptors of the dorsal periaqueductal gray matter (DPAG) in the panicolytic effect of antidepressants, rats treated with pindolol (5.0mg/kg, i.p.) and paroxetine (1.5mg/kg, i.p.) received a previous intra-DPAG injection of the selective 5-HT(1A) antagonist, WAY-100635 (0.4 μg) and were submitted to the ETM. Pretreatment with WAY-100635 reversed the increase in escape latency, a panicolytic effect, determined by the pindolol-paroxetine combination. These results implicate the 5-HT(1A) receptors of the DPAG in the panicolytic effect of the pindolol-paroxetine combination administered systemically. They also give further preclinical support for the use of this drug combination in the treatment of panic disorder.

  14. Pirenzepine Promotes the Dimerization of Muscarinic M1 Receptors through a Three-step Binding Process*

    Science.gov (United States)

    Ilien, Brigitte; Glasser, Nicole; Clamme, Jean-Pierre; Didier, Pascal; Piemont, Etienne; Chinnappan, Raja; Daval, Sandrine B.; Galzi, Jean-Luc; Mely, Yves

    2009-01-01

    Ligand binding to G protein-coupled receptors is a complex process that involves sequential receptor conformational changes, ligand translocation, and possibly ligand-induced receptor oligomerization. Binding events at muscarinic acetylcholine receptors are usually interpreted from radioligand binding studies in terms of two-step ligand-induced receptor isomerization. We report here, using a combination of fluorescence approaches, on the molecular mechanisms for Bodipy-pirenzepine binding to enhanced green fluorescent protein (EGFP)-fused muscarinic M1 receptors in living cells. Real time monitoring, under steady-state conditions, of the strong fluorescence energy transfer signal elicited by this interaction permitted a fine kinetic description of the binding process. Time-resolved fluorescence measurements allowed us to identify discrete EGFP lifetime species and to follow their redistribution upon ligand binding. Fluorescence correlation spectroscopy, with EGFP brightness analysis, showed that EGFP-fused muscarinic M1 receptors predominate as monomers in the absence of ligand and dimerize upon pirenzepine binding. Finally, all these experimental data could be quantitatively reconciled into a three-step mechanism, with four identified receptor conformational states. Fast ligand binding to a peripheral receptor site initiates a sequence of conformational changes that allows the ligand to access to inner regions of the protein and drives ligand-receptor complexes toward a high affinity dimeric state. PMID:19451648

  15. Pirenzepine promotes the dimerization of muscarinic M1 receptors through a three-step binding process.

    Science.gov (United States)

    Ilien, Brigitte; Glasser, Nicole; Clamme, Jean-Pierre; Didier, Pascal; Piemont, Etienne; Chinnappan, Raja; Daval, Sandrine B; Galzi, Jean-Luc; Mely, Yves

    2009-07-17

    Ligand binding to G protein-coupled receptors is a complex process that involves sequential receptor conformational changes, ligand translocation, and possibly ligand-induced receptor oligomerization. Binding events at muscarinic acetylcholine receptors are usually interpreted from radioligand binding studies in terms of two-step ligand-induced receptor isomerization. We report here, using a combination of fluorescence approaches, on the molecular mechanisms for Bodipy-pirenzepine binding to enhanced green fluorescent protein (EGFP)-fused muscarinic M1 receptors in living cells. Real time monitoring, under steady-state conditions, of the strong fluorescence energy transfer signal elicited by this interaction permitted a fine kinetic description of the binding process. Time-resolved fluorescence measurements allowed us to identify discrete EGFP lifetime species and to follow their redistribution upon ligand binding. Fluorescence correlation spectroscopy, with EGFP brightness analysis, showed that EGFP-fused muscarinic M1 receptors predominate as monomers in the absence of ligand and dimerize upon pirenzepine binding. Finally, all these experimental data could be quantitatively reconciled into a three-step mechanism, with four identified receptor conformational states. Fast ligand binding to a peripheral receptor site initiates a sequence of conformational changes that allows the ligand to access to inner regions of the protein and drives ligand-receptor complexes toward a high affinity dimeric state.

  16. Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization

    Science.gov (United States)

    Barmina, O. Y.; Walling, H. W.; Fiacco, G. J.; Freije, J. M.; Lopez-Otin, C.; Jeffrey, J. J.; Partridge, N. C.

    1999-01-01

    We have previously identified a specific receptor for collagenase-3 that mediates the binding, internalization, and degradation of this ligand in UMR 106-01 rat osteoblastic osteosarcoma cells. In the present study, we show that collagenase-3 binding is calcium-dependent and occurs in a variety of cell types, including osteoblastic and fibroblastic cells. We also present evidence supporting a two-step mechanism of collagenase-3 binding and internalization involving both a specific collagenase-3 receptor and the low density lipoprotein receptor-related protein. Ligand blot analysis shows that (125)I-collagenase-3 binds specifically to two proteins ( approximately 170 kDa and approximately 600 kDa) present in UMR 106-01 cells. Western blotting identified the 600-kDa protein as the low density lipoprotein receptor-related protein. Our data suggest that the 170-kDa protein is a specific collagenase-3 receptor. Low density lipoprotein receptor-related protein-null mouse embryo fibroblasts bind but fail to internalize collagenase-3, whereas UMR 106-01 and wild-type mouse embryo fibroblasts bind and internalize collagenase-3. Internalization, but not binding, is inhibited by the 39-kDa receptor-associated protein. We conclude that the internalization of collagenase-3 requires the participation of the low density lipoprotein receptor-related protein and propose a model in which the cell surface interaction of this ligand requires a sequential contribution from two receptors, with the collagenase-3 receptor acting as a high affinity primary binding site and the low density lipoprotein receptor-related protein mediating internalization.

  17. Reevaluation of ANS binding to human and bovine serum albumins: key role of equilibrium microdialysis in ligand - receptor binding characterization.

    Directory of Open Access Journals (Sweden)

    Irina M Kuznetsova

    Full Text Available In this work we return to the problem of the determination of ligand-receptor binding stoichiometry and binding constants. In many cases the ligand is a fluorescent dye which has low fluorescence quantum yield in free state but forms highly fluorescent complex with target receptor. That is why many researchers use dye fluorescence for determination of its binding parameters with receptor, but they leave out of account that fluorescence intensity is proportional to the part of the light absorbed by the solution rather than to the concentration of bound dye. We showed how ligand-receptor binding parameters can be determined by spectrophotometry of the solutions prepared by equilibrium microdialysis. We determined the binding parameters of ANS - human serum albumin (HSA and ANS - bovine serum albumin (BSA interaction, absorption spectra, concentration and molar extinction coefficient, as well as fluorescence quantum yield of the bound dye. It was found that HSA and BSA have two binding modes with significantly different affinity to ANS. Correct determination of the binding parameters of ligand-receptor interaction is important for fundamental investigations and practical aspects of molecule medicine and pharmaceutics. The data obtained for albumins are important in connection with their role as drugs transporters.

