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Sample records for 5-ht1a receptor expression

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

    PubMed Central

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

    2011-01-01

    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. PMID:21362435

  2. Prenatal stress alters diazepam withdrawal syndrome and 5HT1A receptor expression in the raphe nuclei of adult rats.

    PubMed

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

    2016-08-25

    Early-life events have long-term effects on brain structures and cause behavioral alterations that persist into adulthood. The present experiments were designed to investigate the effects of prenatal stress on diazepam-induced withdrawal syndrome and serotonin-1A (5HT1A) receptor expression in the raphe nuclei of adult offspring. The results of the present study reveal that maternal exposure to chronic footshock stress increased the anxiety-like behavior in the prenatally stressed (PS) animals withdrawn from chronic diazepam (2.5mg/kg/day i.p for 1week). Moreover, prenatal stress induced a down-regulation of 5HT1A mRNA in the raphe nuclei of adult offspring. To our knowledge, this study is the first to demonstrate that maternal exposure to chronic footshock stress enhances diazepam withdrawal symptoms and alters 5HT1A receptor gene expression in the raphe nuclei of adult offspring. Thus, more studies are needed to clarify the mechanisms underlying the decrease of 5HT1A receptors expression in the raphe nuclei of PS rats. PMID:27235743

  3. Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site

    PubMed Central

    Le François, Brice; Soo, Jeremy; Millar, Anne M.; Daigle, Mireille; Le Guisquet, Anne-Marie; Leman, Samuel; Minier, Frédéric; Belzung, Catherine; Albert, Paul R.

    2015-01-01

    The serotonin 1A receptor (5-HT1A), a critical regulator of the brain serotonergic tone, is implicated in major depressive disorder (MDD) where it is often found to be dys-regulated. However, the extent to which stress and antidepressant treatment impact 5-HT1A expression in adults remains unclear. To address this issue, we subjected adult male BALB/c mice to unpredictable chronic mild stress (UCMS) to induce a depression-like phenotype that was reversed by chronic treatment with the antidepressant imipramine. In prefrontal cortex (PFC) and midbrain tissue, UCMS increased 5-HT1A RNA and protein levels, changes that are expected to decrease the brain serotonergic activity. The stress-induced increase in 5-HT1A expression was paralleled by a specific increase in DNA methylation of the conserved -681 CpG promoter site, located within a Sp1-like element. We show that the -681 CpG site is recognized and repressed by Sp4, the predominant neuronal Sp1-like factor and that Sp4-induced repression is attenuated by DNA methylation, despite a stress-induced increase in PFC Sp4 levels. These results indicate that adult life stress induces DNA methylation of the conserved promoter site, antagonizing Sp4 repression to increase 5-HT1A expression. Chronic imipramine treatment fully reversed the UCMS-induced increase in methylation of the -681 CpG site in the PFC but not midbrain of stressed animals and also increased 5-HT1A expression in the PFC of control animals. Incomplete reversal by imipramine of stress-induced changes in 5-HT1A methylation and expression indicates a persistence of stress vulnerability, and that sustained reversal of behavioral impairments may require additional pathways. PMID:26188176

  4. Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site.

    PubMed

    Le François, Brice; Soo, Jeremy; Millar, Anne M; Daigle, Mireille; Le Guisquet, Anne-Marie; Leman, Samuel; Minier, Frédéric; Belzung, Catherine; Albert, Paul R

    2015-10-01

    The serotonin 1A receptor (5-HT1A), a critical regulator of the brain serotonergic tone, is implicated in major depressive disorder (MDD) where it is often found to be dys-regulated. However, the extent to which stress and antidepressant treatment impact 5-HT1A expression in adults remains unclear. To address this issue, we subjected adult male BALB/c mice to unpredictable chronic mild stress (UCMS) to induce a depression-like phenotype that was reversed by chronic treatment with the antidepressant imipramine. In prefrontal cortex (PFC) and midbrain tissue, UCMS increased 5-HT1A RNA and protein levels, changes that are expected to decrease the brain serotonergic activity. The stress-induced increase in 5-HT1A expression was paralleled by a specific increase in DNA methylation of the conserved -681 CpG promoter site, located within a Sp1-like element. We show that the -681 CpG site is recognized and repressed by Sp4, the predominant neuronal Sp1-like factor and that Sp4-induced repression is attenuated by DNA methylation, despite a stress-induced increase in PFC Sp4 levels. These results indicate that adult life stress induces DNA methylation of a conserved promoter site, antagonizing Sp4 repression to increase 5-HT1A expression. Chronic imipramine treatment fully reversed the UCMS-induced increase in methylation of the -681 CpG site in the PFC but not midbrain of stressed animals and also increased 5-HT1A expression in the PFC of control animals. Incomplete reversal by imipramine of stress-induced changes in 5-HT1A methylation and expression indicates a persistence of stress vulnerability, and that sustained reversal of behavioral impairments may require additional pathways. PMID:26188176

  5. Yokukansan Increases 5-HT1A Receptors in the Prefrontal Cortex and Enhances 5-HT1A Receptor Agonist-Induced Behavioral Responses in Socially Isolated Mice

    PubMed Central

    Ueki, Toshiyuki; Mizoguchi, Kazushige; Yamaguchi, Takuji; Nishi, Akinori; Ikarashi, Yasushi; Hattori, Tomohisa; Kase, Yoshio

    2015-01-01

    The traditional Japanese medicine yokukansan has an anxiolytic effect, which occurs after repeated administration. In this study, to investigate the underlying mechanisms, we examined the effects of repeated yokukansan administration on serotonin 1A (5-HT1A) receptor density and affinity and its expression at both mRNA and protein levels in the prefrontal cortex (PFC) of socially isolated mice. Moreover, we examined the effects of yokukansan on a 5-HT1A receptor-mediated behavioral response. Male mice were subjected to social isolation stress for 6 weeks and simultaneously treated with yokukansan. Thereafter, the density and affinity of 5-HT1A receptors were analyzed by a receptor-binding assay. Levels of 5-HT1A receptor protein and mRNA were also measured. Furthermore, (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT; a 5-HT1A receptor agonist) was injected intraperitoneally, and rearing behavior was examined. Social isolation stress alone did not affect 5-HT1A receptor density or affinity. However, yokukansan significantly increased receptor density and decreased affinity concomitant with unchanged protein and mRNA levels. Yokukansan also enhanced the 8-OH-DPAT-induced decrease in rearing behavior. These results suggest that yokukansan increases 5-HT1A receptors in the PFC of socially isolated mice and enhances their function, which might underlie its anxiolytic effects. PMID:26681968

  6. Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice.

    PubMed

    Sonego, Andreza B; Gomes, Felipe V; Del Bel, Elaine A; Guimaraes, Francisco S

    2016-08-01

    Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant. Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic. In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol. To further investigate this latter effect, we tested whether CBD (15-60mg/kg) would attenuate the catalepsy and c-Fos protein expression in the dorsal striatum induced by haloperidol (0.6mg/kg). We also evaluated if these effects occur through the facilitation of 5-HT1A receptor-mediated neurotransmission. For this, male Swiss mice were treated with CBD and haloperidol systemically and then subjected to the catalepsy test. Independent groups of animals were also treated with the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). As expected, haloperidol induced catalepsy throughout the experiments, an effect that was prevented by systemic CBD treatment 30min before haloperidol administration. Also, CBD, administered 2.5h after haloperidol, reversed haloperidol-induced catalepsy. Haloperidol also increased c-Fos protein expression in the dorsolateral striatum, an effect attenuated by previous CBD administration. CBD effects on catalepsy and c-Fos protein expression induced by haloperidol were blocked by the 5-HT1A receptor antagonist. We also evaluated the effects of CBD (60nmol) injection into the dorsal striatum on haloperidol-induced catalepsy. Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors. PMID:27131780

  7. Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.

    PubMed

    Li, Qian; Holmes, Andrew; Ma, Li; Van de Kar, Louis D; Garcia, Francisca; Murphy, Dennis L

    2004-12-01

    Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors. PMID:15574737

  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.

    PubMed

    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. PMID:27150226

  9. The 5-HT1A receptor in Major Depressive Disorder.

    PubMed

    Kaufman, Joshua; DeLorenzo, Christine; Choudhury, Sunia; Parsey, Ramin V

    2016-03-01

    Major Depressive Disorder (MDD) is a highly prevalent psychiatric diagnosis that is associated with a high degree of morbidity and mortality. This debilitating disorder is currently one of the leading causes of disability nationwide and is predicted to be the leading cause of disease burden by the year 2030. A large body of previous research has theorized that serotonergic dysfunction, specifically of the serotonin (5-HT) 1A receptor, plays a key role in the development of MDD. The purpose of this review is to describe the evolution of our current understanding of the serotonin 1A (5-HT1A) receptor and its role in the pathophysiology MDD through the discussion of animal, post-mortem, positron emission tomography (PET), pharmacologic and genetic studies. PMID:26851834

  10. 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

    PubMed Central

    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

  11. Anxiolytic effects of prelimbic 5-HT(1A) receptor activation in the hemiparkinsonian rat.

    PubMed

    Hui, Yan Ping; Wang, Tao; Han, Ling Na; Li, Li Bo; Sun, Yi Na; Liu, Jian; Qiao, Hong Fei; Zhang, Qiao Jun

    2015-01-15

    This study sought to assess whether unilateral lesions of the medial forebrain bundle (MFB) using 6-hydroxydopamine in rats are able to induce anxiety-like behaviors, the role of serotonin-1A (5-HT1A) receptors of the prelimbic (PrL) sub-region of ventral medial prefrontal cortex in the regulation of these behaviors, the density of 5-HT neurons in the dorsal raphe nucleus (DRN) and co-localization of 5-HT1A receptor and neuronal glutamate transporter EAAC1-immunoreactive (EAAC1-ir) cells in the PrL. Unilaterally lesioning the MFB induced anxiety-like behaviors as measured by the open-field and elevated plus maze tests when compared to sham-operated rats. Intra-PrL injection of 5-HT1A receptor agonist 8-OH-DPAT (50, 100, and 500 ng/rat) decreased the percentage of time spent in the center of the open-field and percentages of open arm entries and open arm time in sham-operated rats, indicating the induction of anxiogenic responses, and administration of 5-HT1A receptor antagonist WAY-100635 (60, 120, and 240 ng/rat) showed anxiolytic effects. However, 8-OH-DPAT, at the same doses, increased the percentage of time spent in the center of the open-field and percentages of open arm entries and open arm time in the lesioned rats, indicating the induction of anxiolytic effects, and WAY-100635 produced anxiogenic responses. Unilateral MFB lesion decreased the density of 5-HT neurons in the DRN, and percentage of EAAC1-ir cells expressing 5-HT1A receptors in the PrL. These results suggest that unilateral lesions of the MFB in rats may induce anxiety-like behaviors, and activation of 5-HT1A receptors in the PrL has anxiolytic effects in the rat model of Parkinson's disease. PMID:24906197

  12. Hippocampal 5-HT1A Receptor and Spatial Learning and Memory

    PubMed Central

    Glikmann-Johnston, Yifat; Saling, Michael M.; Reutens, David C.; Stout, Julie C.

    2015-01-01

    Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory. PMID:26696889

  13. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors.

    PubMed

    Campos, Alline Cristina; Ferreira, Frederico Rogério; Guimarães, Francisco Silveira

    2012-11-01

    Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD. Male Wistar rats exposed to a predator (cat) received, 1 h later, singled or repeated i.p. administration of vehicle or CBD. Seven days after the stress animals were submitted to the elevated plus maze. To investigate the involvement of 5HT1A receptors in CBD effects animals were pre-treated with WAY100635, a 5HT1A receptor antagonist. To explore possible neurobiological mechanisms involved in these effects, 5HT1A receptor mRNA and BDNF protein expression were measured in the hippocampus, frontal cortex, amygdaloid complex and dorsal periaqueductal gray. Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure. Pretreatment with WAY100635 attenuated CBD effects. Seven days after predator exposure 5HT1A mRNA expression was up regulated in the frontal cortex and hippocampus. CBD and paroxetine failed to prevent this effect. No change in BDNF expression was found. In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission. Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder. PMID:22979992

  14. 5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

    PubMed Central

    Garcia-Garcia, Alvaro; Tancredi, Adrian Newman-; Leonardo, E. David

    2014-01-01

    Rationale Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders. Objectives In this review, we examine the function of 5-HT1A receptor sub-populations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor vs heteroreceptor) and the temporal (developmental vs adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. Results It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for distinct roles of these populations in governing emotion related behavior are emerging. Conclusions There is strong and growing evidence for a functional dissociation between auto and heteroreceptor populations in mediating anxiety and depressive-like behaviors respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. PMID:24337875

  15. Characterization of the 5-HT1A receptor of the honeybee (Apis mellifera) and involvement of serotonin in phototactic behavior.

    PubMed

    Thamm, Markus; Balfanz, Sabine; Scheiner, Ricarda; Baumann, Arnd; Blenau, Wolfgang

    2010-07-01

    Serotonin plays a key role in modulating various physiological and behavioral processes in both protostomes and deuterostomes. The vast majority of serotonin receptors belong to the superfamily of G-protein-coupled receptors. We report the cloning of a cDNA from the honeybee (Am5-ht1A) sharing high similarity with members of the 5-HT(1) receptor class. Activation of Am5-HT(1A) by serotonin inhibited the production of cAMP in a dose-dependent manner (EC(50) = 16.9 nM). Am5-HT(1A) was highly expressed in brain regions known to be involved in visual information processing. Using in vivo pharmacology, we could demonstrate that Am5-HT(1A) receptor ligands had a strong impact on the phototactic behavior of individual bees. The data presented here mark the first comprehensive study-from gene to behavior-of a 5-HT(1A) receptor in the honeybee, paving the way for the eventual elucidation of additional roles of this receptor subtype in the physiology and behavior of this social insect. PMID:20349263

  16. Nicotine alters limbic function in adolescent rat by a 5-HT1A receptor mechanism.

    PubMed

    Dao, Jasmin M; McQuown, Susan C; Loughlin, Sandra E; Belluzzi, James D; Leslie, Frances M

    2011-06-01

    Epidemiological studies have shown that adolescent smoking is associated with health risk behaviors, including high-risk sexual activity and illicit drug use. Using rat as an animal model, we evaluated the behavioral and biochemical effects of a 4-day, low-dose nicotine pretreatment (60 μg/kg; intravenous) during adolescence and adulthood. Nicotine pretreatment significantly increased initial acquisition of cocaine self-administration, quinpirole-induced locomotor activity, and penile erection in adolescent rats, aged postnatal day (P)32. These effects were long lasting, remaining evident 10 days after the last nicotine treatment, and were observed when nicotine pretreatment was administered during early adolescence (P28-31), but not late adolescence (P38-41) or adulthood (P86-89). Neurochemical analyses of c-fos mRNA expression, and of monoamine transmitter and transporter levels, showed that forebrain limbic systems are continuing to develop during early adolescence, and that this maturation is critically altered by brief nicotine exposure. Nicotine selectively increased c-fos mRNA expression in the nucleus accumbens shell and basolateral amygdala in adolescent, but not adult animals, and altered serotonin markers in these regions as well as the prefrontal cortex. Nicotine enhancement of cocaine self-administration and quinpirole-induced locomotor activity was blocked by co-administration of WAY 100 635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide), a selective serotonin 1A (5-HT1A) receptor antagonist. Early adolescent pretreatment with the mixed autoreceptor/heteroceptor 5-HT1A receptor agonist, 8-OH-DPAT, but not the autoreceptor-selective agonist, S-15535, also enhanced quinpirole-induced locomotor activation. Nicotine enhancement of quinpirole-induced penile erection was not blocked by WAY 100 635 nor mimicked by 8-OH-DPAT. These findings indicate that early adolescent nicotine exposure uniquely alters limbic

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

    PubMed

    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. PMID:17553555

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

    DOEpatents

    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.

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

    DOEpatents

    Mukherjee, Jogeshwar; Saigal, Neil; Saigal, legal representative, Harsh

    2012-09-25

    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.

  20. Role of 5-HT(1A) receptors in fluoxetine-induced lordosis inhibition.

    PubMed

    Guptarak, Jutatip; Sarkar, Jhimly; Hiegel, Cindy; Uphouse, Lynda

    2010-07-01

    The selective serotonin reuptake inhibitor (SSRI), fluoxetine (Prozac(R)), is an effective antidepressant that is also prescribed for other disorders (e.g. anorexia, bulimia, and premenstrual dysphoria) that are prevalent in females. However, fluoxetine also produces sexual side effects that may lead patients to discontinue treatment. The current studies were designed to evaluate several predictions arising from the hypothesis that serotonin 1A (5-HT(1A)) receptors contribute to fluoxetine-induced sexual dysfunction. In rodent models, 5-HT(1A) receptors are potent negative modulators of female rat sexual behavior. Three distinct experiments were designed to evaluate the contribution of 5-HT(1A) receptors to the effects of fluoxetine. In the first experiment, the ability of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635), to prevent fluoxetine-induced lordosis inhibition was examined. In the second experiment, the effects of prior treatment with fluoxetine on the lordosis inhibitory effect of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), were studied. In the third experiment, the ability of progesterone to reduce the acute response to fluoxetine was evaluated. WAY100635 attenuated the effect of fluoxetine; prior treatment with fluoxetine decreased 8-OH-DPAT's potency in reducing lordosis behavior; and progesterone shifted fluoxetine's dose-response curve to the right. These findings are consistent with the hypothesis that 5-HT(1A) receptors contribute to fluoxetine-induced sexual side effects. PMID:20223238

  1. Neuronal Ablation of p-Akt at Ser473 Leads to Altered 5-HT1A/2A Receptor Function

    PubMed Central

    Saunders, Christine; Siuta, Michael; Robertson, Sabrina D.; Davis, Adeola R.; Sauer, Jennifer; Matthies, Heinrich J.G.; Gresch, Paul J.; Airey, David; Lindsley, Craig W.; Schetz, John A.; Niswender, Kevin D.

    2014-01-01

    The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function. PMID:24090638

  2. Differential interactions of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 receptors.

    PubMed

    Deliganis, A V; Pierce, P A; Peroutka, S J

    1991-06-01

    The interactions of the indolealkylamine N,N-dimethyltryptamine (DMT) with 5-hydroxytryptamine1A (5-HT1A) and 5-HT2 receptors in rat brain were analyzed using radioligand binding techniques and biochemical functional assays. The affinity of DMT for 5-HT1A sites labeled by [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) was decreased in the presence of 10(-4) M GTP, suggesting agonist activity of DMT at this receptor. Adenylate cyclase studies in rat hippocampi showed that DMT inhibited forskolin-stimulated cyclase activity, a 5-HT1A agonist effect. DMT displayed full agonist activity with an EC50 of 4 x 10(-6) M in the cyclase assay. In contrast to the agonist actions of DMT at 5-HT1A receptors, DMT appeared to have antagonistic properties at 5-HT2 receptors. The ability of DMT to compete for [3H]-ketanserin-labeled 5-HT2 receptors was not affected by the presence of 10(-4) M GTP, suggesting antagonist activity of DMT at 5-HT2 receptors. In addition, DMT antagonized 5-HT2-receptor-mediated phosphatidylinositol (PI) turnover in rat cortex at concentrations above 10(-7) M, with 70% of the 5-HT-induced PI response inhibited at 10(-4) M DMT. Micromolar concentrations of DMT produced a slight PI stimulation that was not blocked by the 5-HT2 antagonist ketanserin. These studies suggest that DMT has opposing actions on 5-HT receptor subtypes, displaying agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2 receptors. PMID:1828347

  3. A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

    PubMed Central

    2012-01-01

    5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA. In addition, we performed patch-clamp recordings followed by single-cell PCR in ePet1-eGFP mice. From 134 recorded 5-HT neurons located in the dorsal, lateral, and median raphe, we found lack of 5-HT1A mRNA expression in 22 cells, evenly distributed across raphe subfields. We compared the cellular characteristics of these neuronal types and found no difference in passive membrane properties and general excitability. However, when injected with large depolarizing current, 5-HT1A-negative neurons fired more action potentials, suggesting a lack of autoinhibitory action of local 5-HT release. Our results support the hypothesis that the 5-HT system is composed of subpopulations of serotonergic neurons with different capacity for adaptation. PMID:23336048

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

    PubMed

    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. PMID:27312422

  5. Synergistic effect of 5-HT1A and σ1 receptor activation on prefrontal dopaminergic transmission under circulating steroid deficiency.