  18. Prenatal exposure to methylmercury alters development of adrenergic receptor binding sites in peripheral sympathetic target tissues

    Energy Technology Data Exchange (ETDEWEB)

    Slotkin, T.A.; Orband, L.; Cowdery, T.; Kavlock, R.J.; Bartolome, J.

    1987-01-01

    In order to assess the impact of prenatal exposure to methylmercury on sympathetic neurotransmission, effects on development of adrenergic receptor binding sites in peripheral tissues was evaluated. In the liver, methylmercury produced a dose-dependent increase in alpha/sub 1/, alpha/sub 2/, and beta-receptor binding of radioliganda throughout the first 5 weeks of postnatal life. Similarly, renal alpha-receptor subtypes showed increased binding capabilities, but binding to alpha-receptor sites was reduced. At least some of the changes in receptors appear to be of functional significance, as physiological reactivity to adrenergic stimulation is altered in the same directions in these two tissues. The actions of methylmercury displayed tissue specificity in that the same receptor populations were largely unaffected in other tissues (lung, heart). These results suggest that methylmercury exposure in utero alters adrenergic responses through targeted effects on postsynaptic receptor populations in specific tissues.

  19. Cycloxaprid insecticide: nicotinic acetylcholine receptor binding site and metabolism.

    Science.gov (United States)

    Shao, Xusheng; Swenson, Tami L; Casida, John E

    2013-08-21

    Cycloxaprid (CYC) is a novel neonicotinoid prepared from the (nitromethylene)imidazole (NMI) analogue of imidacloprid. In this study we consider whether CYC is active per se or only as a proinsecticide for NMI. The IC50 values (nM) for displacing [(3)H]NMI binding are 43-49 for CYC and 2.3-3.2 for NMI in house fly and honeybee head membranes and 302 and 7.2, respectively, in mouse brain membranes, potency relationships interpreted as partial conversion of some CYC to NMI under the assay conditions. The 6-8-fold difference in toxicity of injected CYC and NMI to house flies is consistent with their relative potencies as in vivo nicotinic acetylcholine receptor (nAChR) inhibitors in brain measured with [(3)H]NMI binding assays. CYC metabolism in mice largely involves cytochrome P450 pathways without NMI as a major intermediate. Metabolites of CYC tentatively assigned are five monohydroxy derivatives and one each of dihydroxy, nitroso, and amino modifications. CYC appears be a proinsecticide, serving as a slow-release reservoir for NMI with selective activity for insect versus mammalian nAChRs.

  20. Binding of antibodies to acetylcholine receptors in Electrophorus and Torpedo electroplax membranes

    Science.gov (United States)

    1978-01-01

    Antisera against purified acetylcholine receptors from the electric tissues of Torpedo californica and of Electrophorus electricus were raised in rabbits. The antisera contain antibodies which bind to both autologous and heterologous receptors in solution as shown by an immunoprecipitation assay. Antibodies in both types of antisera bind specifically to the postjunctional membrane on the innervated surface of the intact electroplax from Electrophorus electric tissue as demonstrated by an indirect immunohistochemical procedure using horseradish peroxidase conjugated to anti-rabbit IgG. Only anti- Electrophorus receptor antisera, however, cause inhibition of the receptor-mediated depolarization of the intact Electrophorus electroplax. The lack of inhibition by anti-Torpedo receptor antibodies, which do bind, suggests that the receptor does not undergo extensive movement during activity. The binding of anti-Torpedo antibodies to receptor-rich vesicles prepared by subcellular fractionation of Torpedo electric tissue was demonstrated by both direct and indirect immunohistochemical methods using ferritin conjugates. These vesicles can be conveniently collected and prepared for electron microscopy on Millipore filters, a procedure requiring only 25 micrograms of membrane protein per filter. In addition, it was possible to visualize the binding of anti-Torpedo receptor antibodies directly, without ferritin. These anti-Torpedo receptor antibodies, however, do not inhibit the binding of acetylcholine or of alpha- neurotoxin to receptor in Torpedo microsacs but do inhibit binding of alpha-neurotoxin to Torpedo receptor in Triton X-100 solution. It is likely that the principal antigenic determinants on receptor are at sites other than the acetylcholine-binding sites and that inhibition of receptor function, when it occurs, may be due to a stabilization by antibody binding of an inactive conformational state. PMID:344325

  1. Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Gerlach, Lars-Ole; Jakobsen, Janus S

    2004-01-01

    AMD3100 is a symmetric bicyclam, prototype non-peptide antagonist of the CXCR4 chemokine receptor. Mutational substitutions at 16 positions located in TM-III, -IV, -V, -VI, and -VII lining the main ligand-binding pocket of the CXCR4 receptor identified three acid residues: Asp(171) (AspIV:20), Asp......, respectively. Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp(262) and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog. The proposed binding site for AMD3100 was confirmed by a gradual build...... that AMD3100 binds through interactions with essentially only three acidic anchor-point residues, two of which are located at one end and the third at the opposite end of the main ligand-binding pocket of the CXCR4 receptor. We suggest that non-peptide antagonists with, for example, improved oral...

  2. The association between romantic relationship status and 5-HT1A gene in young adults

    OpenAIRE

    Jinting Liu; Pingyuan Gong; Xiaolin Zhou

    2014-01-01

    What factors determine whether or not a young adult will fall in love? Sociological surveys and psychological studies have shown that non-genetic factors, such as socioeconomic status, external appearance, and personality attributes, are crucial components in romantic relationship formation. Here we demonstrate that genetic variants also contribute to romantic relationship formation. As love-related behaviors are associated with serotonin levels in the brain, this study investigated to what e...

  3. Modulation of glutamate transport and receptor binding by glutamate receptor antagonists in EAE rat brain.

    Science.gov (United States)

    Sulkowski, Grzegorz; Dąbrowska-Bouta, Beata; Salińska, Elżbieta; Strużyńska, Lidia

    2014-01-01

    The etiology of multiple sclerosis (MS) is currently unknown. However, one potential mechanism involved in the disease may be excitotoxicity. The elevation of glutamate in cerebrospinal fluid, as well as changes in the expression of glutamate receptors (iGluRs and mGluRs) and excitatory amino acid transporters (EAATs), have been observed in the brains of MS patients and animals subjected to experimental autoimmune encephalomyelitis (EAE), which is the predominant animal model used to investigate the pathophysiology of MS. In the present paper, the effects of glutamatergic receptor antagonists, including amantadine, memantine, LY 367583, and MPEP, on glutamate transport, the expression of mRNA of glutamate transporters (EAATs), the kinetic parameters of ligand binding to N-methyl-D-aspartate (NMDA) receptors, and the morphology of nerve endings in EAE rat brains were investigated. The extracellular level of glutamate in the brain is primarily regulated by astrocytic glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Excess glutamate is taken up from the synaptic space and metabolized by astrocytes. Thus, the extracellular level of glutamate decreases, which protects neurons from excitotoxicity. Our investigations showed changes in the expression of EAAT mRNA, glutamate transport (uptake and release) by synaptosomal and glial plasmalemmal vesicle fractions, and ligand binding to NMDA receptors; these effects were partially reversed after the treatment of EAE rats with the NMDA antagonists amantadine and memantine. The antagonists of group I metabotropic glutamate receptors (mGluRs), including LY 367385 and MPEP, did not exert any effect on the examined parameters. These results suggest that disturbances in these mechanisms may play a role in the processes associated with glutamate excitotoxicity and the progressive brain damage in EAE.

  4. Accelerated Molecular Dynamics Simulations of Ligand Binding to a Muscarinic G-protein Coupled Receptor

    Science.gov (United States)

    Kappel, Kalli; Miao, Yinglong; McCammon, J. Andrew

    2017-01-01

    Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc), and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein-ligand binding, especially the drug recognition of GPCRs. PMID:26537408

  5. Genetic Polymorphism of 1019C/G (rs6295) Promoter of Serotonin 1A Receptor and Catechol-O-Methyltransferase in Panic Disorder

    Science.gov (United States)

    Ishiguro, Shin; Aoki, Akiko; Ueda, Mikito; Hayashi, Yuki; Akiyama, Kazufumi; Kato, Kazuko; Shimoda, Kazutaka

    2017-01-01

    Objective Family and twin studies have suggested genetic liability for panic disorder (PD) and therefore we sought to determine the role of noradrenergic and serotonergic candidate genes for susceptibility for PD in a Japanese population. Methods In this age- and gender-matched case-control study involving 119 PD patients and 119 healthy controls, we examined the genotype distributions and allele frequencies of the serotonin transporter gene linked polymorphic region (5-HTTLPR), −1019C/G (rs6295) promoter polymorphism of the serotonin receptor 1A (5-HT1A), and catechol-O-methyltransferase (COMT) gene polymorphism (rs4680) and their association with PD. Results No significant differences were evident in the allele frequencies or genotype distributions of the COMT (rs4680), 5-HTTLPR polymorphisms or the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients and controls. Although there were no significant associations of these polymorphisms with in subgroups of PD patients differentiated by gender or in subgroup comorbid with agoraphobia (AP), significant difference was observed in genotype distributions of the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients without AP and controls (p=0.047). Conclusion In this association study, the 1019C/G (rs6295) promoter polymorphism of the 5-HT1A receptor G/G genotype was associated with PD without AP in a Japanese population. PMID:28096880

  6. Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT₁A receptors and stressful experiences.

    Science.gov (United States)

    Marinho, A L Z; Vila-Verde, C; Fogaça, M V; Guimarães, F S

    2015-06-01

    The infralimbic (IL) and prelimbic (PL) regions of the prefrontal cortex are involved in behavioral responses observed during defensive reactions. Intra-PL or IL injections of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, result in opposite behavioral effects in the contextual fear conditioning (CFC) paradigm. The intra-PL effects of CBD are mediated by 5HT1A receptors and depend on previous stressful experiences but the mechanisms and effects of intra-IL CBD injected are unknown. To this aim the present work verified the effects of intra-IL administration of CBD on two animal models of anxiety, the elevated plus maze (EPM) and CFC. We also investigated if these effects were mediated by 5HT1A receptors and depended on previous stressful experience. Male Wistar rats received bilateral microinjections of vehicle, WAY100635 (5HT1A receptor antagonist, 0.37 nmol) and/or CBD (15, 30 or 60 nmol) before being submitted to the behavioral tests. Intra-IL CBD induced anxiolytic and anxiogenic in the EPM and CFC, respectively. To verify if these effects are influenced by the previous stressful experience (footshocks) in the CFC model, we tested the animals in the EPM 24h after a 2-h restraint period. The anxiolytic-like effect of CBD in the EPM disappeared when the animals were previously stressed. Both responses, i.e., anxiolytic and anxiogenic, were prevented by WAY100635, indicating that they involve local 5HT1A-mediated neurotransmission. Together these results indicate that CBD effects in the IL depend on the nature of the animal model, being influenced by previous stressful experiences and mediated by facilitation of 5HT1A receptors-mediated neurotransmission.

  7. Ancestral reconstruction of the ligand-binding pocket of Family C G protein-coupled receptors

    OpenAIRE

    Kuang, Donghui; Yao, Yi; MacLean, David; Wang, Minghua; Hampson, David R.; Chang, Belinda S. W.

    2006-01-01

    The metabotropic glutamate receptors (mGluRs) within the Family C subclass of G protein-coupled receptors are crucial modulators of synaptic transmission. However, their closest relatives include a diverse group of sensory receptors whose biological functions are not associated with neurotransmission, raising the question of the evolutionary origin of amino acid-binding Family C receptors. A common feature of most, if not all, functional Family C receptors is the presence of an amino acid-bin...

  8. Mutation in apolipoprotein B associated with hypobetalipoproteinemia despite decreased binding to the low density lipoprotein receptor

    DEFF Research Database (Denmark)

    Benn, Marianne; Nordestgaard, Børge G; Jensen, Jan Skov;

    2005-01-01

    Mutations in apolipoprotein B (APOB) may reduce binding of low density lipoprotein (LDL) to the LDL receptor and cause hypercholesterolemia. We showed that heterozygotes for a new mutation in APOB have hypobetalipoproteinemia, despite a reduced binding of LDL to the LDL receptor. APOB R3480P hete...