    PubMed

    Hiramatsu, Naoki; Ago, Yukio; Hasebe, Shigeru; Nishimura, Akira; Mori, Kazuya; Takuma, Kazuhiro; Matsuda, Toshio

    2013-12-01

    Serotonin (5-HT)1A and σ1 receptors have been implicated in psychiatric disorders. We previously found that combined 5-HT reuptake inhibition and σ1 receptor activation has a synergistic effect on prefrontal dopaminergic transmission in adrenalectomized/castrated mice lacking circulating steroid hormones. In the present study, we examined the mechanisms underlying this neurochemical synergism. Systemic administration of fluvoxamine, a selective 5-HT reuptake inhibitor with agonistic activity towards the σ1 receptor, increased prefrontal dopamine (DA) levels, and adrenalectomy/castration potentiated this fluvoxamine-induced increase in DA. This enhancement of DA release was blocked by WAY100635 (a 5-HT1A receptor antagonist), but not by ritanserin (a 5-HT2 receptor antagonist), azasetron (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist). Individually, osemozotan (a 5-HT1A receptor agonist) and (+)-SKF-10,047 (a σ1 receptor agonist) did not alter prefrontal monoamine levels in adrenalectomized/castrated and sham-operated mice differentially. In contrast, co-administration of these drugs increased prefrontal DA levels to a greater extent in adrenalectomized/castrated mice than in sham-operated animals. Furthermore, co-administration of osemozotan and (+)-SKF-10,047 increased expression of the neuronal activity marker c-Fos in the ventral tegmental area of adrenalectomized/castrated mice, but not in sham-operated animals. These findings suggest that combined activation of 5-HT1A and σ1 receptors has a synergistic effect on prefrontal dopaminergic transmission under circulating steroid deficiency, and that this interaction may play an important role in the regulation of the prefrontal DA system. PMID:23851260

  6. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding.

    PubMed

    Pompeiano, M; Palacios, J M; Mengod, G

    1992-02-01

    In order to localize the cells expressing 5-HT1A receptors in the rat brain, we used in situ hybridization histochemistry to visualize the distribution of the mRNA coding for 5-HT1A receptors. Oligonucleotides derived from different parts of the coding region of the rat 5-HT1A receptor gene were used as hybridization probes. 5-HT1A binding sites were visualized on consecutive sections by receptor autoradiography using 3H-8-hydroxy-2-(di-n-propylamino)tetralin as ligand. The highest levels of hybridization were observed in the dorsal raphe nucleus, septum, hippocampus, entorhinal cortex, and interpeduncular nucleus. Positive hybridization signals were also present in other areas, such as the olfactory bulb; cerebral cortex; some thalamic and hypothalamic nuclei; several nuclei of the brainstem, including all the remaining raphe nuclei, nucleus of the solitary tract, and nucleus of the spinal tract of the trigeminus; and the dorsal horn of the spinal cord. The distribution and abundance of 5-HT1A receptor mRNA in different rat brain areas generally correlate with those of the binding sites, suggesting that 5-HT1A receptors are predominantly somatodendritic receptors. PMID:1531498

  7. 5-HT-1A receptor-mediated modulation of medullary expiratory neurones in the cat.

    PubMed Central

    Lalley, P M; Bischoff, A M; Richter, D W

    1994-01-01

    The involvement of the 5-HT-1A receptor in serotoninergic responses of stage 2 expiratory (E-2) neurones was investigated in pentobarbitone-anaesthetized, mechanically ventilated cats. The specific agonist of the 5-HT-1A receptor, 8-hydroxy-diproplaminotetralin (8-OH-DPAT), administered systemically or by ionophoresis directly on to the neurones, had a clear depressant effect. Administration of 8-OH-DPAT at doses of 10-50 micrograms kg-1 (I.V.) increased the membrane hyperpolarizations of E-2 neurones during the inspiratory and postinspiratory phases, and shortened their duration of activity in association with shortening of phrenic nerve activity. Discharges of E-2 neurones were also less intense. At doses of 50-90 micrograms kg-1, 8-OH-DPAT reduced or abolished inspiratory hyperpolarizations, and reduced expiratory depolarizations of membrane potential and discharge in parallel with inhibition of phrenic nerve discharges. The effects of the larger doses were reversed by I.V. injection of NAN-190, an antagonist at the 5-HT-1A receptor. Dose-dependent effects on the membrane potential and discharge of E-2 neurones, but not on phrenic nerve activity, were also seen by ionophoretic administration of 8-OH-DPAT on to E-2 neurones. At low currents, ejection of 8-OH-DPAT hyperpolarized the neurones without affecting the duration of inspiratory hyperpolarization and expiratory depolarization. This hyperpolarization depressed the intensity and the duration of expiratory discharges. Ejection with larger currents hyperpolarized the E-2 neurones further, and depressed expiratory depolarization leading to blockade of expiratory discharges. The effects on membrane potential were accompanied by decreased neuronal input resistance. This depressed the excitability of E-2 neurones as tested by discharge evoked by intracellular current injection. The amplitudes of action potentials decreased in parallel with the changes in input resistance. The effects were attributed to a

  8. Evidence for 5-HT1A receptor control of pineal melatonin concentrations in the rat.

    PubMed

    Nathan, P J; Burrows, G D; Norman, T R

    1998-08-01

    The effect of some serotonin agonists on day and night-time melatonin in the pineal gland was investigated in male rats. Dose dependent increases in nocturnal melatonin concentrations were observed for all serotonin agonists investigated. Statistically significant increases were observed only for D-fenfluramine (20 mg/kg) and the full 5-HT1A agonists S(+)-20499 (10 mg/kg, 20 mg/kg) and flesinoxan (20 mg/kg). Both paroxetine and D-fenfluramine dose dependently increased day-time pineal melatonin, but only for D-fenfluramine (20 mg/kg) was there a statistically significant increase. The data suggest that acute increases in synaptic serotonin concentrations can be used to manipulate day- or night-time melatonin. Data suggests an influence of the 5-HT1A receptor subtype in mediating nocturnal melatonin concentrations, perhaps through a functional coupling to beta1-adrenoceptors on the pineal gland. PMID:9716310

  9. PET imaging of the serotonin transporter and 5HT1A receptor in alcohol dependence

    PubMed Central

    Martinez, Diana; Slifstein, Mark; Gil, Roberto; Hwang, Dah-Ren; Huang, Yiyun; Perez, Audrey; Frankle, W. Gordon; Laruelle, Marc; Krystal, John; Abi-Dargham, Anissa

    2009-01-01

    Background Rodent models as well as studies in humans have suggested alterations in serotonin (5HT) innervation and transmission in early onset genetically determined or type II alcoholism. This study examines two indices of serotonergic transmission, 5HT transporter levels and 5-HT1A availability, in vivo, in type II alcoholism. This is the first report of combined tracers for pre and post-synaptic serotonergic transmission in the same alcoholic subjects and the first study of 5HT1A receptors in alcoholism. Method Fourteen alcohol dependent subjects were scanned (11 with both tracers, 1 with [11C]DASB only and two with [11C]WAY100635 only). Twelve healthy controls (HC) subjects were scanned with [11C]DASB and another 13 were scanned with [11C]WAY100635. Binding Potential (BPp, mL/cm3) and the specific to nonspecific partition coefficient (BPND, unitless) were derived for both tracers using 2 tissue compartment model and compared to HC across different brain regions. Relationships to severity of alcoholism were assessed. Results No significant differences were observed in regional BPp or BPND between patients and controls in any of the regions examined. No significant relationships were observed between regional 5HT transporter availability, 5-HT1A availability, and disease severity with the exception of a significant negative correlation between SERT and years of dependence in amygdala and insula. Conclusion This study did not find alterations in measures of 5-HT1A or 5HT transporter levels in patients with type II alcoholism. PMID:18962444

  10. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research.

    PubMed

    Celada, Pau; Bortolozzi, Analía; Artigas, Francesc

    2013-09-01

    Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT1A receptor (5-HT1A-R) function and the role of pre- and postsynaptic 5-HT1A-Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT1A-Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT1A-Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT1A-Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT1A-Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT1A-Rs, thus reducing the effectiveness of the 5-HT1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and

  11. Oleanolic acid acrylate elicits antidepressant-like effect mediated by 5-HT1A receptor

    PubMed Central

    Fajemiroye, James O.; Polepally, Prabhakar R.; Chaurasiya, Narayan D.; Tekwani, Babu L.; Zjawiony, Jordan K.; Costa, Elson A.

    2015-01-01

    The development of new drugs for the treatment of depression is strategic to achieving clinical needs of patients. This study evaluates antidepressant-like effect and neural mechanisms of four oleanolic acid derivatives i.e. acrylate (D1), methacrylate (D2), methyl fumarate (D3) and ethyl fumarate (D4). All derivatives were obtained by simple one-step esterification of oleanolic acid prior to pharmacological screening in the forced swimming (FS) and open field (OF) tests. Pharmacological tools like α-methyl-p-tyrosine (AMPT, catecholamine depletor), p-chlorophenylalanine (serotonin depletor), prazosin (PRAZ, selective α1-receptor antagonist), WAY-100635 (selective serotonin 5-HT1A receptor antagonist) as well as monoamine oxidase (MAO) and functional binding assays were conducted to investigate possible neural mechanisms. In the FS test, D1 showed the most promising antidepressant-like effect without eliciting locomotor incoordination. Unlike group of mice pretreated with AMPT 100 mg/kg, PCPA 100 mg/kg or PRAZ 1 mg/kg, the effect of D1 was attenuated by WAY-100635 0.3 mg/kg pretreatment. D1 demonstrated moderate inhibition of MAO-A (IC50 = 48.848 ± 1.935 μM), potency (pEC50 = 6.1 ± 0.1) and intrinsic activity (Emax = 26 ± 2.0%) on 5-HT1A receptor. In conclusion, our findings showed antidepressant-like effect of D1 and possible involvement of 5-HT1A receptor. PMID:26199018

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

    PubMed Central

    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

  13. Asymmetric Clustering Index in a Case Study of 5-HT1A Receptor Ligands

    PubMed Central

    Śmieja, Marek; Warszycki, Dawid; Tabor, Jacek; Bojarski, Andrzej J.

    2014-01-01

    The automatic clustering of chemical compounds is an important branch of chemoinformatics. In this paper the Asymmetric Clustering Index (Aci) is proposed to assess how well an automatically created partition reflects the reference. The asymmetry allows for a distinction between the fixed reference and the numerically constructed partition. The introduced index is applied to evaluate the quality of hierarchical clustering procedures for 5-HT1A receptor ligands. We find that the most appropriate combination of parameters for the hierarchical clustering of compounds with a determined activity for this biological target is the Klekota Roth fingerprint combined with the complete linkage function and the Buser similarity metric. PMID:25019251

  14. Drug-induced defaecation in rats: role of central 5-HT1A receptors.

    PubMed Central

    Croci, T.; Landi, M.; Bianchetti, A.; Manara, L.

    1995-01-01

    1. We investigated the acute effects of 5-hydroxytryptamine (5-HT), and of the 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and SR 57746A, on rat faecal pellet output and water content. 2. 5-HT, 8-OH-DPAT, buspirone and SR 57746A, a new selective 5-HT1A receptor agonist, displaced [3H]-8-OH-DPAT from specific binding sites in rat hippocampus membranes (Ki, nM; 1.8, 1.2, 15, 3.1 respectively) and stimulated rat defaecation dose-dependently. SR 57746A and buspirone induced 1 g dry weight of faeces at 1.3 and 6.1 mg kg-1, p.o. (AD1) respectively. 8-OH-DPAT and 5-HT stimulated defaecation after s.c. injection (AD1, 0.07 and 7.5 mg kg-1, respectively). All these agents increased faecal water content. 3. The putative 5-HT1A receptor antagonist, pindolol, injected s.c. or i.c.v., significantly reduced the defaecation induced by systemically administered 8-OH-DPAT, buspirone or SR 57746A, but not 5-HT. 4. Pretreatment with p-chlorophenylalanine (i.p.) or 5,7-dihydroxytryptamine (i.c.v.), according to protocols designed to cause either generalized or CNS-limited 5-HT depletion respectively, also reduced the defaecation induced by buspirone or SR 57746A. 5. No specific 5-HT1A binding sites could be labelled by incubating rat colon membranes with [3H]-8-OH-DPAT, and in vitro preparations of rat colon segments showed no response to 8-OH-DPAT or SR 57746A up to 5 microM. 6. After eight days' repeated daily treatment, complete tolerance developed to the stimulant effects of SR 57746A and buspirone on faecal water content, but not on faecal pellet output.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7647978

  15. The phytocannabinoid, Δ9-tetrahydrocannabivarin, can act through 5-HT1A receptors to produce antipsychotic effects

    PubMed Central

    Cascio, Maria Grazia; Zamberletti, Erica; Marini, Pietro; Parolaro, Daniela; Pertwee, Roger G

    2015-01-01

    Background and Purpose This study aimed to address the questions of whether Δ9-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1A receptors in vitro and (ii) induce any apparent 5-HT1A receptor-mediated antipsychotic effects in vivo. Experimental Approach In vitro studies investigated the effect of THCV on targeting by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) of 5-HT1A receptors in membranes obtained from rat brainstem or human 5-HT1A CHO cells, using [35S]-GTPγS and 8-[3H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated antipsychotic effects in rats. Key Results THCV (i) potently, albeit partially, displaced 8-[3H]-OH-DPAT from specific binding sites in rat brainstem membranes; (ii) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of receptors in these membranes; (iii) produced concentration-related increases in 8-[3H]-OH-DPAT binding to specific sites in membranes of human 5-HT1A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT1A receptors. In phencyclidine-treated rats, THCV, like clozapine (i) reduced stereotyped behaviour; (ii) decreased time spent immobile in the forced swim test; and (iii) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5-HT1A receptor antagonist, WAY100635, or could be reproduced by the CB1 antagonist, AM251. Conclusions and Implications Our findings suggest that THCV can enhance 5-HT1A receptor activation, and that some of its apparent antipsychotic effects may depend on this enhancement. We conclude that THCV has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia. PMID:25363799

  16. Layer II/III of the prefrontal cortex: inhibition by the serotonin 5-HT1A receptor in development and stress

    PubMed Central

    Goodfellow, Nathalie M.; Benekareddy, Madhurima; Vaidya, Vidita A.; Lambe, Evelyn K.

    2009-01-01

    The modulation of the prefrontal cortex by the neurotransmitter serotonin (5-HT) is thought to play a key role in determining adult anxiety levels. Layer II/III of the prefrontal cortex, which mediates communication across cortical regions, displays a of high level 5-HT1A receptor binding in normal individuals and a significantly lower level in patients with mood and anxiety disorders. Here, we examine how serotonin modulates pyramidal neurons in layer II/III of the rat prefrontal cortex throughout postnatal development and in adulthood. Using whole cell recordings in brain slices of the rat medial prefrontal cortex, we observed that serotonin directly inhibits layer II/III pyramidal neurons through 5-HT1A receptors across postnatal development (P6 to P96). In adulthood, a sex difference in these currents emerges, consistent with human imaging studies of 5-HT1A receptor binding. We examined the effects of early life stress on the 5-HT1A receptor currents in layer II/III. Surprisingly, animals subjected to early life stress displayed significantly larger 5-HT1A-mediated outward currents throughout the third and fourth postnatal weeks following elevated 5-HT1A expression during the second postnatal week. Subsequent exposure to social isolation in adulthood resulted in the almost-complete elimination of 5-HT1A currents in layer II/III neurons suggesting an interaction between early life events and adult experiences. These data represent the first examination of functional 5-HT1A receptors in layer II/III of the prefrontal cortex during normal development as well as after stress. PMID:19675243

  17. Differential effects of amyloid-beta 1-40 and 1-42 fibrils on 5-HT1A serotonin receptors in rat brain.

    PubMed

    Verdurand, Mathieu; Chauveau, Fabien; Daoust, Alexia; Morel, Anne-Laure; Bonnefoi, Frédéric; Liger, François; Bérod, Anne; Zimmer, Luc

    2016-04-01

    Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT(1A)R) after intrahippocampal injections of amyloid-beta 1-40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [(18)F]MPPF revealing an overexpression of 5-HT(1A)R in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT(1A)R reactivity by injecting them, separately, into the hippocampus or striatum of rats. [(18)F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT(1A)R in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils-induced 5-HT(1A)R expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed. PMID:26973100

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

    PubMed

    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. PMID:24321837

  19. 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.

    PubMed

    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. PMID:19958758

  20. 5-HT1A receptor agonist-antagonist binding affinity difference as a measure of intrinsic activity in recombinant and native tissue systems

    PubMed Central

    Watson, J; Collin, L; Ho, M; Riley, G; Scott, C; Selkirk, J V; Price, G W

    2000-01-01

    It has been reported that radiolabelled agonist : antagonist binding affinity ratios can predict functional efficacy at several different receptors. This study investigates whether this prediction is true for recombinant and native tissue 5-HT1A receptors. Saturation studies using [3H]-8-OH-DPAT and [3H]-MPPF revealed a single, high affinity site (KD∼1 nM) in HEK293 cells expressing human 5-HT1A receptors and rat cortex. In recombinant cells, [3H]-MPPF labelled 3–4 fold more sites than [3H]-8-OH-DPAT suggesting the presence of more than one affinity state of the receptor. [3H]-Spiperone labelled a single, lower affinity site in HEK293 cells expressing h5-HT1A receptors but did not bind to native tissue 5-HT1A receptors. These data suggest that, in transfected HEK293 cells, human 5-HT1A receptors exist in different affinity states but in native rat cortical tissue the majority of receptors appear to exist in the high agonist affinity state. Receptor agonists inhibited [3H]-MPPF binding from recombinant 5-HT1A receptors in a biphasic manner, whereas antagonists and partial agonists gave monophasic inhibition curves. All compounds displaced [3H]-8-OH-DPAT and [3H]-spiperone binding in a monophasic manner. In rat cortex, all compounds displaced [3H]-MPPF and [3H]-8-OH-DPAT in a monophasic manner. Functional evaluation of compounds, using [35S]-GTPγS binding, produced a range of intrinsic activities from full agonism, displayed by 5-HT and 5-CT to inverse agonism displayed by spiperone. [3H]-8-OH-DPAT : [3H]-MPPF pKi difference correlated well with functional intrinsic activity (r=0.86) as did [3H]-8-OH-DPAT : [3H]-spiperone pKi difference with functional intrinsic activity (r=0.96). Thus agonist : antagonist binding affinity differences may be used to predict functional efficacy at human 5-HT1A receptors expressed in HEK293 cells where both high and low agonist affinity states are present but not at native rat cortical 5-HT1A receptors in which

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

    PubMed

    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

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

    PubMed

    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. PMID:25139282

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

    PubMed

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

    2013-01-01

    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. PMID:24287473

  4. Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study.

    PubMed

    Becker, G; Bolbos, R; Costes, N; Redouté, J; Newman-Tancredi, A; Zimmer, L

    2016-01-01

    Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology. PMID:27211078

  5. Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study

    PubMed Central

    Becker, G.; Bolbos, R.; Costes, N.; Redouté, J.; Newman-Tancredi, A.; Zimmer, L.

    2016-01-01

    Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology. PMID:27211078

  6. 5-HT1a Receptor Antagonists Block Perforant Path-Dentate LTP Induced in Novel, but Not Familiar, Environments

    ERIC Educational Resources Information Center

    Sanberg, Cyndy Davis; Jones, Floretta L.; Do, Viet H.; Dieguez, Dario, Jr.; Derrick, Brian E.

    2006-01-01

    Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated…

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

    PubMed

    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. PMID:25896010

  8. Blockade of dorsolateral pontine 5HT1A receptors destabilizes the respiratory rhythm in C57BL6/J wild-type mice.

    PubMed

    Dhingra, R R; Dutschmann, M; Dick, T E

    2016-06-01

    The neurotransmitter serotonin (5HT) acting via 5HT1a receptors (5HT1aR) is a potent determinant of respiratory rhythm variability. Here, we address the 5HT1aR-dependent control of respiratory rhythm variability in C57BL6/J mice. Using the in situ perfused preparation, we compared the effects of systemic versus focal blockade of 5HT1aRs. Blocking 5HT1aRs in the Kölliker-Fuse nucleus (KFn) increased the occurrence of spontaneous apneas and accounted for the systemic effects of 5HT1aR antagonists. Further, 5HT1aRs of the KFn stabilized the respiratory rhythm's response to arterial chemoreflex perturbations; reducing the recovering time, e.g., the latency to return to the baseline pattern. Together, these results suggest that the KFn regulates both intrinsic and sensory determinants of respiratory rhythm variability. PMID:26840837

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

    PubMed

    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

  10. The Role of 5-HT1A Receptors in Long-Term Adaptation of Newborn Rats to Hypoxia.

    PubMed

    Mikhailenko, V A; Butkevich, I P

    2016-08-01

    We studied the effects of neonatal hypoxia on adaptive behavior of rats during prepubertal and pubertal periods in the control and after repeated injections of 5-HT1A receptor agonist buspirone. Hypoxia enhanced the inflammatory nociceptive response and exacerbated the depressive-like behavior. Repeated injections of buspirone starting from the neonatal period produced a long-term normalizing effect on the inflammatory nociceptive response and psychoemotional behavior disturbed by hypoxia. The protective effect of buspirone can result from strengthening of the adaptive potencies of the serotoninergic system via activation of 5-HT1A receptors that up-regulate secretion of trophic factor S100β under conditions of serotonin deficiency typical of rats exposed to neonatal hypoxia. Buspirone promotes recovery of the afferent and efferent connections of the raphe nuclei with the prefrontal cortex and spinal cord involved in integration of the anti-nociceptive and psychoemotional systems. PMID:27591870

  11. The antipsychotic aripiprazole induces antinociceptive effects: Possible role of peripheral dopamine D2 and serotonin 5-HT1A receptors.

    PubMed

    Almeida-Santos, Ana F; Ferreira, Renata C M; Duarte, Igor D; Aguiar, Daniele C; Romero, Thiago R L; Moreira, Fabricio A

    2015-10-15

    Aripiprazole is an antipsychotic that acts by multiple mechanisms, including partial agonism at dopamine D2 and serotonin 5-HT1A receptors. Since these neurotransmitters also modulate pain and analgesia, we tested the hypothesis that systemic or local administration of aripiprazole induces antinociceptive responses. Systemic aripiprazole (0.1-10 mg/kg; i.p.) injection in mice inhibited formalin-induced paw licking and PGE2-induced hyperalgesia in the paw pressure test. This effect was mimicked by intra-plantar administration (12.5-100 µg/paw) in the ipsi, but not contralateral, paw. The peripheral action of aripiprazole (100 µg/paw) was reversed by haloperidol (0.1-10 µg/paw), suggesting the activation of dopamine receptors as a possible mechanism. Accordingly, quinpirole (25-100 µg/paw), a full agonist at D2/D3 receptors, also reduced nociceptive responses.. In line with the partial agoniztic activity of aripiprazole, low dose of this compound inhibited the effect of quinpirole (both at 25 µg/paw). Finally, peripheral administration of NAN-190 (0.1-10 μg/paw), a 5-HT1A antagonist, also prevented aripiprazole-induced antinociception. In conclusion, systemic or local administration of aripiprazole induces antinociceptive effects. Similar to its antipsychotic activity, the possible peripheral mechanism involves dopamine D2 and serotoninergic 5-HT1A receptors. Aripiprazole and other dopaminergic modulators should be further investigated as new treatments for certain types of pain. PMID:26325094

  12. Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters

    PubMed Central

    Moriya, T; Yoshinobu, Y; Ikeda, M; Yokota, S; Akiyama, M; Shibata, S

    1998-01-01

    Serotonergic projections from the midbrain raphe nuclei to the suprachiasmatic nuclei (SCN) are known to regulate the photic entrainment of circadian clocks. However, it is not known which 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the circadian regulation. In order to verify the role of 5-HT1A receptors, we examined the effects of 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCl (MKC-242), a selective 5-HT1A receptor agonist, on photic entrainment of wheel-running circadian rhythms of hamsters.MKC-242 (3 mg kg−1, i.p.) significantly accelerated the re-entrainment of wheel-running rhythms to a new 8 h delayed or advanced light-dark cycle.MKC-242 (3 mg kg−1, i.p.) also potentiated the phase advance of the wheel-running rhythm produced by low (5 lux) or high (60 lux) intensity light pulses. In contrast, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT)(5 mg kg−1, i.p.), a well known 5-HT1A/5-HT7 receptor agonist, only suppressed low intensity (5 lux) light-induced phase advances.The potentiating actions of MKC-242 on light pulse-induced phase advances were observed even when injected 20 or 60 min after the light exposure.The potentiating action of MKC-242 was antagonized by WAY100635, a selective 5-HT1A receptor blocker, but not by ritanserin, a 5-HT2/5-HT7 receptor blocker, indicating that MKC-242 is activating 5-HT1A receptors.Light pulse-induced c-fos expression in the SCN and the intergeniculate leaflet (IGL) were unaffected by MKC-242 (3 mg kg−1, i.p.).HPLC analysis demonstrated that MKC-242 (3 mg kg−1, i.p.) decreased the 5-HIAA content in the SCN.The present results suggest that presynaptic 5-HT1A receptor activation may be involved in the potentiation of photic entrainment by MKC-242 in hamsters. PMID:9863658

  13. Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters.

    PubMed

    Moriya, T; Yoshinobu, Y; Ikeda, M; Yokota, S; Akiyama, M; Shibata, S

    1998-11-01

    Serotonergic projections from the midbrain raphe nuclei to the suprachiasmatic nuclei (SCN) are known to regulate the photic entrainment of circadian clocks. However, it is not known which 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the circadian regulation. In order to verify the role of 5-HT1A receptors, we examined the effects of 5-¿3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]-propoxy¿-1,3-b enzodioxole HCl (MKC-242), a selective 5-HT1A receptor agonist, on photic entrainment of wheel-running circadian rhythms of hamsters. MKC-242 (3 mg kg(-1), i.p.) significantly accelerated the re-entrainment of wheel-running rhythms to a new 8 h delayed or advanced light-dark cycle. MKC-242 (3 mg kg(-1), i.p.) also potentiated the phase advance of the wheel-running rhythm produced by low (5 lux) or high (60 lux) intensity light pulses. In contrast, 8-hydroxydipropylaminotetralin (8-OH-DPAT)(5 mg kg(-1), i.p.), a well known 5-HT1A/5-HT7 receptor agonist, only suppressed low intensity (5 lux) light-induced phase advances. The potentiating actions of MKC-242 on light pulse-induced phase advances were observed even when injected 20 or 60 min after the light exposure. The potentiating action of MKC-242 was antagonized by WAY100635, a selective 5-HT1A receptor blocker, but not by ritanserin, a 5-HT2/5-HT7 receptor blocker, indicating that MKC-242 is activating 5-HT1A receptors. Light pulse-induced c-fos expression in the SCN and the intergeniculate leaflet (IGL) were unaffected by MKC-242 (3 mg kg(-1), i.p.). HPLC analysis demonstrated that MKC-242 (3 mg kg(-1), i.p.) decreased the 5-HIAA content in the SCN. The present results suggest that presynaptic 5-HT1A receptor activation may be involved in the potentiation of photic entrainment by MKC-242 in hamsters. PMID:9863658

  14. Preclinical profile of the mixed 5-HT1A/5-HT2A receptor antagonist S 21,357.

    PubMed

    Griebel, G; Blanchard, D C; Rettori, M C; Guardiola-Lemaître, B; Blanchard, R J

    1996-06-01

    This study evaluated the pharmacological and behavioral effects of S 21,357, a drug with high affinity for both 5-HT1A and 5-HT2A receptors. The drug behaved as antagonist at both 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, as it prevented the inhibitory effect of lesopitron on the electrical discharge of the dorsal raphé nucleus (DRN) 5-HT neurons and the activity of forskolin-stimulated adenylate cyclase in hippocampal homogenates. In addition, S 21,357 (4 and 128 mg/kg, PO) inhibited 5-HTP-induced head-twitch responses in mice, indicating that it possesses 5-HT2A antagonistic properties. In a test battery designed to assess defensive behaviors of Swiss-Webster mice to the presence of, or situations associated with, a natural threat stimulus (i.e., rat), S 21,357 (0.12-2 mg/kg, IP) reduced contextual defense reactions after the rat was removed, risk assessment activities when the subject was chased, and finally, defensive attack behavior. These behavioral changes are consistent with fear/anxiety reduction. Furthermore, the drug strongly reduced flight reactions in response to the approaching rat. This last finding, taken together with recent results with panic-modulating drugs, suggest that S 21,357 may have potential efficacy against panic attack. Finally, our results suggest that compounds sharing high affinities for both 5-HT1A and 5-HT2A receptors may directly or synergistically increase the range of defensive behaviors affected. PMID:8743616

  15. Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone.

    PubMed

    Hughes, Zoë A; Starr, Kathryn R; Langmead, Christopher J; Hill, Matthew; Bartoszyk, Gerd D; Hagan, James J; Middlemiss, Derek N; Dawson, Lee A

    2005-03-01

    Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPgammaS binding in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic activity comparable to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1-10 mg/kg p.o.) dose-dependently displaced in vivo [3H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo. Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels in frontal cortex of freely moving rats. In contrast, administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.), produced no increase in cortical 5-HT whilst increasing noradrenaline and dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT levels (but no change in noradrenaline or dopamine levels) was observed after combination of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary, vilazodone behaved as a high efficacy partial agonist at the rat hippocampal 5-HT1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo vilazodone induced a selective increase in extracellular levels of 5-HT in the rat frontal cortex. This profile was similar to that seen with a 5-HT1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine. PMID:15740724

  16. A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome

    PubMed Central

    Levitt, Erica S.; Hunnicutt, Barbara J.; Knopp, Sharon J.; Williams, John T.

    2013-01-01

    Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci U S A 107: 18208–18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT1b/d receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release. PMID:24092697

  17. TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling.

    PubMed

    Ye, Dongqing; Li, Yang; Zhang, Xiangrong; Guo, Fei; Geng, Leiyu; Zhang, Qi; Zhang, Zhijun

    2015-12-01

    Current antidepressants often remain the inadequate efficacy for many depressive patients, which warrant the necessary endeavor to develop the new molecules and targets for treating depression. Recently, the two-pore domain potassium channel TREK1 has been implicated in mood regulation and TREK-1 antagonists could be the promising antidepressant. This study has screened a TREK1 blocker (SID1900) with a satisfactory blood-brain barrier permeation and bioavailability. Electrophysiological research has shown that SID1900 and the previously reported TREK1 blocker (spadin) efficiently blocked TREK-1 current in HEK293 cells and specifically blocked two-pore domain potassium channels in primary-cultured rat hippocampal neurons. SID1900 and spadin induced a significant antidepressant-like response in the rat model of chronic unpredictable mild stress (CUMS). Both two TREK1 blockers substantially increased the firing rate of 5-HT-ergic neurons in the dorsal raphe nuclei (DRN) and PFC of CUMS rats. SID1900 and spadin significantly up-regulated the expression of PKA-pCREB-BDNF signaling in DRN, hippocampus and PFC of CUMS rats, which were enhanced and reversed by a 5-HTR1A agonist (8-OH-DPAT) and antagonist (WAY100635) respectively. The present findings suggested that TREK1 channel blockers posses the substantial antidepressant-like effect and have the potential synergistic effect with 5-HT1A receptor activation through the common CREB-BDNF signal transduction. PMID:26441141

  18. 5-HT(1A) receptors transactivate the platelet-derived growth factor receptor type beta in neuronal cells.

    PubMed

    Kruk, Jeff S; Vasefi, Maryam S; Liu, Hui; Heikkila, John J; Beazely, Michael A

    2013-01-01

    In the absence of ligand, certain growth factor receptors can be activated via G-protein coupled receptor (GPCR) activation in a process termed transactivation. Serotonin (5-HT) receptors can transactivate platelet-derived growth factor (PDGF) β receptors in smooth muscle cells, but it is not known if similar pathways occur in neuronal cells. Here we show that 5-HT can transiently increase the phosphorylation of PDGFβ receptors through 5-HT(1A) receptors in a time- and dose-dependent manner in SH-SY5Y neuroblastoma cells. 5-HT also transactivates PDGFβ receptors in primary cortical neurons. This transactivation pathway is pertussis-toxin sensitive and Src tyrosine kinase-dependent. This pathway is also dependent on phospholipase C activity and intracellular calcium signaling. Several studies involving PDGFβ receptor transactivation by GPCRs have also demonstrated a PDGFβ receptor-dependent increase in the phosphorylation of ERK1/2. Yet in SH-SY5Y cells, 5-HT treatment causes a PDGFβ receptor-independent increase in ERK1/2 phosphorylation. This crosstalk between 5-HT and PDGFβ receptors identifies a potentially important signaling link between the serotonergic system and growth factor signaling in neurons. PMID:23006663

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

    PubMed

    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. PMID:26775837

  20. Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors.

    PubMed

    Sagarduy, A; Llorente, J; Miguelez, C; Morera-Herreras, T; Ruiz-Ortega, J A; Ugedo, L

    2016-03-01

    The most effective treatment for Parkinson's disease (PD), l-DOPA, induces dyskinesia after prolonged use. We have previously shown that in 6-hydroxydopamine (6-OHDA) lesioned rats rendered dyskinetic by prolonged l-DOPA administration, lesion of the subthalamic nucleus (STN) reduces not only dyskinesias but also buspirone antidyskinetic effect. This study examined the effect of buspirone on STN neuron activity. Cell-attached recordings in parasagittal slices from naïve rats showed that whilst serotonin excited the majority of STN neurons, buspirone showed an inhibitory main effect but only in 27% of the studied cells which was prevented by the 5-HT1A receptor selective antagonist WAY-100635. Conversely, single-unit extracellular recordings were performed in vivo on STN neurons from four different groups, i.e., control, chronically treated with l-DOPA, 6-OHDA lesioned and lesioned treated with l-DOPA (dyskinetic) rats. In control animals, systemic-buspirone administration decreased the firing rate in a dose-dependent manner in every cell studied. This effect, prevented by WAY-100635, was absent in 6-OHDA lesioned rats and was not modified by prolonged l-DOPA administration. Altogether, buspirone in vivo reduces consistently the firing rate of the STN neurons through 5-HT1A receptors whereas ex vivo buspirone seems to affect only a small population of STN neurons. Furthermore, the lack of effect of buspirone in 6-OHDA lesioned rats, suggests the requirement of not only the activation of 5-HT1A receptors but also an intact nigrostriatal pathway for buspirone to inhibit the STN activity. PMID:26687972

  1. The Functional Activity of the Human Serotonin 5-HT1A Receptor Is Controlled by Lipid Bilayer Composition.

    PubMed

    Gutierrez, M Gertrude; Mansfield, Kylee S; Malmstadt, Noah

    2016-06-01

    Although the properties of the cell plasma membrane lipid bilayer are broadly understood to affect integral membrane proteins, details of these interactions are poorly understood. This is particularly the case for the large family of G protein-coupled receptors (GPCRs). Here, we examine the lipid dependence of the human serotonin 5-HT1A receptor, a GPCR that is central to neuronal function. We incorporate the protein in synthetic bilayers of controlled composition together with a fluorescent reporting system that detects GPCR-catalyzed activation of G protein to measure receptor-catalyzed oligonucleotide exchange. Our results show that increased membrane order induced by sterols and sphingomyelin increases receptor-catalyzed oligonucleotide exchange. Increasing membrane elastic curvature stress also increases this exchange. These results reveal the broad dependence that the 5-HT1A receptor has on plasma membrane properties, demonstrating that membrane lipid composition is a biochemical control parameter and highlighting the possibility that compositional changes related to aging, diet, or disease could impact cell signaling functions. PMID:27276266

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

    PubMed

    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

  3. Sex-specific and region-specific changes in BDNF-TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice.

    PubMed

    Wu, YeeWen Candace; Hill, Rachel A; Klug, Maren; van den Buuse, Maarten

    2012-05-01

    Brain-derived neurotrophic factor (BDNF) and serotonin 5-HT1A receptors are implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs. Here, we explore possible reciprocal interactions of 5-HT1A receptor knockout and the expression of BDNF, its receptor TrkB and downstream mitogen-activated protein kinase (MAPK) in the ventral (VHP) and dorsal hippocampus (DHP). We compared female and male double mutant mice (5-HT1A(-/-)/BDNF(+/-)) with single mutant mice (5-HT1A(-/-), BDNF(+/-)) and wildtype (WT) controls. Protein expression of BDNF, TrkB, phosphorylation of TrkB (pTrkB) and MAPKs (ERK1, ERK2) was examined using Western blot analysis (n=5-7). As expected, the BDNF(+/-) mice showed ~50% BDNF reduction. Loss of 5-HT1A receptors induced a significant decrease in BDNF levels in the VHP in female mice. The pTrkB/TrkB ratio was also significantly decreased in female 5-HT1A(-/-) mice and 5-HT1A(-/-)/BDNF(+/-) mice but not in males. Despite markedly reduced BDNF levels in BDNF(+/-) mice and double mutants, ERK1 activation was unchanged in the female mice. In contrast, ERK2 activation was significantly elevated in the VHP of female BDNF(+/-) mice and double mutants. Given the greater vulnerability of women to develop depression and the role of the VHP in stress responses and anxiety-related behaviours, our results may shed more light on sex differences in depression and other psychiatric disorders with BDNF and 5-HT1A receptor dysfunction. PMID:22464183

  4. Role of maternal 5-HT1A receptor in programming offspring emotional and physical development

    PubMed Central

    van Velzen, Annelies; Toth, Miklos

    2010-01-01

    Serotonin1A receptor (5-HT1AR) deficiency has been associated with anxiety and depression and mice with genetic receptor inactivation exhibit heightened anxiety. We have reported that 5-HT1AR is not only a genetic but also a maternal “environmental” factor in the development of anxiety in Swiss-Webster mice. Here we tested if the emergence of maternal genotype dependent adult anxiety is preceded by early behavioral abnormalities or if it is manifested following a normal emotional development. Pups born to null or heterozygote mothers had significantly reduced ultrasonic vocalization between postnatal day (P) 4 and 12 indicating an influence of the maternal genotype. The offspring’s own genotype had an effect limited to P4. Furthermore, we observed reduced weight gain in the null offspring of null but not heterozygote mothers indicating that a complete maternal receptor deficiency compromises offspring physical development. Except a short perinatal deficit during the dark period, heterozygote females displayed normal maternal behavior which, with the early appearance of ultrasonic vocalization deficit, suggests a role for 5-HT1AR during pre/perinatal development. Consistent with this notion, adult anxiety in the offspring is determined during the pre/perinatal period. In contrast to heterozygote females, null mothers exhibited impaired pup retrieval and nest building that may explain the reduced weight gain of their offspring. Taken together, our data indicate an important role for the maternal 5-HT1AR in regulating offspring emotional and physical development. Since reduced receptor binding has been reported in depression, including postpartum depression, reduced 5-HT1AR function in mothers may influence the emotional development of their offspring. PMID:20633050

  5. 5-HT1A receptors of the rat dorsal raphe lateral wings and dorsomedial subnuclei differentially control anxiety- and panic-related defensive responses.