  9. Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

    Directory of Open Access Journals (Sweden)

    Aaron S Coyner

    Full Text Available To assess the neuroprotective effects of flibanserin (formerly BIMT-17, a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal

  10. Blockade of glucocorticoid receptors with ORG 34116 does not normalize stress-induced symptoms in male tree shrews.

    Science.gov (United States)

    Van Kampen, Marja; De Kloet, E Ronald; Flügge, Gabriele; Fuchs, Eberhard

    2002-12-20

    Glucocorticoid receptors play an important role in the regulation of the activity of the hypothalamo-pituitary-adrenal axis, and are thought to be involved in the pathophysiology of depressive disorders. The present study investigated the effect of the specific glucocorticoid receptor antagonist ORG 34116 (a substituted 11,21 bisarylsteroid compound) in the tree shrew (Tupaia belangeri) chronic psychosocial stress model, an established animal model for depressive disorders. Animals were stressed for 10 days before treatment with ORG 34116 started (25 mg/kg p.o. for 28 days). Stress induced a decrease in body weight, which just failed significance, whereas ORG 34116 did not affect body weight in stress and control animals. ORG 34116 enhanced the stress-induced increase in the concentration of urinary-free cortisol, although no differences between the different experimental groups existed during the last week of treatment. In stressed animals, ORG 34116 did not affect marking behavior, but decreased locomotor activity. Post mortem analysis of 5-HT(1A) receptors revealed a decreased affinity of 3[H]-8-OH-DPAT (3[H]-8-hydroxy-2-[di-n-propylamino]tetralin) binding sites in the hippocampus of animals treated with the glucocorticoid receptor antagonist. In conclusion, under our experimental conditions, the glucocorticoid receptor antagonist ORG 34116 did not normalize the depressive-like symptoms in the psychosocial stress model of male tree shrews. This finding, however, does not exclude that specific central, neuroendocrine and behavioral features are affected by the compound.

  11. A pharmacological analysis of serotonergic receptors: effects of their activation of blockade in learning.

    Science.gov (United States)

    Meneses, A; Hong, E

    1997-02-01

    1. The authors have tested several 5-HT selective agonists and antagonists (5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3 or 5-HT4), an uptake inhibitor and 5-HT depletors in the autoshaping learning task. 2. The present work deals with the receptors whose stimulation increases or decreases learning. 3. Impaired consolidation of learning was observed after the presynaptic activation of 5-HT1B, 5-HT3 or 5-HT4 or the blockade of postsynaptic 5-HT2C/2B receptors. 4. In contrast, an improvement occurred after the presynaptic activation of 5-HT1A, 5-HT2C, and the blockade of presynaptic 5-HT2A, 5-HT2C and 5-HT3 receptors. 5. The blockade of postsynaptic 5-HT1A, 5-HT1B, 5-HT3 or 5-HT4 receptors and 5-HT inhibition of synthesis and its depletion did no alter learning by themselves. 6. The present data suggest that multiple pre- and postsynaptic serotonergic receptors are involved in the consolidation of learning. 7. Stimulation of most 5-HT receptors increases learning, however, some of 5-HT subtypes seem to limit the data storage. 8. Furthermore, the role of 5-HT receptors in learning seem to require an interaction with glutamatergic, GABAergic and cholinergic neurotransmission systems.

  12. Differential effects of exercise on brain opioid receptor binding and activation in rats.

    Science.gov (United States)

    Arida, Ricardo Mario; Gomes da Silva, Sérgio; de Almeida, Alexandre Aparecido; Cavalheiro, Esper Abrão; Zavala-Tecuapetla, Cecilia; Brand, Serge; Rocha, Luisa

    2015-01-01

    Physical exercise stimulates the release of endogenous opioid peptides supposed to be responsible for changes in mood, anxiety, and performance. Exercise alters sensitivity to these effects that modify the efficacy at the opioid receptor. Although there is evidence that relates exercise to neuropeptide expression in the brain, the effects of exercise on opioid receptor binding and signal transduction mechanisms downstream of these receptors have not been explored. Here, we characterized the binding and G protein activation of mu opioid receptor, kappa opioid receptor or delta opioid receptor in several brain regions following acute (7 days) and chronic (30 days) exercise. As regards short- (acute) or long-term effects (chronic) of exercise, overall, higher opioid receptor binding was observed in acute-exercise animals and the opposite was found in the chronic-exercise animals. The binding of [(35) S]GTPγS under basal conditions (absence of agonists) was elevated in sensorimotor cortex and hippocampus, an effect more evident after chronic exercise. Divergence of findings was observed for mu opioid receptor, kappa opioid receptor, and delta opioid receptor receptor activation in our study. Our results support existing evidence of opioid receptor binding and G protein activation occurring differentially in brain regions in response to diverse exercise stimuli. We characterized the binding and G protein activation of mu, kappa, and delta opioid receptors in several brain regions following acute (7 days) and chronic (30 days) exercise. Higher opioid receptor binding was observed in the acute exercise animal group and opposite findings in the chronic exercise group. Higher G protein activation under basal conditions was noted in rats submitted to chronic exercise, as visible in the depicted pseudo-color autoradiograms.

  13. Synthesis and evaluation of 1-[2-(4-[(11)C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT7 receptor in the rat brain.

    Science.gov (United States)

    Shimoda, Yoko; Yui, Joji; Xie, Lin; Fujinaga, Masayuki; Yamasaki, Tomoteru; Ogawa, Masanao; Nengaki, Nobuki; Kumata, Katsushi; Hatori, Akiko; Kawamura, Kazunori; Zhang, Ming-Rong

    2013-09-01

    1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki=2.6nM) with a low binding affinity for the 5-HT1A receptor (Ki=476nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [(11)C]4 was synthesized at high radiochemical yield and specific activity, by O-[(11)C]methylation of 2'-(piperazin-1-yl)-[1,1'-biphenyl]-4-ol (6) with [(11)C]methyl iodide. Autoradiography revealed that [(11)C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [(11)C]4 in the brain exceeded 90% of the radioactive components at 15min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [(11)C]4 in the brain (1.2SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [(11)C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4.