    PubMed

    Spiacci, Ailton; Pobbe, Roger Luis Henschel; Matthiesen, Melina; Zangrossi, Helio

    2016-08-01

    The dorsal raphe nucleus (DR), the main source of 5-HT projections to brain areas involved in anxiety regulation, is composed by 5 subnuclei that differ morphologically, functionally and neurochemically. Based on immunohistochemical evidence, it has been proposed that whereas 5-HT cells of the dorsomedial (dmDR) and caudal subnuclei are implicated in the pathophysiology of generalized anxiety disorder (GAD), neurons of the lateral wings (lwDR) are associated with panic disorder (PD). We here tested this hypothesis from a behavioral perspective by investigating the consequences of the non-selective stimulation of neurons within the dmDR and lwDR, or the pharmacological manipulation of 5-HT1A receptors located in these nuclei, of male Wistar rats exposed to the elevated T-maze. This test allows the measurement of both a GAD- (i.e. inhibitory avoidance) and a PD- (i.e. escape) related response in the same animal. Intra-dmDR injection of either the excitatory amino acid kainic acid or the 5-HT1A receptor antagonist WAY-100635 facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, and inhibited escape expression, a panicolytic-like effect. Microinjection of the 5-HT1A receptor agonist 8-OH-DPAT caused the opposite effect. Administration of the same drugs into the lwDR only altered escape performance. Whereas kainic acid and 8-OH-DPAT facilitated its expression, WAY-100635 inhibited it. At higher doses, kainic acid administration evoked vigorous escape reactions as measured in an open-field. These findings implicate 5-HT neurons of the dmDR in the regulation of both GAD- and PD-related defensive behaviors. They also support a primary role of the lwDR in the mediation of PD-associated responses. PMID:26145183

  6. 5-HT(1A) receptor antagonist improves behavior performance of delirium rats through inhibiting PI3K/Akt/mTOR activation-induced NLRP3 activity.

    PubMed

    Qiu, Yimin; Huang, Xiaojing; Huang, Lina; Tang, Liang; Jiang, Jihong; Chen, Lianhua; Li, Shitong

    2016-04-01

    Postoperative delirium is a common complication that often results in poor outcomes in surgical and elderly patients. Accumulating evidences suggest that the pathophysiology of delirium results from multiple neurotransmitter system dysfunctions. To further clarify the effects of the selective serotonin (5-HT) (1A) antagonist WAY-100635 on the behaviors in scopolamine induced-delirium rats and to explore the molecular mechanism, in this study, we investigated the change of monoamine levels in the cerebrospinal fluid (CSF) and different brain regions using high-performance liquid chromatography and assessed the behavioral retrieval of delirium rats treated with WAY-100635. It was found that 5-hydroxy-3-indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations in the CSF of scopolamine-induced delirium rats were significantly increased, among which 5-HIAA was also increased in hippocampus and basolateral amygdala (BLA), and 5-HT(1A) receptor was significantly higher in the hippocampuses and BLA than other brain regions. Furthermore, intrahippocampus and intra-BLA stereotactic injection of WAY-100635 improved the delirium-like behavior of rats. Mechanistically, after WAY-100635 treatment, significant reduction of IL-1β release into CSF and NOD-like receptor family, pyrin domain containing 3 (NLRP3) expression, phosphorylated phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and S6K was observed. Altogether, these results suggest that delirium rats induced by scopolamine may be correlated with an increased cerebral concentration of 5-HT and dopamine neurotransmitters system; the selective 5-HT(1A) antagoniszts can reverse the delirium symptoms at some extent through tendering PI3K/Akt/mammalian target of rapamycin complex 1 (mTOR) activation-induced NLRP3 activity and then reducing IL-1β release. © 2016 IUBMB Life, 68(4):311-319, 2016. PMID:26946964

  7. Potentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT(1A) receptors.

    PubMed

    Wang, L-E; Cui, X-Y; Cui, S-Y; Cao, J-X; Zhang, J; Zhang, Y-H; Zhang, Q-Y; Bai, Y-J; Zhao, Y-Y

    2010-05-01

    Previous results have suggested that spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, potentiates pentobarbital-induced sleep via the serotonergic system. The present study investigated whether spinosin potentiates pentobarbital-induced sleep via serotonin-1A (5-hydroxytryptamine, 5-HT(1A)) receptors. The results demonstrated that spinosin significantly augmented pentobarbital (35 mg/kg, i.p.)-induced sleep in rats, reflected by reduced sleep latency and increased total sleep time, non-rapid eye movement (NREM) sleep time, and REM sleep time. With regard to NREM sleep duration, spinosin mainly increased slow-wave sleep (SWS). Additionally, spinosin (15mg/kg, i.g.) significantly antagonized 5-HT(1A) agonist 8-OH-DPAT (0.1mg/kg, i.p.)-induced reductions in total sleep time, NREM sleep, REM sleep, and SWS in pentobarbital-treated rats. These results suggest that spinosin may be an antagonist at postsynaptic 5-HT(1A) receptors because these effects of 8-OH-DPAT were considered to be mediated via postsynaptic 5-HT(1A) receptors. Moreover, co-administration of spinosin and the 5-HT(1A) antagonist 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylbenzamide (p-MPPI), at doses that are ineffective when administered alone (spinosin 5mg/kg, p-MPPI 1mg/kg), had significant augmentative effects on pentobarbital-induced sleep, reflected by reduced sleep latency and increased total sleep time, NREM sleep, and REM sleep. In contrast to the attenuating effects of p-MPPI on REM sleep via presynaptic 5-HT(1A) autoreceptors, 15mg/kg spinosin significantly increased REM sleep. These results suggest that the effect of spinosin on REM sleep in pentobarbital-treated rats may be related to postsynaptic 5-HT(1A) receptors. PMID:20171860

  8. Evaluation of Serotonin 5-HT1A Receptors in Rodent Models using [18F]Mefway PET¶

    PubMed Central

    Saigal, Neil; Bajwa, Alisha K.; Faheem, Sara S.; Coleman, Robert A.; Pandey, Suresh K.; Constantinescu, Cristian C.; Fong, Vanessa; Mukherjee, Jogeshwar

    2013-01-01

    Introduction Serotonin 5-HT1A receptors have been investigated in various CNS disorders, including epilepsy, mood disorders and neurodegeneration. [18F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[18F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [18F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies. Methods Normal Sprague-Dawley rats and Balb/C mice were used for PET/CT imaging using intravenously injected [18F]trans-mefway. Brain PET data were coregistered with rat and mouse magnetic resonance (MR) imaging template and regional distribution of radioactivity was quantitated. Select animals were used for ex vivo autoradiographic studies in order to confirm regional brain distribution and quantitative measures of binding, using brain region to cerebellum ratios. Binding affinity of trans-mefway and WAY-100635 was measured in rat brain homogenates. Distribution of [18F]trans-4-fluoromethylcyclohexane carboxylate ([18F]FMCHA), a major metabolite of [18F] trans-mefway, was assessed in the rat by PET/CT. Results The inhibition constant, Ki for trans-mefway was 0.84 nM and that for WAY-100635 was 1.07 nM. Rapid brain uptake of [18F]trans-mefway was observed in all rat brain regions and clearance from cerebellum was fast and was used as a reference region in all studies. Distribution of [18F]trans-mefway in various brain regions was consistent in PET and in vitro studies. The dorsal raphe was visualized and quantified in the rat PET but identification in the mouse was difficult. The rank order of binding to the various brain regions was hippocampus>frontal cortex>anterior cingulate cortex>lateral septal nuclei>dorsal raphe nuclei. Conclusion [18F]trans-Mefway appears to be an effective 5-HT1A

  9. Selective reduction by isolation rearing of 5-HT1A receptor-mediated dopamine release in vivo in the frontal cortex of mice.

    PubMed

    Ago, Y; Sakaue, M; Baba, A; Matsuda, T

    2002-10-01

    Serotonin (5-HT)1A receptors modulate in vivo release of brain monoaminergic neurotransmitters which may be involved in isolation-induced aggressive behavior. The present study examined the effect of isolation rearing on the 5-HT1A receptor-mediated modulation of dopamine (DA), 5-HT and noradrenaline (NA) release in the frontal cortex of mice. The selective 5-HT1A receptor agonist (S)-5-[-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) increased the release of DA and NA and decreased the release of 5-HT in the frontal cortex of mice. The effect of MKC-242 on DA release was significantly less in isolation-reared mice than in group-reared mice, while effects of the drug on NA and 5-HT release did not differ between both groups. The effect of the other 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin on cortical DA release was also less in isolation-reared mice than in group-reared mice, and that of the drug on cortical 5-HT release did not differ between both groups. In contrast to MKC-242-induced DA release, amphetamine-induced increase in cortical DA release in vivo was greater in isolation-reared mice. The present findings suggest that isolation rearing enhances the activity of cortical dopaminergic neurons and reduces selectively the 5-HT1A receptor-mediated release of DA in the cortex. PMID:12423245

  10. 5-HT1A Receptor Binding is Increased After Recovery from Bulimia Nervosa Compared to Control Women and is Associated with Behavioral Inhibition in Both Groups

    PubMed Central

    Bailer, Ursula F.; Bloss, Cinnamon S.; Frank, Guido K.; Price, Julie C.; Meltzer, Carolyn C.; Mathis, Chester A.; Geyer, Mark A.; Wagner, Angela; Becker, Carl R.; Schork, Nicholas J.; Kaye, Walter H.

    2014-01-01

    Objective Because altered serotonin (5-HT) function appears to persist after recovery from bulimia nervosa (RBN), we investigated the 5-HT1A receptor, which could contribute to regulation of appetite, mood, impulse control, or the response to antidepressants. Method Thirteen RBN individuals were compared to 21 healthy control women (CW) using positron emission tomography and [carbonyl-11C]WAY100635 ([11C]WAY). Results RBN had a 23–34% elevation of [11C]WAY binding potential (BP)P in subgenual cingulate, mesial temporal, and parietal regions after adjustments for multiple comparisons. For CW, [11C]WAY BPP was related negatively to novelty seeking, whereas for RBN, [11C]WAY BPP was related positively to harm avoidance and negatively related to sensation seeking. Discussion Alterations of 5-HT1A receptor function may provide new insight into efficacy of 5-HT medication in BN, as well as symptoms such as the ability to inhibit or self-control the expression of behaviors related to stimulus seeking, aggression, and impulsivity. PMID:20872754

  11. Effects of chronic citalopram treatment on 5-HT1A and 5-HT2A receptors in group- and isolation-housed mice.

    PubMed

    Günther, Lydia; Liebscher, Sabine; Jähkel, Monika; Oehler, Jochen

    2008-09-28

    Selective serotonin reuptake inhibitors (SSRI) are characterized by high clinical effectiveness and good tolerability. A 2-3 week delay in the onset of effects is caused by adaptive mechanisms, probably at the serotonergic (5-HT) receptor level. To analyze this in detail, we measured 5-HT(1A) and 5-HT(2A) receptor bindings in vitro after 3 weeks of citalopram treatment (20 mg/kg i.p. daily) in group-housed as well as isolation-housed mice, reflecting neurobiological aspects seen in psychiatric patients. Isolation housing increased somatodendritic (+52%) and postsynaptic (+30-95%) 5-HT(1A) as well as postsynaptic 5-HT(2A) receptor binding (+25-34%), which confirms previous findings. Chronic citalopram treatment did not induce alterations in raphe 5-HT(1A) autoreceptor binding, independent of housing conditions. Housing-dependent citalopram effects on postsynaptic 5-HT(1A) receptor binding were found with increases in group- (+11-42%) but decreases in isolation-housed (-11 to 35%) mice. Forebrain 5-HT(2A) receptor binding decreased between 11 and 38% after chronic citalopram administration, independent of housing conditions. Citalopram's long-term action comprises alterations at the postsynaptic 5-HT(1A) and 5-HT(2A) receptor binding levels. Housing conditions interact with citalopram effects, especially on 5-HT(1A) receptor binding, and should be more strongly considered in pharmacological studies. In general, SSRI-induced alterations were more pronounced and affected more brain regions in isolates, supporting the concept of a higher responsiveness in "stressed" animals. Isolation-induced receptor binding changes were partly normalized by chronic citalopram treatment, suggesting the isolation housing model for further analyses of SSRI effects, especially at the behavioral level. PMID:18657534

  12. Oestradiol alters central 5HT1A receptor binding potential differences related to psychosocial stress but not differences related to 5HTTLPR genotype in female rhesus monkeys

    PubMed Central

    Michopoulos, Vasiliki; Diaz, Maylen Perez; Embree, Molly; Reding, Kathy; Votaw, John R.; Mun, Jiyoung; Voll, Ronald J.; Goodman, Mark M.; Wilson, Mark; Sanchez, Mar; Toufexis, Donna

    2014-01-01

    Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5HTTLPR) in the regulatory region of the serotonin (5HT) transporter (5HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to what has been described in humans with an analogous 5HTTLPR polymorphism. The present study determined the effects of social status and the 5HTTLPR genotype on 5HT1A receptor binding potential (5HT1A BPND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol (E2) treatment. Areas analyzed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography (PET) using p-[18F]MPPF was performed to determine the levels of 5HT1A BPND under a non-E2 and a 3-wk E2 treatment condition. The short variant (s-variant) 5HTTLPR genotype produced a significant reduction in 5HT1A BPND in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5HT1A BPND within the ACC. Both these effects of 5HTTLPR were unaffected by E2. Additionally, E2 reduced 5HT1A BPND in the dorsal raphe of all females irrespective of psychosocial stress or 5HTTLPR genotype. Hippocampal 5HT1A BPND was attenuated in subordinate females regardless of 5HTTLPR genotype during the non-E2 condition, an effect that was normalised with E2. Similarly, 5HT1A BPND in the hypothalamus was significantly lower in subordinate females regardless of 5HTTLPR genotype, an effect reversed with E2. Together, the data indicate that the effect of E2 on modulation of central 5HT1A BPND may only occur in brain regions that show no 5HTTLPR genotype-linked control of 5HT1A binding. PMID:24382202

  13. Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state.

    PubMed

    Pauwels, P J; Palmier, C; Dupuis, D S; Colpaert, F C

    1998-05-01

    Many 5-HT1B/D receptor ligands have affinity for 5-HT1A receptors. In the present study, the intrinsic activity of a series of 5-HT1B/D ligands was investigated at human 5-HT1A (h 5-HT1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [35S]GTPgammaS binding. In these two membrane preparations, the density of h 5-HT1A receptors (i.e., 246 to 320 fmol mg(-1) protein) and of their G-proteins, and the receptor: G-protein density ratio (0.08 to 0.18) appeared to be similar. It was found that: (i) the maximal [35S]GTPgammaS binding responses induced by the 5-HT1B/D receptor ligands in the HeLa preparation at 30 microM GDP were comparable to that of the native agonist 5-HT; (ii) as compared to 5-HT (1.00), similar potencies but lower maximal responses were observed in the C6-glial preparation at 0.3 microM GDP for zolmitriptan (0.89), dihydroergotamine (0.81), rizatriptan (0.71), CP122638 (0.69), naratriptan (0.60) and sumatriptan (0.53); and that (iii) maximal [35S]GTPgammaS binding responses induced by 5-HT1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration from 0.3 to 30 microM and higher concentrations. These features differ from those observed with 5-HT1A receptor agonists; the latter display the same rank order of potency and efficacy in both membrane preparations, and increasing the amount of GDP with C6-glial membranes results in an attenuation of both the agonist's maximal effect and the apparent potency of partial agonists. The differential regulation of 5-HT1A and 5-HT1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT1A receptor activation by 5-HT1A and 5-HT1B/D agonists. PMID:9650800

  14. Interaction between μ-opioid and 5-HT1A receptors in the regulation of panic-related defensive responses in the rat dorsal periaqueductal grey.

    PubMed

    Rangel, Marcel P; Zangrossi, Hélio; Roncon, Camila M; Graeff, Frederico G; Audi, Elisabeth A

    2014-12-01

    A wealth of evidence indicates that the activation of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal grey matter (dPAG) inhibits escape, a panic-related defensive behaviour. Results that were previously obtained with the elevated T-maze test of anxiety/panic suggest that 5-HT1A and μ-opioid receptors in this midbrain area work together to regulate this response. To investigate the generality of this finding, we assessed whether the same cooperative mechanism is engaged when escape is evoked by a different aversive stimulus electrical stimulation of the dPAG. Administration of the μ-receptor blocker CTOP into the dPAG did not change the escape threshold, but microinjection of the μ-receptor agonist DAMGO (0.3 and 0.5 nmol) or the 5-HT1A receptor agonist 8-OHDPAT (1.6 nmol) increased this index, indicating a panicolytic-like effect. Pretreatment with CTOP antagonised the anti-escape effect of 8-OHDPAT. Additionally, combined administration of subeffective doses of DAMGO and 8-OHDPAT increased the escape threshold, indicating drug synergism. Therefore, regardless of the aversive nature of the stimulus, μ-opioid and 5-HT1A receptors cooperatively act to regulate escape behaviour. A better comprehension of this mechanism might allow for new therapeutic strategies for panic disorder. PMID:25315826

  15. The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression.

    PubMed

    Rahn, K A; Cao, Y-J; Hendrix, C W; Kaplin, A I

    2015-01-01

    Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed. PMID:25942044

  16. The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression

    PubMed Central

    Rahn, K A; Cao, Y-J; Hendrix, C W; Kaplin, A I

    2015-01-01

    Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed. PMID:25942044

  17. Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer's disease: A post-mortem study with PET radiopharmaceuticals.