  14. Reassessment of the unique mode of binding between angiotensin II type 1 receptor and their blockers.

    Directory of Open Access Journals (Sweden)

    Shin-Ichiro Miura

    Full Text Available While the molecular structures of angiotensin II (Ang II type 1 (AT1 receptor blockers (ARBs are very similar, they are also slightly different. Although each ARB has been shown to exhibit a unique mode of binding to AT1 receptor, different positions of the AT1 receptor have been analyzed and computational modeling has been performed using different crystal structures for the receptor as a template and different kinds of software. Therefore, we systematically analyzed the critical positions of the AT1 receptor, Tyr(113, Tyr(184, Lys(199, His(256 and Gln(257 using a mutagenesis study, and subsequently performed computational modeling of the binding of ARBs to AT1 receptor using CXCR4 receptor as a new template and a single version of software. The interactions between Tyr(113 in the AT1 receptor and the hydroxyl group of olmesartan, between Lys(199 and carboxyl or tetrazole groups, and between His(256 or Gln(257 and the tetrazole group were studied. The common structure, a tetrazole group, of most ARBs similarly bind to Lys(199, His(256 and Gln(257 of AT1 receptor. Lys(199 in the AT1 receptor binds to the carboxyl group of EXP3174, candesartan and azilsartan, whereas oxygen in the amidecarbonyl group of valsartan may bind to Lys(199. The benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr(113. On the other hand, the n-butyl group of irbesartan may bind to Tyr(113. In conclusion, we confirmed that the slightly different structures of ARBs may be critical for binding to AT1 receptor and for the formation of unique modes of binding.

  15. Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage.

    Science.gov (United States)

    Willis, Monte S; Klassen, Lynell W; Carlson, Deborah L; Brouse, Chad F; Thiele, Geoffrey M

    2004-07-01

    There is evidence that the chemical modification of proteins (haptens) with malondialdehyde-acetaldehyde (MAA) and the immune response to these haptenated proteins is associated with the initiation and/or progression of alcohol liver disease. Experimentally, proteins modified with MAA induce antibody and T cell responses, which are mediated by scavenger receptor(s). Moreover, macrophages have been shown to play an important role in processing and presenting MAA-haptenated proteins in vitro. In vitro, MAA-modified proteins have been shown to induce both apoptosis and necrosis in a dose- and cell-type-dependent manner. Natural ligands modified by oxidative stress, such as oxidized LDL, similarly initiate not only antibody responses, but also cause cell death by disrupting lysosomes after binding to scavenger receptors and internalization. We therefore investigated the binding, internalization, and lysosomal integrity in a macrophage cell line to a MAA-haptenated protein. We demonstrate for the first time that MAA-haptenated proteins are preferentially bound by scavenger receptors on macrophages, which internalize the ligands and shuttle them to lysosomes. Moreover, MAA-haptenated proteins are demonstrated to be associated with a rapid dose-dependent disruption in lysosomal integrity, resulting in leakage and caspase activation. Similarly, as hen egg lysozyme (HEL)-MAA concentrations increased (>31.3 microg/ml), increased levels of apoptosis and a G1/S cell cycle checkpoint inhibition were identified. This study identifies mechanisms by which MAA-haptenated proteins are taken up by a representative antigen-presenting cell and may delineate steps by which MAA-haptenated proteins induce cell death and induce their immunogenicity to the carrier protein. Copyright 2004 Elsevier B.V.

  16. Role of 5-HT6 receptors in memory formation.

    Science.gov (United States)

    Meneses, A

    2001-09-01

    Mice lacking the 5-HT(6) receptor presented neither gross anatomical or behavioral abnormalities nor obvious changes in microscopic brain morphology, and their performance in rotarod, open field and novel object testing paradigms revealed no differences compared with wild-type animals. Nevertheless, an association between the 5-HT(6) receptor polymorphism C267T and Alzheimer's disease has been reported. Interestingly, the 5-HT(6) antisense oligonucleotide decreased 5-HT(6) gene expression and enhanced spatial learning acquisition in the water maze. Similarly, injection of the 5-HT(6) receptor antagonist Ro-04-6790 improved learning consolidation in an autoshaping task, while mCPP, scopolamine and dizocilpine decreased performance. The effect induced by scopolamine or dizocilpine, but not that induced by mCPP, was completely or partially reversed by Ro-04-6790. Ro-04-6790 did not modify the 8-OH-DPAT facilitatory effects on learning consolidation. Since Ro-04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A/2B/2C), 5-HT(3), 5-HT(4) or 5-HT(7) receptor blockade, the facilitatory effect induced by Ro-04-6790 involved specifically 5-HT6 receptors. Similarly, the 5-HT(6) receptor antagonist SB-271046 improved retention in the water maze and produced a significant performance improvement in aged rats in an operant-delayed alternation task. A series of Ro-04-6790 analogues that penetrate the brain and specifically bind to 5-HT(6) receptors reversed scopolamine-induced retention deficit in a passive avoidance learning test. Collectively, these data provide further support to the notion that 5-HT systems, via 5-HT(6) receptors, also play a significant role in memory formation under normal and dysfunctional memory conditions.

  17. Differential ligand binding affinities of human estrogen receptor-α isoforms

    OpenAIRE

    Amanda H.Y. Lin; Li, Rachel W. S.; Ho, Eva Y. W.; George P H Leung; Susan W S Leung; Paul M Vanhoutte; Man, Ricky Y K

    2013-01-01

    Rapid non-genomic effects of 17β-estradiol are elicited by the activation of different estrogen receptor-α isoforms. Presence of surface binding sites for estrogen have been identified in cells transfected with full-length estrogen receptor-α66 (ER66) and the truncated isoforms, estrogen receptor-α46 (ER46) and estrogen receptor-α36 (ER36). However, the binding affinities of the membrane estrogen receptors (mERs) remain unknown due to the difficulty of developing of stable mER-transfected cel...

  18. Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses.

    Science.gov (United States)

    Shi, Yi; Zhang, Wei; Wang, Fei; Qi, Jianxun; Wu, Ying; Song, Hao; Gao, Feng; Bi, Yuhai; Zhang, Yanfang; Fan, Zheng; Qin, Chengfeng; Sun, Honglei; Liu, Jinhua; Haywood, Joel; Liu, Wenjun; Gong, Weimin; Wang, Dayan; Shu, Yuelong; Wang, Yu; Yan, Jinghua; Gao, George F

    2013-10-11

    An avian-origin human-infecting influenza (H7N9) virus was recently identified in China. We have evaluated the viral hemagglutinin (HA) receptor-binding properties of two human H7N9 isolates, A/Shanghai/1/2013 (SH-H7N9) (containing the avian-signature residue Gln(226)) and A/Anhui/1/2013 (AH-H7N9) (containing the mammalian-signature residue Leu(226)). We found that SH-H7N9 HA preferentially binds the avian receptor analog, whereas AH-H7N9 HA binds both avian and human receptor analogs. Furthermore, an AH-H7N9 mutant HA (Leu(226) → Gln) was found to exhibit dual receptor-binding property, indicating that other amino acid substitutions contribute to the receptor-binding switch. The structures of SH-H7N9 HA, AH-H7N9 HA, and its mutant in complex with either avian or human receptor analogs show how AH-H7N9 can bind human receptors while still retaining the avian receptor-binding property.