    PubMed

    Vidal, Benjamin; Sebti, Johan; Verdurand, Mathieu; Fieux, Sylvain; Billard, Thierry; Streichenberger, Nathalie; Troakes, Claire; Newman-Tancredi, Adrian; Zimmer, Luc

    2016-10-01

    PET imaging studies using 5-HT1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radiotracer, which binds selectively to functional receptors, with the PET imaging obtained using an antagonist radiotracer would therefore provide original information on 5-HT1A receptor impairment during AD. Quantitative autoradiography using [(18)F]F13640 and [(18)F]MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of patients with AD (n = 25, at different Braak stages) and control subjects (n = 9). The neuronal density was measured in the same tissues by NeuN immunohistochemistry. The specific binding of both radiotracers was determined by addition of WAY-100635, a selective 5-HT1A receptor antagonist. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was in the pyramidal layer of CA1. Incubation with Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [(18)F]F13640 binding in hippocampal regions, confirming its preferential interaction with G-coupled receptors, and slightly increased [(18)F]MPPF binding. In the CA1 subfield, [(18)F]F13640 binding was significantly decreased at Braak stages I/II (-19%), Braak stages III/IV (-23%), and Braak stages V/VI (-36%) versus control. In contrast, [(18)F]MPPF binding was statistically reduced only at the most advanced Braak stages V/VI compared to control (-33%). Since [(18)F]F13640 and [(18)F]MPPF can be used in vivo in humans, this

  18. Neuropsychopharmacological profile in rodents of SR 57746A, a new, potent 5-HT1A receptor agonist.

    PubMed

    Simiand, J; Keane, P E; Barnouin, M C; Keane, M; Soubrié, P; Le Fur, G

    1993-01-01

    tone and locomotor activity, impairment of motor co-ordination, and potentiation of the effects of centrally-acting sedative-hypnotics. SR 57746A was also inactive as an analgesic in the PBQ writhing test. Thus, SR 57746A is active in a number of tests indicative of 5-HT1A receptor stimulation in vivo, and, more particularly, in a number of tests predictive of anxiolytic, anti-aggressive and antidepressant activities. SR 57746A is as potent as diazepam in anxiolytic tests, and more potent than imipramine in antidepressant tests, whereas it is devoid of neuroleptic potential. In view of this profile of activity, SR 57746A merits evaluation as a potential anxiolytic and antidepressant in humans. PMID:7904976

  19. Effect of Dopaminergic D1 Receptors on Plasticity Is Dependent of Serotoninergic 5-HT1A Receptors in L5-Pyramidal Neurons of the Prefrontal Cortex

    PubMed Central

    Meunier, Claire Nicole Jeanne; Callebert, Jacques; Cancela, José-Manuel; Fossier, Philippe

    2015-01-01

    Major depression and schizophrenia are associated with dysfunctions of serotoninergic and dopaminergic systems mainly in the prefrontal cortex (PFC). Both serotonin and dopamine are known to modulate synaptic plasticity. 5-HT1A receptors (5-HT1ARs) and dopaminergic type D1 receptors are highly represented on dendritic spines of layer 5 pyramidal neurons (L5PyNs) in PFC. How these receptors interact to tune plasticity is poorly understood. Here we show that D1-like receptors (D1Rs) activation requires functional 5HT1ARs to facilitate LTP induction at the expense of LTD. Using 129/Sv and 5-HT1AR-KO mice, we recorded post-synaptic currents evoked by electrical stimulation in layer 2/3 after activation or inhibition of D1Rs. High frequency stimulation resulted in the induction of LTP, LTD or no plasticity. The D1 agonist markedly enhanced the NMDA current in 129/Sv mice and the percentage of L5PyNs displaying LTP was enhanced whereas LTD was reduced. In 5-HT1AR-KO mice, the D1 agonist failed to increase the NMDA current and orientated the plasticity towards L5PyNs displaying LTD, thus revealing a prominent role of 5-HT1ARs in dopamine-induced modulation of plasticity. Our data suggest that in pathological situation where 5-HT1ARs expression varies, dopaminergic treatment used for its ability to increase LTP could turn to be less and less effective. PMID:25775449

  20. Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments.

    PubMed

    Connors, Kristin A; Valenti, Theodore W; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S; Brooks, Bryan W; Gould, Georgianna G

    2014-06-01

    The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitalizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [(3)H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of similarly Gαi/o-coupled cannabinoid receptors. [(3)H] 8-OH-DPAT specific binding was 176±8, 275±32, and 230±36fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [(3)H] WIN55,212-2 binding density was higher in those same brain regions at 6±0.3, 5.5±0.4 and 7.3±0.3pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50mg/L), or dietary exposure to WIN55,212-2 (7μg/week) zebrafish spent more time in and/or entered white arms more often than controls (p<0.05). Acute exposure to WIN55,212-2 at 0.5-50mg/L reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future. PMID:24411165

  1. Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments

    PubMed Central

    Connors, Kristin A.; Valenti, Theodore W.; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S.; Brooks, Bryan W.; Gould, Georgianna G.

    2014-01-01

    The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitolizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [3H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of simalarly Gαi/o-coupled cannabinoid receptors. [3H] 8-OH-DPAT specific binding was 176 ± 8, 275 ± 32, and 230 ± 36 fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [3H] WIN55,212-2 binding density was higher in those same brain regions at 6 ± 0.3, 5.5 ± 0.4 and 7.3 ± 0.3 pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50 mg/L), or dietary exposure to WIN55,212-2 (7 μg/week) zebrafish spent more time in and/or entered white arms more often than controls (p < 0.05). Acute exposure to WIN55,212-2 at 0.5-50 mg/L, reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future. PMID

  2. Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys.

    PubMed

    May, Jesse A; McLaughlin, Marsha A; Sharif, Najam A; Hellberg, Mark R; Dean, Thomas R

    2003-07-01

    Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans. PMID:12676887

  3. Uncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780.

    PubMed

    Mize, A L; Young, L J; Alper, R H

    2003-04-01

    Previously we have shown that 17beta-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin(1A) (5-HT(1A)) receptors, allowing us to hypothesize that 17beta-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17beta-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding (a measure of 5-HT(1A) receptor coupling and function). In both hippocampus and frontal cortex, 17beta-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17beta-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar experiments were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 microM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 (1 microM) blocked the ability of tamoxifen to decrease 5-HT(1A) receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacologically distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT(1A) receptors. PMID:12668044

  4. Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT

    PubMed Central

    Descarries, Laurent; Riad, Mustaph

    2012-01-01

    Serotonin (5-HT) 5-HT1A autoreceptors (5-HT1AautoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT1AautoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT1A radioligand [18F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT1AautoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion. PMID:22826342

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

    PubMed

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

    2015-03-01

    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. PMID:25555143

  6. Long-Term Citalopram Treatment Alters the Stress Responses of the Cortical Dopamine and Noradrenaline Systems: the Role of Cortical 5-HT1A Receptors

    PubMed Central

    Kaneko, Fumi; Kishikawa, Yuki; Hanada, Yuuki; Yamada, Makiko; Kakuma, Tatsuyuki; Kawahara, Hiroshi; Nishi, Akinori

    2016-01-01

    Background: Cortical dopamine and noradrenaline are involved in the stress response. Citalopram, a selective serotonin reuptake inhibitor, has direct and indirect effects on the serotonergic system. Furthermore, long-term treatment with citalopram affects the dopamine and noradrenaline systems, which could contribute to the therapeutic action of antidepressants. Methods: The effects of long-term treatment with citalopram on the responses of the dopamine and noradrenaline systems in the rat prefrontal cortex to acute handling stress were evaluated using in vivo microdialysis. Results: Acute handling stress increased dopamine and noradrenaline levels in the prefrontal cortex. The dopamine and noradrenaline responses were suppressed by local infusion of a 5-HT1A receptor agonist, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol;hydrobromide, into the prefrontal cortex. The dopamine response was abolished by long-term treatment with citalopram, and the abolished dopamine response was reversed by local infusion of a 5-HT1A receptor antagonist, (Z)-but-2-enedioic acid;N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexanecarboxamide into the prefrontal cortex. On the other hand, long-term treatment with citalopram reduced the basal noradrenaline levels (approximately 40% of the controls), but not the basal dopamine levels. The noradrenaline response was maintained despite the low basal noradrenaline levels. Signaling from the 5-HT1A receptors and α2-adrenoceptors was not involved in the decrease in the basal noradrenaline levels but partially affected the noradrenaline response. Conclusions: Chronic citalopram treatment differentially suppresses the dopamine and noradrenaline systems in the prefrontal cortex, and the dopamine stress response was preferentially controlled by upregulating 5-HT1A receptor signaling. Our findings provide insight into how antidepressants modulate the dopamine and noradrenaline systems to overcome acute stress. PMID

  7. Deletion of GIRK2 Subunit of GIRK Channels Alters the 5-HT1A Receptor-Mediated Signaling and Results in a Depression-Resistant Behavior

    PubMed Central

    Llamosas, Nerea; Bruzos-Cidón, Cristina; Rodríguez, José Julio; Ugedo, Luisa

    2015-01-01

    Background: Targeting dorsal raphe 5-HT1A receptors, which are coupled to G-protein inwardly rectifying potassium (GIRK) channels, has revealed their contribution not only to behavioral and functional aspects of depression but also to the clinical response to its treatment. Although GIRK channels containing GIRK2 subunits play an important role controlling excitability of several brain areas, their impact on the dorsal raphe activity is still unknown. Thus, the goal of the present study was to investigate the involvement of GIRK2 subunit-containing GIRK channels in depression-related behaviors and physiology of serotonergic neurotransmission. Methods: Behavioral, functional, including in vivo extracellular recordings of dorsal raphe neurons, and neurogenesis studies were carried out in wild-type and GIRK2 mutant mice. Results: Deletion of the GIRK2 subunit promoted a depression-resistant phenotype and determined the behavioral response to the antidepressant citalopram without altering hippocampal neurogenesis. In dorsal raphe neurons of GIRK2 knockout mice, and also using GIRK channel blocker tertiapin-Q, the basal firing rate was higher than that obtained in wild-type animals, although no differences were observed in other firing parameters. 5-HT1A receptors were desensitized in GIRK2 knockout mice, as demonstrated by a lower sensitivity of dorsal raphe neurons to the inhibitory effect of the 5-HT1A receptor agonist, 8-OH-DPAT, and the antidepressant citalopram. Conclusions: Our results indicate that GIRK channels formed by GIRK2 subunits determine depression-related behaviors as well as basal and 5-HT1A receptor-mediated dorsal raphe neuronal activity, becoming alternative therapeutic targets for psychiatric diseases underlying dysfunctional serotonin transmission. PMID:25956878

  8. Stimulation of 5-HT1A receptors in the dorsal hippocampus and inhibition of limbic seizures induced by kainic acid in rats.

    PubMed Central

    Gariboldi, M.; Tutka, P.; Samanin, R.; Vezzani, A.

    1996-01-01

    1. We studied whether the stimulation of 5-HT1A receptors by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a specific 5-HT1A receptor agonist, reduced electroencephalographic (EEG) seizures induced by intrahippocampal injection of 0.04 microgram in 0.5 microliter of the glutamate analogue kainic acid in freely-moving rats. 2. Pretreatment with 8-OH-DPAT 15 min earlier at the same site as kainic acid injection, caused a dose-dependent decrease of kainic acid-induced seizure activity. One and 10 micrograms significantly reduced the total time spent in seizures by 72% on average and the total number of seizures by 58% (P < 0.01) and 43% (P < 0.05) respectively. The latency to onset of the first seizure was increased 2.8 times (P < 0.01) only after 1 microgram 8-OH-DPAT; 0.1 microgram was ineffective on all seizure parameters. 3. Systemic administration of 25, 100 and 1000 micrograms kg-1 8-OH-DPAT significantly reduced the total number of seizures and the total time in seizures induced by intrahippocampal kainic acid by 52% and 74% on average. The latency to onset of the first seizure was delayed 1.8 times by 100 and 1000 micrograms kg-1 (P < 0.05). 4. The anticonvulsant action of 8-OH-DPAT given intrahippocampally or systemically was significantly blocked by 5 micrograms, but not 1 microgram WAY 100635, a selective 5-HT1A receptor antagonist, administered in the hippocampus before the agonist. 5. These results indicate that postsynaptic 5-HT1A receptors in the hippocampus mediate the anticonvulsant action of 8-OH-DPAT and that their stimulation has an inhibitory role in the generation of limbic seizures. PMID:8922726

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

    PubMed

    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. PMID:26711860

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

    PubMed Central

    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 the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ1–42 induced impairment of neurite outgrowth and spine density, and reversed Aβ1–42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ1–42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway. PMID:26950279

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

    PubMed

    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

    2016-03-22

    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 the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ1-42 induced impairment of neurite outgrowth and spine density, and reversed Aβ1-42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ1-42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway. PMID:26950279

  12. Vilazodone does not inhibit sexual behavior in male rats in contrast to paroxetine: A role for 5-HT1A receptors?

    PubMed

    Oosting, Ronald S; Chan, Johnny S W; Olivier, Berend; Banerjee, Pradeep

    2016-08-01

    Vilazodone (VLZ) is a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. In preclinical studies, VLZ had significantly lower sexual side effects than SSRIs and reduced serotonin transporter (SERT) levels in forebrain regions. In the current study, once-daily paroxetine (PAR, 10 mg/kg), VLZ (10 mg/kg), PAR + buspirone (BUS, 3 mg/kg; a 5-HT1A partial agonist), or vehicle (VEH) was administered to male rats for 2 weeks then switched for 7 days (eg, PAR switched to VLZ, PAR + BUS, or VEH). Sexual behavior (eg, ejaculation frequency and latency) was evaluated 1-hr postdose on days 1, 7, 14, and 21. After 2 weeks, treatment with PAR but not VLZ resulted in a significant decrease in sexual behavior. In a 30-min test, the range of ejaculation frequency was 3.08-3.5 with VLZ and 1.00-1.92 with PAR (P < 0.05 vs VEH). After switching from PAR to VEH, PAR + BUS, or VEH, sexual behaviors were normalized to control levels. In contrast, the switch from VLZ to PAR resulted in reduced sexual behaviors. This preclinical study showed that unlike PAR, an SSRI with no 5-HT1A receptor activity, initial treatment with VLZ did not result in sexual side effects at therapeutically relevant doses. Results in male rats switched from PAR to VLZ or PAR + BUS strongly suggest that activation of 5-HT1A receptors may mitigate the sexual side effects associated with conventional SSRIs. PMID:27040795

  13. Anxiolytic-Like Effects of Chrysanthemum indicum Aqueous Extract in Mice: Possible Involvement of GABAA Receptors and 5-HT1A Receptors.

    PubMed

    Hong, Sa-Ik; Kwon, Seung-Hwan; Kim, Min-Jung; Ma, Shi-Xun; Kwon, Je-Won; Choi, Seung-Min; Choi, Soo-Im; Kim, Sun-Yeou; Lee, Seok-Yong; Jang, Choon-Gon

    2012-07-01

    Chrysanthemum indicum Linne is an ancient herbal medicine used to treat bone and muscle deterioration, ocular infl ammation, headache, and anxiety in Korea, China, and Japan. Furthermore, tea derived from Chrysanthemum indicum Linne has been used to treat anxiety by facilitating relaxation and curing insomnia. However, no reports exist on the anxiolytic-like effects of Chrysanthemum indicum Linne water extract (CWE) in mice. In the present study, we investigated the anxiolytic-like effects of CWE using the elevated plus-maze (EPM) test in mice. CWE, at a dose of 500 mg/kg (p.o.), signifi cantly increased the time spent in the open arms of the EPM compared to a vehicle-injected control group. Moreover, the effect of CWE (500 mg/kg) was blocked by bicuculline (a selective GABAA receptor antagonist) and WAY 100635 (a selective 5-HT1A receptor antagonist). Taken together, these fi ndings suggest that the anxiolytic-like effects of CWE might be mediated by the GABAA receptor and the 5-HT1A receptor. PMID:24009829

  14. Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism.

    PubMed

    Ichikawa, Junji; Dai, Jin; Meltzer, Herbert Y

    2005-07-12

    Anticonvulsant mood stabilizers, e.g., valproic acid and carbamazepine, and atypical antipsychotic drugs (APDs), e.g., clozapine, quetiapine, olanzapine, risperidone, and ziprasidone, have been reported to preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect partially or fully inhibited by WAY100635, a selective 5-HT(1A) antagonist. These atypical APDs have themselves been reported to be effective mood stabilizers, although the importance of increased cortical DA release to mood stabilization has not been established. The purpose of the present study was to determine whether zonisamide, another anticonvulsant mood stabilizer, as well as lithium, a mood stabilizer without anticonvulsant properties, also increases prefrontal cortical DA release and, if so, whether this release is also inhibited by 5-HT(1A) antagonism. As with valproic acid and carbamazepine, zonisamide (12.5 and 25 mg/kg) increased DA release in the mPFC, but not the NAC, an increase abolished by WAY100635 (0.2 mg/kg). However, lithium (100 and 250 mg/kg) decreased DA release in the NAC, an effect also attenuated by WAY100635 (0.2 mg/kg). Lithium itself had no effect in the mPFC but the combination of WAY100635 (0.2 mg/kg) and lithium (100 and 250 mg/kg) markedly increased DA release in the mPFC. Furthermore, M100907 (0.1 mg/kg), a selective 5-HT(2A) antagonist, abolished this increase in DA release in the mPFC. These results indicate that not all mood-stabilizing agents but only those, which have anticonvulsant mood-stabilizing properties, increase DA release in the cortex, and that the effect is dependent upon 5-HT(1A) receptor stimulation. However, the combination of lithium and 5-HT(1A) blockade may result in excessive 5-HT(2A) receptor stimulation, relative to 5-HT(1A) receptor stimulation, both of which can increase prefrontal cortical DA release. PMID:15936730

  15. Autoradiography of serotonin 5-HT1A receptor-activated G proteins in guinea pig brain sections by agonist-stimulated [35S]GTPgammaS binding.

    PubMed

    Dupuis, D S; Palmier, C; Colpaert, F C; Pauwels, P J

    1998-03-01

    G protein activation mediated by serotonin 5-HT1A and 5-HT(1B/D) receptors in guinea pig brain was investigated by using quantitative autoradiography of agonist-stimulated [35S]GTPgammaS binding to brain sections. [35S]GTPgammaS binding was stimulated by the mixed 5-HT1A/5-HT(1B/D) agonist L694247 in brain structures enriched in 5-HT1A binding sites, i.e., hippocampus (+140 +/- 14%), dorsal raphe (+70 +/- 8%), lateral septum (+52 +/- 12%), cingulate (+36 +/- 8%), and entorhinal cortex (+34 +/- 5%). L694247 caused little or no stimulation of [35S]GTPgammaS binding in brain regions with high densities of 5-HT(1B/D) binding sites (e.g., substantia nigra, striatum, central gray, and dorsal subiculum). The [35S]GTPgammaS binding response was antagonized by WAY100635 (10 microM) and methiothepin (10 microM). In contrast, the 5-HT1B inverse agonist SB224289 (10 microM) did not affect the L694247-mediated [35S]GTPgammaS binding response, and the mixed 5-HT(1B/D) antagonist GR127935 (10 microM) yielded a partial blockade. The distribution pattern of the [35S]GTPgammaS binding response and the antagonist profile suggest the L694247-mediated response in guinea pig brain to be mediated by 5-HT1A receptors. In addition to L694247, 8-hydroxy-2-(di-n-propylamino)tetralin, and flesinoxan also stimulated [35S]GTPgammaS binding; their maximal responses varied between 46 and 52% compared with L694247, irrespective of the brain structure being considered. Sumatriptan, rizatriptan, and zolmitriptan (10 microM) stimulated [35S]GTPgammaS binding in the hippocampus by 20-50%. Naratriptan, CP122638, and dihydroergotamine stimulated [35S]GTPgammaS binding to a similar level as L694247 in hippocampus, lateral septum, and dorsal raphe. It appears that under the present experimental conditions, G protein activation through 5-HT1A but not 5-HT(1B/D) receptors can be measured in guinea pig brain sections. PMID:9489749

  16. NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.

    PubMed

    Iderberg, H; McCreary, A C; Varney, M A; Kleven, M S; Koek, W; Bardin, L; Depoortère, R; Cenci, M A; Newman-Tancredi, A

    2015-09-01

    L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance

  17. (3H)WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity

    SciTech Connect

    Norman, A.B.; Battaglia, G.; Creese, I.

    1985-12-01

    In the presence of a 30 nM prazosin mask, (/sup 3/H)-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ((/sup 3/H)WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for (/sup 3/H) WB4101 binding in cerebral cortex. We have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at (/sup 3/H)WB4101-binding sites in the presence of 30 nM prazosin and (/sup 3/H) lysergic acid diethylamide ((/sup 3/H)LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5 mM MgSO4, the Bmax of (/sup 3/H)WB4101 is significantly lower than the Bmax of (/sup 3/H)LSD in various brain regions. WB4101 competition for (/sup 3/H) LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of (/sup 3/H)WB4101 binding derived from saturation experiments. This suggests that (/sup 3/H)WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by (/sup 3/H)LSD. The selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for (/sup 3/H)WB4101 but compete for multiple (/sup 3/H)LSD 5-HT1 binding sites. These data indicate that (/sup 3/H)WB4101 selectively labels the 5-HT1A serotonin receptor, whereas (/sup 3/H) LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of (/sup 3/H)WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of (/sup 3/H)WB4101 binding.

  18. Aggressive Encounters Alter the Activation of Serotonergic Neurons and the Expression of 5-HT1A mRNA in the Hamster Dorsal Raphe Nucleus

    PubMed Central

    Cooper, Matthew A.; Grober, Matthew S.; Nicholas, Christopher; Huhman, Kim L.

    2009-01-01

    Serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) have been implicated in stress-induced changes in behavior. Previous research indicates that stressful stimuli activate 5-HT neurons in select subregions of the DRN. Uncontrollable stress is thought to sensitize 5-HT neurons in the DRN and allow for an exaggerated 5-HT response to future stimuli. In the current study, we tested the hypothesis that following aggressive encounters, losing male Syrian hamsters would exhibit increased c-Fos immunoreactivity in 5-HT DRN neurons compared to winners or controls. In addition, we tested the hypothesis that losers would have decreased 5-HT1A mRNA levels in the DRN compared to winners or controls. We found that a single 15-min aggressive encounter increased c-Fos expression in 5-HT and non-5-HT neurons in losers compared to winners and controls. The increased c-Fos expression in losers was restricted to ventral regions of the rostral DRN. We also found that four 5-min aggressive encounters reduced total 5-HT1A mRNA levels in the DRN in losers compared to winners and controls, and that differences in mRNA levels were not restricted to specific DRN subregions. These results suggest that social defeat activates neurons in select subregions of the DRN and reduces message for DRN 5-HT1A autoreceptors. Our results support the hypothesis that social stress can activate 5-HT neurons in the DRN, reduce 5-HT1A autoreceptor-mediated inhibition, and lead to hyperactivity of 5-HT neurons. PMID:19362123

  19. Age-Dependent Switch of the Role of Serotonergic 5-HT1A Receptors in Gating Long-Term Potentiation in Rat Visual Cortex In Vivo

    PubMed Central

    Gagolewicz, Peter J.; Dringenberg, Hans C.

    2016-01-01

    The rodent primary visual cortex (V1) is densely innervated by serotonergic axons and previous in vitro work has shown that serotonin (5-HT) can modulate plasticity (e.g., long-term potentiation (LTP)) at V1 synapses. However, little work has examined the effects of 5-HT on LTP under in vivo conditions. We examined the role of 5-HT on LTP in V1 elicited by theta burst stimulation (TBS) of the lateral geniculate nucleus in urethane-anesthetized (adult and juvenile) rats. Thalamic TBS consistently induced potentiation of field postsynaptic potentials (fPSPs) recorded in V1. While 5-HT application (0.1–10 mM) itself did not alter LTP levels, the broad-acting 5-HT receptor antagonists methiothepin (1 mM) resulted in a clear facilitation of LTP in adult animals, an effect that was mimicked by the selective 5-HT1A receptor antagonist WAY 100635 (1 mM). Interestingly, in juvenile rats, WAY 100635 application inhibited LTP, indicative of an age-dependent switch in the role of 5-HT1A receptors in gating V1 plasticity. Analyses of spontaneous electrocorticographic (ECoG) activity in V1 indicated that the antagonist-induced LTP enhancement was not related to systematic changes in oscillatory activity in V1. Together, these data suggest a facilitating role of 5-HT1A receptor activation on LTP in the juvenile V1, which switches to a tonic, inhibitory influence in adulthood. PMID:27247804

  20. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation

    PubMed Central

    Bolognini, D; Rock, EM; Cluny, NL; Cascio, MG; Limebeer, CL; Duncan, M; Stott, CG; Javid, FA; Parker, LA; Pertwee, RG

    2013-01-01

    Background and Purpose To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT1A receptor activation in animal models. Experimental Approach We investigated the effect of CBDA on (i) lithium chloride (LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5-HT1A receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB1 receptor activation by CP55940, using [35S]GTPγS-binding assays. Key Results In shrews, CBDA (0.1 and/or 0.5 mg·kg−1 i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg−1 i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5-HT1A receptor antagonist, WAY100635 (0.1 mg·kg−1 i.p.), and, at 0.01 mg·kg−1 i.p., enhanced saccharin palatability. CBDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg−1 i.p.). In vitro, CBDA (0.1–100 nM) increased the Emax of 8-OH-DPAT. Conclusions and Implications Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5-HT1A receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available. PMID:23121618

  1. Activation of GABAA or 5HT1A receptors in the raphé pallidus abolish the cardiovascular responses to exogenous stress in conscious rats.

    PubMed

    Pham-Le, Nhut Minh; Cockburn, Chelsea; Nowell, Katherine; Brown, Justin

    2011-11-25

    Dysfunction in serotonin (5HT) neurotransmission in the brainstem of infants may disrupt protective responses to stress and increase the risk for Sudden Infant Death Syndrome (SIDS). The raphé pallidus (NRP) and other brainstem nuclei are rich in 5HT and are thought to mediate stress responses, including increases in blood pressure (BP) and heart rate (HR). Determining how 5HT neurotransmission in the brainstem mediates responses to stress will help to explain how dysfunction in neurotransmission could increase the risk of SIDS. It was hypothesized that alterations in neurotransmission in the NRP, specifically activation of the 5HT(1A) receptor subtype, would block cardiovascular responses to various types of exogenous stress. Using aseptic techniques, male Sprague-Dawley rats were instrumented with radiotelemetry probes which enabled non-invasive measurement of BP and HR. An indwelling microinjection cannula was also stereotaxically implanted into the NRP for injection of drugs that altered local 5HT neurotransmission. Following a one week recovery period, rats were microinjected with either muscimol (GABA(A) receptor agonist), 8-OH-DPAT (agonist to the inhibitory 5HT(1A) receptor), or a vehicle control (artificial cerebral spinal fluid; ACSF) immediately prior to exposure to one of three stressors: handling, air jet, or restraint. Physical handling and restraint of the animal were designed to elicit a mild and a maximal stress response respectively; while an air jet directed at the rat's face was used to provoke a psychological stress that did not require physical contact. All three stressors elicited similar and significant elevations in HR and BP following ACSF that persisted for at least 15 min with BP and HR elevated by ∼14.0 mmHg and ∼56.3 bpm respectively. The similarity in the stress responses suggest even mild handling of a rat elicits a maximal sympathoexcitatory response. The stress response was abolished following 8-OH-DPAT or muscimol

  2. Higher pretreatment 5-HT1A receptor binding potential in bipolar disorder depression is associated with treatment remission: a naturalistic treatment pilot PET study.

    PubMed

    Lan, Martin J; Hesselgrave, Natalie; Ciarleglio, Adam; Ogden, R Todd; Sullivan, Gregory M; Mann, J John; Parsey, Ramin V

    2013-11-01

    Bipolar disorder is a major cause of disability and a high risk for suicide. The pathophysiology of the disorder remains largely unknown. Medication choice for bipolar depression patients involves trial and error. Our group reported previously that brain serotonin 1A (5-HT(1A)) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5-HT(1A) levels correlates with antidepressant medication outcome. Forty-one medication-free DSM-IV diagnosed, bipolar patients in a major depressive episode had brain PET scans performed using [(11)C]WAY-100635 and a metabolite corrected arterial input function. The patients then received naturalistic psychopharmacologic treatment as outpatients and a follow up Hamilton Depression Rating Scale (HDRS) after 3 months of treatment. Patients with 24 item HDRS scores less than 10 were considered to have remitted. A linear mixed effects model was used to compare BP(F) (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and nonremitters. Thirty-four patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and nonremitters did not differ in age, sex, or recent medication history with serotonergic medications. Remitters had higher [(11)C]WAY-100635 BP(F) across all brain regions compared with nonremitters (P = 0.02). Higher pretreatment brain 5-HT(1A) receptor binding was associated with remission after 3 months of pharmacological treatment in bipolar depression. Prospective treatment studies are warranted to determine whether this test predicts outcome of specific types of treatment. PMID:23720414

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

    PubMed

    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. PMID:23598399

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

    PubMed

    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. PMID:25908624

  5. 5-hydroxytryptamine1A (5-HT1A) receptor agonists: A decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma.

    PubMed

    Cheng, Jeffrey P; Leary, Jacob B; Sembhi, Aerin; Edwards, Clarice M; Bondi, Corina O; Kline, Anthony E

    2016-06-01

    Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led to enhanced motor and/or cognitive performance, the benefits of these treatments have not translated to the clinic. One plausible explanation is that the therapies may not have been rigorously evaluated, thus rendering the bench-to-bedside leap premature and subsequently unsuccessful. An approach that has undergone considerable empirical research after TBI is pharmacological targeting of 5-HT1A receptors with agonists such as repinotan HCl, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and buspirone. The goal of this review is to integrate and interpret the findings from a series of studies that evaluated the efficacy of 5-HT1A receptor agonists on functional, histological, and molecular outcome after acquired brain injury. The overwhelming consensus of this exhaustive review is that a decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID:26612522

  6. Agonist activity of a novel compound, 1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenyl piperazine (BP-554), at central 5-HT1A receptors.

    PubMed

    Matsuda, T; Seong, Y H; Aono, H; Kanda, T; Baba, A; Saito, K; Tobe, A; Iwata, H

    1989-10-24

    We used an in vitro radioligand receptor binding assay with rat cerebral cortex, hippocampus and striatum membrane preparations to show that 1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenyl piperazine (BP-554) had much higher affinity for 5-HT1A recognition sites than for 5-HT1-non-A, 5-HT2, benzodiazepine, dopamine D-2 and alpha 2-adrenergic recognition sites. The compound inhibited the activity of forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Intraperitoneal injection of BP-554 to mice decreased the concentration of only 5-hydroxy-indoleacetic acid of the amines and their metabolites in the brain and decreased the accumulation of 5-hydroxytryptophan in the brain after decarboxylase inhibition by 3-hydroxybenzylhydrazine. Furthermore, the administration of BP-554 caused hypothermia and increased serum corticosterone levels in mice. The observed effects of BP-554 were similar to those of 8-hydroxy-2-(di-n-propylamino)tetralin. These results suggest that BP-554 acts as a selective 5-HT1A receptor agonist in vivo. PMID:2533078

  7. The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements.

    PubMed

    McCreary, Andrew C; Varney, Mark A; Newman-Tancredi, Adrian

    2016-06-01

    Although l-DOPA alleviates the motor symptoms of Parkinson's disease (PD), it elicits troublesome l-DOPA-induced dyskinesia (LID) in a majority of PD patients after prolonged treatment. This is likely due to conversion of l-DOPA to dopamine as a 'false neurotransmitter' from serotoninergic neurons. The highly selective and efficacious 5-HT1A receptor agonist, NLX-112 (befiradol or F13640) shows potent activity in a rat model of LID (suppression of Abnormal Involuntary Movements, AIMs) but its anti-AIMs effects have not previously been investigated following repeated administration. Acute administration of NLX-112 (0.04 and 0.16 mg/kg i.p.) reversed l-DOPA (6 mg/kg)-induced AIMs in hemiparkinsonian rats with established dyskinesia. The activity of NLX-112 was maintained following repeated daily i.p. administration over 14 days and was accompanied by pronounced decrease of striatal 5-HT extracellular levels, as measured by in vivo microdialysis, indicative of the inhibition of serotonergic activity. A concurrent blunting of l-DOPA-induced surge in dopamine levels on the lesioned side of the brain was observed upon NLX-112 administration and these neurochemical responses were also seen after 14 days of treatment. NLX-112 also suppressed the expression of AIMs in rats that were being primed for dyskinesia by repeated l-DOPA administration. However, when treatment of these rats with NLX-112 was stopped, l-DOPA then induced AIMs with scores that resembled those of control rats. The present study shows that the potent anti-AIMs activity of NLX-112 is maintained upon repeated administration and supports the ongoing clinical development of NLX-112 as a novel antidyskinetic agent for PD patients receiving l-DOPA treatment. PMID:26777281

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

    PubMed

    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. PMID:27150816

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

    PubMed

    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

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

    PubMed Central

    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. PMID:27375424

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

    PubMed

    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. PMID:27375424

  12. Chemoproteomic Approach to Explore the Target Profile of GPCR ligands: Application to 5-HT1A and 5-HT6 Receptors.

    PubMed

    Gamo, Ana M; González-Vera, Juan A; Rueda-Zubiaurre, Ainoa; Alonso, Dulce; Vázquez-Villa, Henar; Martín-Couce, Lidia; Palomares, Óscar; López, Juan A; Martín-Fontecha, Mar; Benhamú, Bellinda; López-Rodríguez, María L; Ortega-Gutiérrez, Silvia

    2016-01-22

    Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of G protein-coupled receptor (GPCR) ligands. In this work we have developed a chemoproteomic platform based on the use of chemical probes to explore the target profile of a compound in biological systems. As proof of concept, this methodology has been applied to selected ligands of the therapeutically relevant serotonin 5-HT1A and 5-HT6 receptors, and we have identified and validated some of their off-targets. This approach could be extended to other drugs of interest to study the targeted proteome in disease-relevant systems. PMID:26560738

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

    PubMed

    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. PMID:26062718

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

    PubMed

    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. PMID:26011730

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

    PubMed Central

    Li, Jian; Liu, Qian-tong; Chen, Yi; Liu, Jie; Shi, Jin-li; Liu, Yong; Guo, Jian-you

    2016-01-01

    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. PMID:27298626

  16. 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor mRNA modulation by antidepressant treatment in the chronic mild stress model of depression: sex differences exposed.

    PubMed

    Pitychoutis, P M; Dalla, C; Sideris, A C; Tsonis, P A; Papadopoulou-Daifoti, Z

    2012-05-17

    It is well established that women experience major depression at roughly twice the rate of men. Interestingly, accumulating clinical and experimental evidence shows that the responsiveness of males and females to antidepressant pharmacotherapy, and particularly to tricyclic antidepressants (TCAs), is sex-differentiated. Herein, we investigated whether exposure of male and female rats to the chronic mild stress (CMS) model of depression, as well as treatment with the TCA clomipramine may affect serotonergic receptors' (5-HTRs) mRNA expression in a sex-dependent manner. Male and female rats were subjected to CMS for 4 weeks and during the next 4 weeks they concurrently received clomipramine treatment (10 mg/ml/kg). CMS and clomipramine's effects on 5-HT(1A)R, 5-HT(2A)R, and 5-HT(2C)R mRNA expression were assessed by in situ hybridization histochemistry in selected subfields of the hippocampus and in the lateral orbitofrontal cortex (OFC), two regions implicated in the pathophysiology of major depression. CMS and clomipramine treatment induced sex-differentiated effects on rats' hedonic status and enhanced 5-HT(1A)R mRNA expression in the cornu ammonis 1 (CA1) hippocampal region of male rats. Additionally, CMS attenuated 5-HT(1A)R mRNA expression in the OFC of male rats and clomipramine reversed this effect. Moreover, 5-HT(2A)R mRNA levels in the OFC were enhanced in females but decreased in males, while clomipramine reversed this effect only in females. CMS increased 5-HT2CR mRNA expression in the CA4 region of both sexes and this effect was attenuated by clomipramine. Present data exposed that both CMS and clomipramine treatment may induce sex-differentiated and region-distinctive effects on 5-HTRs mRNA expression and further implicate the serotonergic system in the manifestation of sexually dimorphic neurobehavioral responses to stress. PMID:22441040

  17. Stress sensitization of ethanol withdrawal-induced reduction in social interaction: inhibition by CRF-1 and benzodiazepine receptor antagonists and a 5-HT1A-receptor agonist.

    PubMed

    Breese, George R; Knapp, Darin J; Overstreet, David H

    2004-03-01

    Repeated withdrawals from chronic ethanol sensitize the withdrawal-induced reduction in social interaction behaviors. This study determined whether stress might substitute for repeated withdrawals to facilitate withdrawal-induced anxiety-like behavior. When two 1-h periods of restraint stress were applied at 1-week intervals to rats fed control diet, social interaction was reduced upon withdrawal from a subsequent 5-day exposure to ethanol diet. Neither this ethanol exposure alone nor exposure to three restraint stresses alone altered this measure of anxiety. Further, the repeatedly stressed singly withdrawn rats continued to exhibit a reduction in social interaction 16 days later, upon withdrawal from re-exposure to 5 days of chronic ethanol, consistent with a persistent adaptation by the multiple-stress/withdrawal protocol. Weekly administration of corticosterone in place of stress induced no significant change in social interaction upon withdrawal from the single chronic ethanol exposure, indicative that corticoid release is not responsible for the stress-induced reduction in anxiety-like behavior during withdrawal. In the multiple-withdrawal protocol, stress applied during withdrawal from voluntary ethanol drinking by P-rats facilitated ethanol drinking sufficiently, to induce a withdrawal-induced reduction in social interaction. Administration of a CRF-1 receptor antagonist, a benzodiazepine receptor antagonist, or a 5-HT(1A) receptor agonist prior to each stress minimized sensitization of the withdrawal-induced reduction in anxiety-like behavior. Since these pharmacological consequences on the induction of anxiety-like behavior following the stress/withdrawal protocol are like those previously seen when these drug treatments were given prior to multiple withdrawals, evidence is provided that repeated stresses and multiple withdrawals sensitize the withdrawal reduction in social interaction by similar central adaptive mechanisms. PMID:12955093

  18. Opposing actions of 5HT1A and 5HT2-like serotonin receptors on modulations of the electric signal waveform in the electric fish Brachyhypopomus pinnicaudatus

    PubMed Central

    Allee, Susan J.; Markham, Michael R.; Salazar, Vielka L.; Stoddard, Philip K.