  19. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

    Science.gov (United States)

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-05-03

    Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

  20. Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors

    Science.gov (United States)

    Jakubík, Jan; Randáková, Alena; Zimčík, Pavel; El-Fakahany, Esam E.; Doležal, Vladimír

    2017-01-01

    Interaction of orthosteric ligands with extracellular domain was described at several aminergic G protein-coupled receptors, including muscarinic acetylcholine receptors. The orthosteric antagonists quinuclidinyl benzilate (QNB) and N-methylscopolamine (NMS) bind to the binding pocket of the muscarinic acetylcholine receptor formed by transmembrane α-helices. We show that high concentrations of either QNB or NMS slow down dissociation of their radiolabeled species from all five subtypes of muscarinic acetylcholine receptors, suggesting allosteric binding. The affinity of NMS at the allosteric site is in the micromolar range for all receptor subtypes. Using molecular modelling of the M2 receptor we found that E172 and E175 in the second extracellular loop and N419 in the third extracellular loop are involved in allosteric binding of NMS. Mutation of these amino acids to alanine decreased affinity of NMS for the allosteric binding site confirming results of molecular modelling. The allosteric binding site of NMS overlaps with the binding site of some allosteric, ectopic and bitopic ligands. Understanding of interactions of NMS at the allosteric binding site is essential for correct analysis of binding and action of these ligands.

  1. Effects of the binding of a dextran derivative on fibroblast growth factor 2: secondary structure and receptor-binding studies.

    Science.gov (United States)

    Bittoun, P; Bagheri-Yarmand, R; Chaubet, F; Crépin, M; Jozefonvicz, J; Fermandjian, S

    1999-06-15

    CMDB (carboxymethyldextran-benzylamide) are dextrans statistically substituted with carboxymethyl and benzylamide groups which can mimick some of the biological properties of heparin. It has previously been shown that CMDB inhibit autocrine growth of breast tumor cells (Bagheri-Yarmand et al., Biochem. Biophys. Res. Commun. 239: 424-428, 1997) and selectively displace fibroblast growth factor 2 (FGF-2) from its receptor. Here, we used circular dichroism and fluorescence anisotropy measurements to show that the conformation of FGF-2 was significantly altered upon its binding to CMDB and to short CMDB fragments prepared within this study. CMDB and fragments formed a stable 1:1 complex with FGF-2, with affinities being estimated as 20+/-10 nM from fluorescence anisotropy analysis. No such a complex was formed with insulin-like growth factor (IGF-1) or epidermal growth factor (EGF). CMDB competed with the FGF-2 receptor for binding to FGF-2 but did not disturb the binding of IGF-1 and EGF to their receptors. Thus, our results highlight the selectivity of CMDB and their fragments towards FGF-2. Heparin, however, competes with CMDB and their fragments for binding to FGF-2. The carboxymethyl and benzylamide groups of these molecules likely interact directly with a heparin-binding region of FGF-2. The resulting change in conformation disturbs the binding of FGF-2 to its receptor and consecutively its mitogenic activity.

  2. Recognition of coxiella burnetii by toll-like receptors and nucleotide-binding oligomerization domain-like receptors

    NARCIS (Netherlands)

    Ammerdorffer, Anne; Schoffelen, Teske; Gresnigt, Mark S.; Oosting, Marije; Brok, Den Martijn H.; Abdollahi-Roodsaz, Shahla; Kanneganti, Thirumala Devi; Jong, De Dirk J.; Deuren, Van Marcel; Roest, Hendrik Jan; Rebel, Johanna M.J.; Netea, Mihai G.; Joosten, Leo A.B.; Sprong, Tom

    2015-01-01

    Background. Infection with Coxiella burnetii can lead to acute and chronic Q fever. Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR6, nucleotide-binding oligomerization domain receptor 1 (NOD1), NOD2, and the mitogen-activated protein kinases are central in the innate immune response against

  3. Recognition of Coxiella burnetii by Toll-like Receptors and Nucleotide-Binding Oligomerization Domain-like Receptors

    NARCIS (Netherlands)

    Ammerdorffer, A.; Schoffelen, T.; Gresnigt, M.S.; Oosting, M.; Brok, M.H.M.G.M. den; Abdollahi-Roodsaz, S.; Kanneganti, T.D.; Jong, D.J. de; Deuren, M. van; Roest, H.J.; Rebel, J.M.; Netea, M.G.; Joosten, L.A.B.; Sprong, T.

    2015-01-01

    BACKGROUND: Infection with Coxiella burnetii can lead to acute and chronic Q fever. Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR6, nucleotide-binding oligomerization domain receptor 1 (NOD1), NOD2, and the mitogen-activated protein kinases are central in the innate immune response against

  4. RAINBOW TROUT ANDROGEN RECEPTOR ALPHA AND THE HUMAN ANDROGEN RECEPTOR: COMPARISONS IN THE COS WHOLE CELL BINDING ASSAY

    Science.gov (United States)

    Rainbow Trout Androgen Receptor Alpha And Human Androgen Receptor: Comparisons in the COS Whole Cell Binding Assay Mary C. Cardon, L. Earl Gray, Jr. and Vickie S. WilsonU.S. Environmental Protection Agency, ORD, NHEERL, Reproductive Toxicology Division, Research Triangle...

  5. Definition of the G protein-coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design

    DEFF Research Database (Denmark)

    Gloriam, David Erik Immanuel; Foord, Steven M; Blaney, Frank E

    2009-01-01

    Recent advances in structural biology for G-protein-coupled receptors (GPCRs) have provided new opportunities to improve the definition of the transmembrane binding pocket. Here a reference set of 44 residue positions accessible for ligand binding was defined through detailed analysis of all curr...

  6. Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism

    OpenAIRE

    Steven C Leiser; Iglesias-Bregna, Deborah; Westrich, Ligia; Pehrson, Alan L.; Sanchez, Connie

    2015-01-01

    Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/inte...