    2008-01-01

    Serotonin (5-HT) is an indirect modulator of the electric organ discharge (EOD) in the weakly electric gymnotiform fish, Brachyhypopomus pinnicaudatus. Injections of 5-HT enhance EOD waveform “masculinity”, increasing both waveform amplitude and the duration of the second phase. This study investigated the pharmacological identity of 5-HT receptors that regulate the electric waveform and their effects on EOD amplitude and duration. We present evidence that two sets of serotonin receptors modulate the EOD in opposite directions. We found that the 5HT1AR agonist 8-OH-DPAT diminishes EOD duration and amplitude while the 5HT1AR antagonist WAY100635 increases these parameters. In contrast, the 5HT2R agonist α-Me-5-HT increases EOD amplitude but not duration, yet 5-HT-induced increases in EOD duration can be inhibited by blocking 5HT2A/2C-like receptors with ketanserin. These results show that 5-HT exerts bi-directional control of EOD modulations in B. pinnicaudatus via action at receptors similar to mammalian 5HT1A and 5HT2 receptors. The discordant amplitude and duration response suggests separate mechanisms for modulating these waveform parameters. PMID:18206154

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

    PubMed

    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. PMID:25446678

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

    PubMed Central

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

    2014-01-01

    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. PMID:25446678

  1. 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.

    PubMed

    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. PMID:23916504

  2. Beneficial effect of the 5-HT1A receptor agonist buspirone on esophageal dysfunction associated with systemic sclerosis: A pilot study

    PubMed Central

    Panopoulos, Stylianos; Karlaftis, Anastasios; Denaxas, Konstantinos; Kamberoglou, Dimitrios; Sfikakis, Petros P; Ladas, Spiros D

    2015-01-01

    Background Esophageal involvement in systemic sclerosis (SSc) carries significant morbidity and is empirically managed with domperidone, albeit with questionable efficacy. The oral 5-HT1A receptor agonist buspirone may enhance esophageal peristalsis and lower esophageal sphincter (LES) function in healthy volunteers. Aim We aimed to test the hypothesis that buspirone may exert a beneficial acute effect on esophageal motor dysfunction in symptomatic patients with SSc. Methods Twenty consecutive patients with SSc reporting esophageal symptoms underwent high-resolution manometry before and 30 minutes after administration of buspirone (10 mg). Ten other patients received domperidone (10 mg) and served as control group. Changes in LES resting and residual pressure, amplitude, duration, and velocity of distal esophageal body contractions were examined. Results Esophageal hypomotility and hypotensive LES was found in 63% and 67% of patients, respectively. Demographic and clinical characteristics, including baseline manometric parameters, were comparable between groups. Resting pressure of LES increased after buspirone from 9.42 ± 2.6 to 11.53 ± 3.4 mmHg (p = 0.0002 by paired t-test), but not after domperidone; a trend for increase of amplitude of contractions was also observed after buspirone (p = 0.09). Comparison of the individual changes revealed that buspirone was superior to domperidone in enhancing LES pressure ( + 2.11 ± 2.0 versus –0.45 ± 2.3 mmHg, p = 0.006). No significant effects of either drug were noted on other examined parameters of esophageal function. Conclusion The beneficial acute effect of buspirone on impaired LES function associated with SSc suggests a role of 5-HT1A receptor-mediated interactions in these patients. Prospective studies to examine whether buspirone is of long-term therapeutic value for SSc-associated esophageal disease are warranted. PMID:26137301

  3. Activation of 5-HT1A receptors in the preBötzinger region has little impact on the respiratory pattern.

    PubMed

    Radocaj, Tomislav; Mustapic, Sanda; Prkic, Ivana; Stucke, Astrid G; Hopp, Francis A; Stuth, Eckehard A E; Zuperku, Edward J

    2015-07-01

    The preBötzinger (preBötC) complex has been suggested as the primary site where systemically administered selective serotonin agonists have been shown to reduce or prevent opioid-induced depression of breathing. However, this hypothesis has not been tested pharmacologically in vivo. This study sought to determine whether 5-HT1A receptors within the preBötC and ventral respiratory column (VRC) mediate the tachypneic response induced by intravenous (IV) (±)-8-Hydroxy-2-diproplyaminotetralin hydrobromide (8-OH-DPAT) in a decerebrated dog model. IV 8-OH-DPAT (19 ± 2 μg/kg) reduced both inspiratory (I) and expiratory (E) durations by ∼ 40%, but had no effect on peak phrenic activity (PPA). Picoejection of 1, 10, and 100 μM 8-OH-DPAT on I and E preBötC neurons produced dose-dependent decreases up to ∼ 40% in peak discharge. Surprisingly, microinjections of 8-OH-DPAT and 5-HT within the VRC from the obex to 9 mm rostral had no effect on timing and PPA. These results suggest that the tachypneic effects of IV 8-OH-DPAT are due to receptors located outside of the areas we studied. PMID:25850079

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

    PubMed

    Kuypers, Kim P C; de la Torre, Rafael; Farre, Magi; Yubero-Lahoz, Samanta; Dziobek, Isabel; Van den Bos, Wouter; Ramaekers, Johannes G

    2014-01-01

    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. PMID:24972084

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

    PubMed Central

    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

  6. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

    PubMed Central

    Seneca, Nicholas; Finnema, Sjoerd J.; Laszlovszky, István; Kiss, Béla; Horváth, Attila; Pásztor, Gabriella; Kapás, Margó; Gyertyán, István; Farkas, Sándor; Innis, Robert B.; Halldin, Christer

    2011-01-01

    Rationale Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D3 and D2 receptors and moderate affinity to serotonin 5-HT1A receptors. Targeting receptors other than D2 may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug. Objectives The objective of this study was to determine dopamine D2/D3 and serotonin 5-HT1A receptor occupancy in monkey brain after the administration of cariprazine. Methods We examined three monkeys using the following PET radioligands: [11C]MNPA (an agonist at D2 and D3 receptors), [11C]raclopride (an antagonist at D2 and D3 receptors), and [11C]WAY-100635 (an antagonist at 5-HT1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose. Results We found that cariprazine occupied D2/D3 receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei. Conclusions We conclude that cariprazine binds preferentially to dopamine D2/D3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans. PMID:21625907

  7. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis.

    PubMed

    Stewart, Adele; Maity, Biswanath; Wunsch, Amanda M; Meng, Fantao; Wu, Qi; Wemmie, John A; Fisher, Rory A

    2014-04-01

    Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT(1A)Rs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT(1A)R-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT(1A)R-expressing cells implicated in mood disorders. RGS6(-/-) mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT(1A)R blockade. Effects of the SSRI fluvoxamine and 5-HT(1A)R agonist 8-OH-DPAT were also potentiated in RGS6(+/-) mice. The phenotype of RGS6(-/-) mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gα(i)-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in RGS6(-/-) animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents. PMID:24421401

  8. 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model.

    PubMed

    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. PMID:23823694

  9. Density and Function of Central Serotonin (5-HT) Transporters, 5-HT1A and 5-HT2A Receptors, and Effects of their Targeting on BTBR T+tf/J Mouse Social Behavior

    PubMed Central

    Gould, Georgianna G.; Hensler, Julie G.; Burke, Teresa F.; Benno, Robert H.; Onaivi, Emmanuel S.; Daws, Lynette C.

    2010-01-01

    BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT1A and 5-HT2A receptor densities among BTBR and C57 strains. Autoradiographic [3H] cyanoimipramine (1nM) binding to SERT was 20–30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates [3H] citalopram maximal binding (Bmax) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (KD) was 2 ± 0.3 nM vs. 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5-HT1A and 5-HT2A receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5-HT1A capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT1A receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5-HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying but failed to improve sociability. Overall, altered SERT and/or 5-HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice. PMID:21070242

  10. 50-kHz calls in rats: effects of MDMA and the 5-HT(1A) receptor agonist 8-OH-DPAT.

    PubMed

    Sadananda, Monika; Natusch, Claudia; Karrenbauer, Britta; Schwarting, Rainer K W

    2012-04-01

    In recent years, 50-kHz ultrasonic vocalizations of laboratory rats have become increasingly important behavioral measures in research on emotion and motivation, since these calls may help to study appetitive subjective states, for example in relation to addiction. Among others, 50-kHz calls occur when rats experience or expect rewards, including drugs of abuse, and it is assumed that these calls depend on dopamine function, especially in the meso-limbic system. One established means to induce 50-kHz calls is to challenge rats with D-amphetamine, a psychomotor stimulant, which acts largely by boosting dopamine and noradrenaline function in the brain. In a 1st experiment, we studied whether another psycho-stimulatory amphetamine, namely the derivative 3,4-methylene-dioxymethamphetamine (MDMA, Ecstasy), could also enhance 50-kHz calls by using an activity box and testing conditions, which had previously been found to be appropriate in case of D-amphetamine. In support of previous work, we found that MDMA (2.5, 5, 10 mg/kg, ip) dose-dependently increased locomotion and center time, together with decreases in rearing activity, but the drug did not elicit 50-kHz calls. Assuming that this lack of effect is due to the drug's substantial pro-serotonergic effects in the brain, which may inhibit 50-kHz calls, we performed a 2nd experiment where we tested the serotonin 5-HT(1A) receptor agonist 8-hydroxy-2-tetralin (8-OH-DPAT; 0.05, 0.5, 2.5 mg/kg, ip). This drug dose-dependently stimulates serotonin autoreceptors and heteroreceptors, can act in a psycho-stimulatory way and can enhance dopamine function. In the activity box, 8-OH-DPAT increased locomotor activity (0.5, 2.5 mg/kg) and decreased rearing (2.5 mg/kg); that is, the drug seemed to share some psycho-stimulatory effects with MDMA. Unlike MDMA, 8-OH-DPAT enhanced 50-kHz calls in a dose-dependent way, namely only with the 0.5 mg/kg dose. These results are discussed with respect to their possible neurochemical

  11. Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice.

    PubMed

    Ase, A R; Reader, T A; Hen, R; Riad, M; Descarries, L

    2000-12-01

    Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts. PMID:11080193

  12. 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.

    PubMed

    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. PMID:24788685

  13. Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D₂ receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.

    PubMed

    Oyamada, Yoshihiro; Horiguchi, Masakuni; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-05-15

    Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism. PMID:25448429

  14. 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; Toward the therapeutics of cognitive impairment of schizophrenia

    PubMed Central

    Uehara, Takashi; Matsuoka, Tadasu; Sumiyoshi, Tomiki

    2014-01-01

    Rationale: Augmentation therapy with serotonin-1A (5-HT1A) receptor partial agonists has been suggested to improve cognitive impairment 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 or 5 mg/kg) on brain energy metabolism, as represented by extracellular lactate concentration (eLAC) in the medial prefrontal cortex (mPFC) of a rat model of schizophrenia. 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 of schizophrenia and related disorders. PMID:25232308

  15. The 5-HT1-like receptors mediating inhibition of sympathetic vasopressor outflow in the pithed rat: operational correlation with the 5-HT1A, 5-HT1B and 5-HT1D subtypes

    PubMed Central

    Villalón, Carlos M; Centurión, David; Rabelo, Gonzalo; de Vries, Peter; Saxena, Pramod R; Sánchez-López, Araceli

    1998-01-01

    It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT1-like receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors.Intravenous (i.v.) continuous infusions of 5-HT and the 5-HT1 receptor agonists, 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP 93,129 (5-HT1B) and sumatriptan (5-HT1B/1D), resulted in a dose-dependent inhibition of sympathetically-induced vasopressor responses.The sympatho-inhibitory responses induced by 5-HT, 8-OH-DPAT, indorenate, CP 93,129 or sumatriptan were analysed before and after i.v. treatment with blocking doses of the putative 5-HT receptor antagonists, WAY 100635 (5-HT1A), cyanopindolol (5-HT1A/1B) or GR 127935 (5-HT1B/1D). Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished.In additional experiments, the inhibition induced by 5-HT was not modified after 5-HT7 receptor blocking doses of mesulergine.The above results suggest that the 5-HT1-like receptors, which inhibit the sympathetic vasopressor outflow in pithed rats, display the pharmacological profile of the 5-HT1A, 5-HT1B and 5-HT1D, but not that of 5-HT7, receptors. PMID:9692787

  16. 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking.

    PubMed

    You, In-Jee; Wright, Sherie R; Garcia-Garcia, Alvaro L; Tapper, Andrew R; Gardner, Paul D; Koob, George F; David Leonardo, E; Bohn, Laura M; Wee, Sunmee

    2016-04-01

    Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction. PMID:26324408

  17. The silent and selective 5-HT1A antagonist, WAY 100635, produces via an indirect mechanism, a 5-HT2A receptor-mediated behaviour in mice during the day but not at night. Short communication.

    PubMed

    Darmani, N A

    1998-01-01

    The head-twitch response (HTR) in rodents is considered to be a functional index for the activation of 5-HT2A receptors. Intraperitoneal administration of the silent and selective 5-HT1A receptor antagonist, WAY 100635, produced the HTR in mice in a dose-dependent bell-shaped manner. The induced behaviour followed a diurnal pattern in that WAY 100635 only produced a robust HTR frequency during the light period of the 24h daily cycle. Pretreatment with the selective 5-HT2A/C receptor antagonist, SR 46349B, potently, and in a dose-dependent manner attenuated the induced behaviour. It appears that WAY 100635 produces the HTR indirectly via disinhibition of endogenous serotonergic inhibitory tone operating on the somatodenritic pulse-modulating 5-HT1A autoreceptors. The latter antagonism seems to potentiate endogenous 5-HT release in serotonergic terminal field synapses which subsequently stimulates postsynaptic 5-HT2A receptors to produce the head-twitch behaviour. PMID:9826108

  18. 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).

    PubMed

    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. PMID:23926240

  19. GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus

    PubMed Central

    McAllister, Carrie E; Mi, Zhen; Mure, Minae; Li, Qian; Muma, Nancy A

    2014-01-01

    Hyperactivity of the hypothalamic-pituitary-adrenal axis is a consistent biological characteristic of depression and response normalization coincides with clinical responsiveness to antidepressant medications. Desensitization of serotonin 1A receptor (5-HT1AR) signaling in the hypothalamic paraventricular nucleus (PVN) follows selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and contributes to the antidepressant response. Estradiol alone produces a partial desensitization of 5-HT1AR signaling, and synergizes with SSRIs to result in a complete and more rapid desensitization than with SSRIs alone as measured by a decrease in the oxytocin and adrenocorticotrophic hormone(ACTH) responses to 5-HT1AR stimulation. G protein-coupled estrogen receptor1 (GPER1) is necessary for estradiol-induced desensitization of 5-HT1AR signaling, although the underlying mechanisms are still unclear. We now find that stimulation of GPER1 with the selective agonist G-1 and non-selective stimulation of estrogen receptors dramatically alter isoform expression of a key component of the 5-HT1AR signaling pathway, RGSz1, a GTPase activating protein selective for Gαz, the Gα subunit necessary for 5-HT1AR-mediated hormone release. RGSz1 isoforms are differentially glycosylated, SUMOylated, and phosphorylated, and differentially distributed in subcellular organelles. High molecular weight RGSz1 is SUMOylated and glycosylated, localized to the detergent-resistant microdomain (DRM) of the cell membrane, and increased by estradiol and G-1 treatment. Because activated Gαz also localizes to the DRM, increased DRM-localized RGSz1 by estradiol and G-1could reduce Gαz activity, functionally uncoupling 5-HT1AR signaling. Peripheral G-1 treatment produced partial reduction in oxytocin and ACTH responses to 5-HT1AR-stimulation similar to direct injections into the PVN. Together, these results identify GPER1 and RGSz1 as novel targets for the treatment of depression. PMID:25402859

  20. Pharmacological evidence that 5-HT1A/1B/1D, α2-adrenoceptors and D2-like receptors mediate ergotamine-induced inhibition of the vasopressor sympathetic outflow in pithed rats.

    PubMed

    Villamil-Hernández, Ma Trinidad; Alcántara-Vázquez, Oscar; Sánchez-López, Araceli; Gutiérrez-Lara, Erika J; Centurión, David

    2014-10-01

    The sympathetic nervous system that innervates the peripheral circulation is regulated by several mechanisms/receptors. It has been reported that prejunctional 5-HT1A, 5-HT1B, 5-HT1D, D2-like receptors and α2-adrenoceptors mediate the inhibition of the vasopressor sympathetic outflow in pithed rats. In addition, ergotamine, an antimigraine drug, displays affinity at the above receptors and may explain some of its adverse/therapeutic effects. Thus, the aims of this study were to investigate in pithed rats: (i) whether ergotamine produces inhibition of the vasopressor sympathetic outflow; and (ii) the major receptors involved in this effect. For this purpose, male Wistar pithed rats were pre-treated with gallamine (25 mg/kg; i.v.) and desipramine (50 µg/kg) and prepared to stimulate the vasopressor sympathetic outflow (T7-T9; 0.03-3 Hz) or to receive i.v. bolus of exogenous noradrenaline (0.03-3 µg/kg). I.v. continuous infusions of ergotamine (1 and 1.8 μg/kgmin) dose-dependently inhibited the vasopressor responses to sympathetic stimulation but not those to exogenous noradrenaline. The sympatho-inhibition elicited by 1.8 μg/kg min ergotamine was (i) unaffected by saline (1 ml/kg); (ii) partially antagonised by WAY 100635 (5-HT1A; 30 μg/kg) and rauwolscine (α2-adrenoceptor; 300 μg/kg), and (iii) dose-dependently blocked by GR 127935 (5-HT1B/1D; 100 and 300 μg/kg) or raclopride (D2-like; 300 and 1000 μg/kg), The above doses of antagonists did not modify per se the sympathetically-induced vasopressor responses. The above results suggest that ergotamine induces inhibition of the vasopressor sympathetic outflow by activation of prejunctional 5-HT1A, 5-HT1B/1D, α2-adrenoceptors and D2-like receptors in pithed rats. PMID:24975101

  1. Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex.