  7. Effects of vitamin B-6 nutrition on benzodiazepine (BDZ) receptor binding in the developing rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Borek, J.P.; Guilarte, T.R. (Johns Hopkins Univ., Baltimore, MD (United States))

    1990-02-26

    A dietary deficiency of vitamin B-6 promotes seizure activity in neonatal animals and human infants. Previous studied have shown that neonatal vitamin B-6 deprivation results in reduced levels of brain gamma-aminobutyric acid (GABA) and increased binding at the GABA site of the GABA/BDZ receptor complex. Since the GABA and BDZ receptors are allosterically linked, this study was undertaken to determine if vitamin B-6 deprivation had an effect on BDZ receptor binding. Benzodiazepine receptor binding isotherms using {sup 3}H-flunitrazepam as ligand were performed in the presence and absence of 10 {mu}M GABA. The results indicate a significant increase in the binding affinity (Kd) in the presence of GABA in cerebellar membranes from deficient rat pups at 14 days of age with no effect on receptor number (Bmax). By 28 days of age, the increase in Kd was no longer present. No change in Kd or Bmax was observed in cortical tissue from deficient animals at 14 or 28 days of age. Preliminary studies of GABA-enhancement of {sup 3}H-flunitrazepam binding indicate that vitamin B-6 deficiency also induces alterations in the ability of GABA to enhance BZD receptor binding. In summary, these results indicate that the effects of vitamin B-6 deprivation on BDZ receptor binding are region specific and age related.

  8. Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Fryer, A.D.; El-Fakahany, E.E. (Univ. of Maryland, Baltimore (USA))

    1990-01-01

    Heterogeneity of the muscarinic receptor population in the rat central and peripheral lung was found in competition binding experiments against ({sup 3}H)quinuclidinyl benzilate (({sup 3}H)QNB) using the selective antagonists pirenzepine, AF-DX 116 and hexahydrosiladifenidol (HHSiD). Pirenzepine displaced ({sup 3}H)QNB with low affinity from preparations of central airways indicating the absence of M{sub 1} receptors in the trachea and bronchi. Muscarinic receptors in the central airways are comprised of both M{sub 2} and M{sub 3} receptors since AF-DX 116, an M{sub 2}-selective antagonist, bound with high affinity to 70% of the available sites while HHSiD, an M{sub 3}-selective antagonist bound with high affinity to the remaining binding sites. In the peripheral lung, pirenzepine bound with high affinity to 14% of the receptor population, AF-DX 116 bound with high affinity 79% of the binding sites while HHSiD bound with high affinity to 18% of the binding sites. The presence of M{sub 1} receptors in the peripheral airways but not in the central airways was confirmed using ({sup 3}H)telenzepine, an M{sub 1} receptor ligand. ({sup 3}H)Telenzepine showed specific saturable binding to 8% of ({sup 3}H)QNB labeled binding sites in homogenates of rat peripheral lung, while there was no detectable specific binding in homogenates of rat trachea or heart.

  9. Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J.H.; el-Fakahany, E.E.

    1985-06-01

    The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/sup 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

  10. Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.

    Science.gov (United States)

    Stepniewski, Tomasz M; Filipek, Slawomir

    2015-07-15

    Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4

    Institute of Scientific and Technical Information of China (English)

    Nianshuang Wang; Xuanling Shi; Liwei Jiang; Senyan Zhang; Dongli Wang; Pei Tong; Dongxing Guo

    2013-01-01

    The spike glycoprotein (S) of recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) targets the cellular receptor,dipeptidyl peptidase 4 (DPP4).Sequence comparison and modeling analysis have revealed a putative receptor-binding domain (RBD) on the viral spike,which mediates this interaction.We report the 3.0 (A)resolution crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4.Our results show that MERS-CoV RBD consists of a core and a receptor-binding subdomain.The receptor-binding subdomain interacts with DPP4 p-propeller but not its intrinsic hydrolase domain.MERS-CoV RBD and related SARS-CoV RBD share a high degree of structural similarity in their core subdomains,but are notably divergent in the receptorbinding subdomain.Mutagenesis studies have identified several key residues in the receptor-binding subdomain that are critical for viral binding to DPP4 and entry into the target cell.The atomic details at the interface between MERS-CoV RBD and DPP4 provide structural understanding of the virus and receptor interaction,which can guide development of therapeutics and vaccines against MERS-CoV infection.

  12. Binding characteristics of sigma2 receptor ligands Características estruturais de ligantes do receptor sigma2

    Directory of Open Access Journals (Sweden)

    Richard A. Glennon

    2005-03-01

    Full Text Available Sigma (sigma receptors, once considered a type of opioid receptor, are now recognized as representing a unique receptive entity and at least two different types of sigma receptors have been identified: sigma1 and sigma2 receptors. Evidence suggests that these receptors might be targeted and exploited for the development of agents potentially useful for the treatment of several central disorders. This review primarily describes some of our efforts to understand those structural features that contribute to sigma2 receptor binding, and some recent work by other investigators is also included. Despite an inability to formulate a unified pharmacophore model for sigma2 binding due to the diversity of structure-types that bind at the receptor, and to the conformational flexibility of these ligands, significant progress has been made toward the development of some very high-affinity agents.Receptores sigma (sigma, considerados como um tipo de receptor opióide, sigma ão hoje considerados como uma entidade receptora singular. Pelo menos dois subtipos desses receptores foram identificados: sigma1e sigma2. Há evidências de que esses receptores devam ser explorados como alvo para o desenvolvimento de agentes potencialmente úteis para o tratamento de várias disfunções centrais. Esta revisão descreve, principalmente, alguns dos nossos esforços para compreender as características estruturais que contribuem para a ligação no receptor sigma2 , e incluem-se alguns trabalhos recentes desenvolvidos por outros pesquisadores. Apesar da incapacidade de formular um modelo de farmacóforo único para ligação no receptor s 2, em razão da diversidade de estruturas que a ele se ligam e da flexibilidade conformacional desses ligantes, houve progresso significativo no desenvolvimento de agentes de alta afinidade.

  13. The human olfactory receptor 17-40: requisites for fitting into the binding pocket.

    Science.gov (United States)

    Anselmi, Cecilia; Buonocore, Anna; Centini, Marisanna; Facino, Roberto Maffei; Hatt, Hanns

    2011-06-01

    To gain structural insight on the interactions between odorants and the human olfactory receptor, we did homology modelling of the receptor structure, followed by molecular docking simulation with ligands. Molecular dynamics simulation on the structures resulting from docking served to estimate the binding free energy of the various odorant families. A correlation with the odorous properties of the ligands is proposed. We also investigated which residues were involved in the binding of a set of properly synthesised ligands and which were required for fitting inside the binding pocket. Olfactive stimulation of the olfactory receptor with odorous molecules was also investigated, using calcium imaging or electrophysiological recordings.

  14. Coupling the Torpedo microplate-receptor binding assay with mass spectrometry to detect cyclic imine neurotoxins.

    Science.gov (United States)

    Aráoz, Rómulo; Ramos, Suzanne; Pelissier, Franck; Guérineau, Vincent; Benoit, Evelyne; Vilariño, Natalia; Botana, Luis M; Zakarian, Armen; Molgó, Jordi

    2012-12-04

    Cyclic imine neurotoxins constitute an emergent family of neurotoxins of dinoflagellate origin that are potent antagonists of nicotinic acetylcholine receptors. We developed a target-directed functional method based on the mechanism of action of competitive agonists/antagonists of nicotinic acetylcholine receptors for the detection of marine cyclic imine neurotoxins. The key step for method development was the immobilization of Torpedo electrocyte membranes rich in nicotinic acetylcholine receptors on the surface of microplate wells and the use of biotinylated-α-bungarotoxin as tracer. Cyclic imine neurotoxins competitively inhibit biotinylated-α-bungarotoxin binding to Torpedo-nicotinic acetylcholine receptors in a concentration-dependent manner. The microplate-receptor binding assay allowed rapid detection of nanomolar concentrations of cyclic imine neurotoxins directly in shellfish samples. Although highly sensitive and specific for the detection of neurotoxins targeting nicotinic acetylcholine receptors as a class, the receptor binding assay cannot identify a given analyte. To address the low selectivity of the microplate-receptor binding assay, the cyclic imine neurotoxins tightly bound to the coated Torpedo nicotinic receptor were eluted with methanol, and the chemical nature of the eluted ligands was identified by mass spectrometry. The immobilization of Torpedo electrocyte membranes on the surface of microplate wells proved to be a high-throughput format for the survey of neurotoxins targeting nicotinic acetylcholine receptors directly in shellfish matrixes with high sensitivity and reproducibility.

  15. Analyzing machupo virus-receptor binding by molecular dynamics simulations

    Directory of Open Access Journals (Sweden)

    Austin G. Meyer

    2014-02-01

    Full Text Available In many biological applications, we would like to be able to computationally predict mutational effects on affinity in protein–protein interactions. However, many commonly used methods to predict these effects perform poorly in important test cases. In particular, the effects of multiple mutations, non alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here an existing method applied in a novel way to a new test case; we interrogate affinity differences resulting from mutations in a host–virus protein–protein interface. We use steered molecular dynamics (SMD to computationally pull the machupo virus (MACV spike glycoprotein (GP1 away from the human transferrin receptor (hTfR1. We then approximate affinity using the maximum applied force of separation and the area under the force-versus-distance curve. We find, even without the rigor and planning required for free energy calculations, that these quantities can provide novel biophysical insight into the GP1/hTfR1 interaction. First, with no prior knowledge of the system we can differentiate among wild type and mutant complexes. Moreover, we show that this simple SMD scheme correlates well with relative free energy differences computed via free energy perturbation. Second, although the static co-crystal structure shows two large hydrogen-bonding networks in the GP1/hTfR1 interface, our simulations indicate that one of them may not be important for tight binding. Third, one viral site known to be critical for infection may mark an important evolutionary suppressor site for infection-resistant hTfR1 mutants. Finally, our approach provides a framework to compare the effects of multiple mutations, individually and jointly, on protein–protein interactions.

  16. A cation-pi interaction in the binding site of the glycine receptor is mediated by a phenylalanine residue

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Millen, Kat S; Hanek, Ariele P;

    2008-01-01

    Cys-loop receptor binding sites characteristically contain many aromatic amino acids. In nicotinic ACh and 5-HT3 receptors, a Trp residue forms a cation-pi interaction with the agonist, whereas in GABA(A) receptors, a Tyr performs this role. The glycine receptor binding site, however, contains pr...

  17. Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors.

    Science.gov (United States)

    Schmeller, T; Sauerwein, M; Sporer, F; Wink, M; Müller, W E

    1994-09-01

    Fourteen quinolizidine alkaloids, isolated from Lupinus albus, L. mutabilis, and Anagyris foetida, were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. Of the compounds tested, the alpha-pyridones, N-methylcytisine and cytisine, showed the highest affinities at the nicotinic receptor, while several quinolizidine alkaloid types were especially active at the muscarinic receptor.

  18. Familial Risk for Major Depression is Associated with Lower Striatal 5-HT4 Receptor Binding

    DEFF Research Database (Denmark)

    Madsen, Karine; Torstensen, Eva; Holst, Klaus Kähler

    2015-01-01

    BACKGROUND: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study......-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression...

  19. Mu receptor binding of some commonly used opioids and their metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zhaorong; Irvine, R.J. (Univ. of Adelaide (Australia)); Somogyi, A.A.; Bochner, F. (Univ. of Adelaide (Australia) Royal Adelaide Hospital (Australia))

    1991-01-01

    The binding affinity to the {mu} receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with {sup 3}H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding. Decreasing the length of the alkyl group at position 3 decreased the K{sub i} values (morphine < codeine < ethylmorphine < pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 had relatively weak receptor binding, while their O-demethylated metabolites had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.

  20. Does protein binding modulate the effect of angiotensin II receptor antagonists?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  1. Binding characteristics of prostaglandin E sub 2 receptor in submandibular glands: Effect of ethanol

    Energy Technology Data Exchange (ETDEWEB)

    Wuwang, C.Y.; Lim, C.; Yao, P.; Wang, S.L.; Slomiany, A.; Slomiany, B.L. (UMDNJ, Newark, NJ (United States))

    1991-03-11

    Prostaglandin (PG) of the E series are known to stimulate saliva flow and mucin secretion in salivary glands, however, the cellular mechanism of this action remains unclear. Binding of PGE to specific binding site may be the initial step in the sequence of events that result in various biological activities. The authors first characterized PGE{sub 2} receptor binding in rat submandibular glandmembranes. The binding was specific and reversible. Scatchard analysis demonstrated that the receptor consists of two binding sites. Since ethanol has been reported to diminish salivary secretion, they further investigated whether this detrimental effect was due to the alteration of PGE receptor. Submandibular glands were dissected from rats, minced, suspended in DMEM and incubated at 37C for 2 hr under 95% O{sub 2}-5% CO{sub 2} in the absence or presence of various concentrations of ethanol. After incubation, cell membranes were prepared and receptor binding assayed. The results indicated that ethanol caused an increase in PGE{sub 2} receptor binding. The specific binding increased by 30% at 2.5% ethanol and by 50%