    PubMed

    Dickson, Eamonn J; Heredia, Dante J; Smith, Terence K

    2010-07-01

    The colonic migrating motor complex (CMMC) is necessary for fecal pellet propulsion in the murine colon. We have previously shown that 5-hydroxytryptamine (5-HT) released from enterochromaffin cells activates 5-HT(3) receptors on the mucosal processes of myenteric Dogiel type II neurons to initiate the events underlying the CMMC. Our aims were to further investigate the roles of 5-HT(1A), 5-HT(3), and 5-HT(7) receptor subtypes in generating and propagating the CMMC using intracellular microelectrodes or tension recordings from the circular muscle (CM) in preparations with and without the mucosa. Spontaneous CMMCs were recorded from the CM in isolated murine colons but not in preparations without the mucosa. In mucosaless preparations, ondansetron (3 microM; 5-HT(3) antagonist) plus hexamethonium (100 microM) completely blocked spontaneous inhibitory junction potentials, depolarized the CM. Ondansetron blocked the preceding hyperpolarization associated with a CMMC. Spontaneous CMMCs and CMMCs evoked by spritzing 5-HT (10 and 100 microM) or nerve stimulation in preparations without the mucosa were blocked by SB 258719 or SB 269970 (1-5 microM; 5-HT(7) antagonists). Both NAN-190 and (S)-WAY100135 (1-5 microM; 5-HT(1A) antagonists) blocked spontaneous CMMCs and neurally evoked CMMCs in preparations without the mucosa. Both NAN-190 and (S)-WAY100135 caused an atropine-sensitive depolarization of the CM. The precursor of 5-HT, 5-hydroxytryptophan (5-HTP) (10 microM), and 5-carboxamidotryptamine (5-CT) (5 microM; 5-HT(1/5/7) agonist) increased the frequency of spontaneous CMMCs. 5-HTP and 5-CT also induced CMMCs in preparations with and without the mucosa, which were blocked by SB 258719. 5-HT(1A), 5-HT(3), and 5-HT(7) receptors, most likely on Dogiel Type II/AH neurons, are important in initiating, generating, and propagating the CMMC. Tonic inhibition of the CM appears to be driven by ongoing activity in descending serotonergic interneurons; by activating 5-HT(7

  2. New Multi-target Antagonists of α1A-, α1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure.

    PubMed

    Nascimento-Viana, Jéssica B; Carvalho, Aline R; Nasciutti, Luiz Eurico; Alcántara-Hernández, Rocío; Chagas-Silva, Fernanda; Souza, Pedro A R; Romeiro, Luiz Antonio S; García-Sáinz, J Adolfo; Noël, François; Silva, Claudia Lucia Martins

    2016-01-01

    Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with α1A-adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of α1D-adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT)1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N-phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on- or off-target receptors. LDTs' potency was estimated in intracellular Ca(2+) elevation assays using cells overexpressing human α1-adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs' effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of α1A-, α1D-adrenoceptors, and 5-HT1A receptors (Ki values in the nanomolar range), and fully inhibited phenylephrine- and 5-HT-induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED50 of 0.15 and 0.09 μg.kg(-1), respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment. PMID:26493747

  3. The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT(1A) and 5-HT(2A/C) receptors activation.

    PubMed

    Pytka, Karolina; Walczak, Maria; Kij, Agnieszka; Rapacz, Anna; Siwek, Agata; Kazek, Grzegorz; Olczyk, Adrian; Gałuszka, Adam; Waszkielewicz, Anna; Marona, Henryk; Sapa, Jacek; Filipek, Barbara

    2015-10-01

    Xanthone derivatives have been shown to posses many biological properties. Some of them act within the central nervous system and show neuroprotective or antidepressant-like properties. Taking this into account we investigated antidepressant-like activity in mice and the possible mechanism of action of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-11) - a new xanthone derivative. We demonstrated that HBK-11 produced antidepressant-like effects in the forced swim test and tail suspension test, comparable to that of venlafaxine. The combined treatment with sub-effective doses of HBK-11 and fluoxetine (but not reboxetine or bupropion) significantly reduced the immobility in the forced swim test. Moreover, the antidepressant-like activity of HBK-11 in the aforementioned test was blocked by p-chlorophenylalanine, and significantly reduced by serotonergic 5HT1A receptor antagonist - WAY-1006335 and 5HT2A/C receptor antagonist - ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, it can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant-like effect involves 5HT1A and 5HT2A/C receptor activation. Furthermore, at antidepressant-like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney tests. Considering the pharmacokinetic profile, HBK-11 demonstrated rapid absorption after i.p. administration, high clearance value, short terminal half-life, very high volume of distribution and incomplete bioavailability. The compound studied had good penetration into the brain tissue of mice. Since studied xanthone derivative seems to present interesting, untypical mechanism of antidepressant-like action i.e. 5HT2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies. PMID:26210317

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

    SciTech Connect

    Erdmann, J.; Noethen, M.M.; Shimron-Abarbanell, D.

    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.

  5. Serotonergic 5-HT(1A) receptor agonist (8-OH-DPAT) ameliorates impaired micturition reflexes in a chronic ventral root avulsion model of incomplete cauda equina/conus medullaris injury.

    PubMed

    Chang, Huiyi H; Havton, Leif A

    2013-01-01

    Trauma to the thoracolumbar spine commonly results in injuries to the cauda equina and the lumbosacral portion of the spinal cord. Both complete and partial injury syndromes may follow. Here, we tested the hypothesis that serotonergic modulation may improve voiding function after an incomplete cauda equina/conus medullaris injury. For this purpose, we used a unilateral L5-S2 ventral root avulsion (VRA) injury model in the rat to mimic a partial lesion to the cauda equina and conus medullaris. Compared to a sham-operated series, comprehensive urodynamic studies demonstrated a markedly reduced voiding efficiency at 12 weeks after the VRA injury. Detailed cystometrogram studies showed injury-induced decreased peak bladder pressures indicative of reduced contractile properties. Concurrent external urethral sphincter (EUS) electromyography demonstrated shortened burst and prolonged silent periods associated with the elimination phase. Next, a 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), was administered intravenously at 12 weeks after the unilateral L5-S2 VRA injury. Both voiding efficiency and maximum intravesical pressure were significantly improved by 8-OH-DPAT (0.3-1.0 mg/kg). 8-OH-DPAT also enhanced the amplitude of EUS tonic and bursting activity as well as duration of EUS bursting and silent period during EUS bursting. The results indicate that 8-OH-DPAT improves voiding efficiency and enhances EUS bursting in rats with unilateral VRA injury. We conclude that serotonergic modulation of the 5-HT(1A) receptor may represent a new strategy to improve lower urinary tract function after incomplete cauda equina/conus medullaris injuries in experimental studies. PMID:23099413

  6. Nonphotic entrainment by 5-HT1A/7 receptor agonists accompanied by reduced Per1 and Per2 mRNA levels in the suprachiasmatic nuclei.

    PubMed

    Horikawa, K; Yokota, S; Fuji, K; Akiyama, M; Moriya, T; Okamura, H; Shibata, S

    2000-08-01

    In mammals, the environmental light/dark cycle strongly synchronizes the circadian clock within the suprachiasmatic nuclei (SCN) to 24 hr. It is well known that not only photic but also nonphotic stimuli can entrain the SCN clock. Actually, many studies have shown that a daytime injection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT), a serotonin 1A/7 receptor agonist, as a nonphotic stimulus induces phase advances in hamster behavioral circadian rhythms in vivo, as well as the neuron activity rhythm of the SCN in vitro. Recent reports suggest that mammalian homologs of the Drosophila clock gene, Period (Per), are involved in photic entrainment. Therefore, we examined whether phase advances elicited by 8-OH DPAT were associated with a change of Period mRNA levels in the SCN. In this experiment, we cloned partial cDNAs encoding hamster Per1, Per2, and Per3 and observed both circadian oscillation and the light responsiveness of Period. Furthermore, we found that the inhibitory effect of 8-OH DPAT on hamster Per1 and Per2 mRNA levels in the SCN occurred only during the hamster's mid-subjective day, but not during the early subjective day or subjective night. The present findings demonstrate that the acute and circadian time-dependent reduction of Per1 and/or Per2 mRNA in the hamster SCN by 8-OH DPAT is strongly correlated with the phase resetting in response to 8-OH DPAT. PMID:10908630

  7. 5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.

    PubMed

    Evrard, A; Laporte, A M; Chastanet, M; Hen, R; Hamon, M; Adrien, J

    1999-11-01

    The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A

  8. Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

    PubMed

    Kim, Joung Min; Jeong, Seong Wook; Yang, Jihoon; Lee, Seong Heon; Kim, Woon Mo; Jeong, Seongtae; Bae, Hong Beom; Yoon, Myung Ha; Choi, Jeong Il

    2015-07-23

    Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation. PMID:26037417

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

    PubMed

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

    2016-05-01

    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

  10. 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.

    PubMed

    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. PMID:26477571

  11. 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants

    PubMed Central

    Richardson-Jones, Jesse W; Craige, Caryne P; Guiard, Bruno P; Stephen, Alisson; Metzger, Kayla L; Kung, Hank F; Gardier, Alain M; Dranovsky, Alex; David, Denis J; Beck, Sheryl G; Hen, René; Leonardo, E David

    2010-01-01

    Summary Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT1A) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT1A autoreceptors in raphe nuclei without affecting 5-HT1A heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT1A risk allele. Furthermore, reducing 5-HT1A autoreceptor levels prior to antidepressant treatment is sufficient to convert non-responders into responders. These results establish a causal relationship between 5-HT1A autoreceptor levels, resilience under stress, and response to antidepressants. PMID:20152112

  12. Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression.

    PubMed

    Simon, N G; Cologer-Clifford, A; Lu, S F; McKenna, S E; Hu, S

    1998-01-01

    Our understanding of the neurochemical and neuroendocrine systems' regulating the display of offensive intermale aggression has progressed substantially over the past twenty years. Pharmacological studies have shown that serotonin, via its action at 5HT1A and/or 5HT1B receptor sites, modulates the display of intermale aggressive behavior and that its effects serve to decrease behavioral expression. Neuroendocrine investigations, in turn, have demonstrated that male-typical aggression is testosterone-dependent and studies of genetic effects, metabolic function and steroid receptor binding have shown that facilitation of behavioral displays can occur via independent androgen-sensitive or estrogen-sensitive pathways. Remarkably, there have been virtually no studies that examined the interrelationship between these facilitative and inhibitory systems. As an initial step toward characterizing the interaction between the systems, studies were conducted that assessed hormonal modulation of serotonin function at 5HT1A and 5HT1B receptor sites. They demonstrated: (1) that the androgenic and estrogenic metabolites of testosterone differentially modulate the ability of systemically administered 8-OH-DPAT (a 5HT1A agonist) and CGS12066B (a 5HT1B agonist) to decrease offensive aggression; and (2) when microinjected into the lateral septum (LS) or medial preoptic area (MPO), the aggression-attenuating effects of 1A and 1B agonists differ regionally and vary with the steroidal milieu. In general, the results suggest that estrogens establish a restrictive environment for attenuation of T-dependent aggression by 8-OH-DPAT and CGS 12066B, while androgens either do not inhibit, or perhaps even facilitate, the ability of 5HT1A and 5HT1B agonists to reduce aggression. Potential mechanisms involved in the production of these steroidal effects are discussed and emerging issues that may impact on efforts to develop an integrative neurobiological model of offensive, intermale aggression

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

    PubMed

    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) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-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. PMID:26875114

  14. Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α1 and 5-HT1A receptors.

    PubMed

    Franchini, Silvia; Battisti, Umberto M; Baraldi, Annamaria; Prandi, Adolfo; Fossa, Paola; Cichero, Elena; Tait, Annalisa; Sorbi, Claudia; Marucci, Gabriella; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio

    2014-11-24

    Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α1 or 5-HT1AR ligands. PMID:25261823

  15. Role of the 5-HT1A autoreceptor in the enhancement of fluvoxamine-induced increases in prefrontal dopamine release by adrenalectomy/castration in mice.

    PubMed

    Hasebe, Shigeru; Hiramatsu, Naoki; Ago, Yukio; Mori, Kazuya; Watabe, Yuji; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio

    2015-02-01

    We have found that fluvoxamine-induced increases in prefrontal dopamine release are enhanced by adrenalectomy/castration and 5-HT1A receptors are involved in the enhancement. This study examined which 5-HT1A autoreceptors or postsynaptic receptor play a key role in the enhancement in mice. Adrenalectomy/castration-induced enhancement of fluvoxamine-induced increase in the dopamine release was not blocked by local perfusion with the 5-HT1A receptor antagonist WAY100635 (10 μM), while it was blocked by systemic administration of WAY100635 at low dose (0.1 mg/kg) which blocked preferentially autoreceptor-mediated responses. These finding suggests that 5-HT1A autoreceptors play a key role in the enhancement of prefrontal dopamine release. PMID:25727963

  16. Postnatal maintenance of the 5-Ht1a-Pet1 autoregulatory loop by serotonin in the raphe nuclei of the brainstem

    PubMed Central

    2014-01-01

    Background Despite the importance of 5-HT1A as a major target for the action of several anxiolytics/antidepressant drugs, little is known about its regulation in central serotonin (5-hydroxytryptamine, 5-HT) neurons. Results We report that expression of 5-HT1A and the transcription factor Pet1 was impaired in the rostral raphe nuclei of mice lacking tryptophan hydroxylase 2 (Tph2) after birth. The downregulation of Pet1 was recapitulated in 5-Ht1a -/- mice. Using an explant culture system, we show that reduction of Pet1 and 5-HT1A was rescued in Tph2 -/- brainstem by exogenous 5-HT. In contrast, 5-HT failed to rescue reduced expression of Pet1 in 5-Ht1a -/- brainstem explant culture. Conclusions These results suggest a causal relationship between 5-HT1A and Pet1, and reveal a potential mechanism by which 5-HT1A-Pet1 autoregulatory loop is maintained by 5-HT in a spatiotemporal-specific manner during postnatal development. Our results are relevant to understanding the pathophysiology of certain psychiatric and developmental disorders. PMID:24972638

  17. The 5-HT1A agonists 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rats.

    PubMed

    Dourish, C T; Kennett, G A; Curzon, G

    1987-01-01

    The effects of 5-HT agonists and antagonists, benzodiazepine anxiolytics and tricyclic antidepressants on restraint stress-induced anorexia in rats were examined. The selective 5-HT(1A) agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, when injected 2 h after the termination of stress, attenuated stress-induced anor exia and body weight loss. The effects of 8-OH-DPAT on stress-induced anorexia were blocked by the 5-HT(1A) antagonist spiperone but not by the 5-HT(2) antagonist ketanserin. The preferential 5-HT(1B) agonists RU-24969 and quipazine induced anorexia in unstressed rats and tended to supplement the anorectic effects of stress. The benzodiazepines chlordiazepoxide and diazepam and the 5-HT antagonist cyproheptadine had no effect on stress-induced anorexia, when given (like the 5-HT(1A) agonists) 2 h after the stress. Similarly, daily injection for 2 weeks of the tricyclic antidepressants desipramine and sertraline had no beneficial effect. The data suggest that 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rodents by a hyperphagic action on 5-HT(1A) receptors. PMID:22158750

  18. Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1 mg/kg.

    PubMed

    Zaretsky, Dmitry V; Zaretskaia, Maria V; DiMicco, Joseph A; Rusyniak, Daniel E

    2015-10-01

    Yohimbine is a prototypical alpha2-adrenergic receptor antagonist. Due to its relatively high selectivity, yohimbine is often used in experiments whose purpose is to examine the role of these receptors. For example, yohimbine has been employed at doses of 1-5 mg/kg to reinstate drug-seeking behavior after extinction or to antagonize general anesthesia, an effects presumably being a consequence of blocking alpha2-adrenergic receptors. In this report we characterized dose-dependent autonomic and behavioral effects of yohimbine and its interaction with an antagonist of 5-HT1A receptors, WAY 100,635. In low doses (0.5-2 mg/kg i.p.) yohimbine induced locomotor activation which was accompanied by a tachycardia and mild hypertension. Increasing the dose to 3-4.5 mg/kg reversed the hypertension and locomotor activation and induced profound hypothermia. The hypothermia as well as the suppression of the locomotion and the hypertension could be reversed by the blockade of 5-HT1A receptors with WAY 100635. Our data confirm that yohimbine possesses 5-HT1A properties, and demonstrated that in doses above 1mg/kg significantly activate these receptors. PMID:26366943

  19. 5-HT1A autoreceptor modulation of locomotor activity induced by nitric oxide in the rat dorsal raphe nucleus.

    PubMed

    Gualda, L B; Martins, G G; Müller, B; Guimarães, F S; Oliveira, R M W

    2011-04-01

    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-HT(1A) 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-HT(1A) receptor and the N-methyl-D-aspartate (NMDA) glutamate receptor in the locomotor effects of NO, animals were pretreated with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 8 nmol), the 5-HT(1A) 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; F(7,63) = 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-HT(1A) receptor activation and/or facilitation of glutamate neurotransmission can modulate the locomotor effects induced by NO in the DRN. PMID:21445531

  20. Structural Insights into 5-HT1A/D4 Selectivity of WAY-100635 Analogues: Molecular Modeling, Synthesis, and in Vitro Binding.

    PubMed

    Dilly, Sébastien; Liégeois, Jean-François

    2016-07-25

    The resurgence of interest in 5-HT1A receptors as a therapeutic target requires the existence of highly selective 5-HT1A ligands. To date, WAY-100635 has been the prototypical antagonist of these receptors. However, this compound also has significant affinity for and activity at D4 dopamine receptors. In this context, this work was aimed at better understanding the 5-HT1A/D4 selectivity of WAY-100635 and analogues from a structural point of view. In silico investigations revealed two key interactions for the 5-HT1A/D4 selectivity of WAY-100635 and analogues. First, a hydrogen bond only found with the Ser 7.36 of D4 receptor appeared to be the key for a higher D4 affinity for newly synthesized aza analogues. The role of Ser 7.36 was confirmed as the affinity of aza analogues for the mutant D4 receptor S7.36A was reduced. Then, the formation of another hydrogen bond with the conserved Ser 5.42 residue appeared to be also critical for D4 binding. PMID:27331407

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

    PubMed Central

    Koller, G; Bondy, B; Preuss, UW; Zill, P; Soyka, M

    2006-01-01

    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(-1019)G 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(-1019)G 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(-1019)G 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. PMID:16504134

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

    PubMed Central

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

    2015-01-01

    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 Ki 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. PMID:26171224

  3. Proopiomelanocortin but not vasopressin or renin-angiotensin system induces resuscitative effects of central 5-HT1A activation in haemorrhagic shock in rats.

    PubMed

    Sowa, P; Adamczyk-Sowa, M; Zwirska-Korczala, K; Pierzchala, K; Adamczyk, D; Paluch, Z; Misiolek, M

    2014-10-01

    The aim of this study was to determine the effectory mechanisms: vasopressin, renin-angiotensin system and proopiomelanocortin-derived peptides (POMC), partaking in the effects of serotonin through central serotonin 1A receptor (5-HT1A) receptors in haemorrhagic shock in rats. The study was conducted on male Wistar rats. All experimental procedures were carried out under full anaesthesia. The principal experiment included a 2 hour observation period in haemorrhagic shock. Drugs used - a selective 5-HT1A agonist 8-OH-DPAT (5 μg/5 μl); V1a receptor antagonist [β-mercapto-β, β-cyclo-pentamethylenepropionyl(1),O-me-Tyr(2),Arg(8)]AVP (10 μg/kg); angiotensin type I receptor antagonist (AT1) ZD7155 (0.5 mg/kg, i.v.); angiotensin-converting-enzyme inhibitor captopril (30 mg/kg, i.v.); melanocortin type 4 (MC4) receptor antagonist HS014 (5 μg, i.c.v.). There was no influence of ZD715, captopril or blocking of the V1a receptors on changes in the heart rate (HR), mean arterial pressure (MAP), peripheral blood flow or resistance caused by the central stimulation of 5-HT1A receptors (P≥0.05). However, selective blocking of central MC4 receptors caused a slight, but significant decrease in HR and MAP (P<0.05). POMC derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8-OH-DPAT. The angiotensin and vasopressin systems do not participate in these actions. PMID:25371525

  4. Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus.

    PubMed Central

    Schoeffter, P.; Hoyer, D.

    1988-01-01

    1. A number of centrally acting hypotensive agents and other ligands with high affinity for 5-hydroxytryptamine1A (5-HT1A) recognition sites have been tested on forskolin-stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5-HT1A-receptors. 2. Concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity was elicited by the reference 5-HT1-receptor agonists (mean EC50 value, nM): 5-HT (22), 5-carboxamidotryptamine (5-CT, 3.2), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 8.6), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT, 2.3), 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine (PAPP or LY 165163, 20), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). Emax amounted to 18-20% inhibition for all but the latter two agonists (14%). 3. The following hypotensive agents with high affinity for 5-HT1A sites were potent agonists in this system (mean EC50 value, nM): flesinoxan (24), indorenate (99), erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl )- 2-benzimidazolinone (R 28935, 2.5), urapidil (390) and 5-methyl-urapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60-80% efficacy. 4. Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl- 1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. 5. Spiperone and methiothepin (each 1 microM) caused rightward shifts of the concentration-effect curve to 8-OH-DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 microM) and the

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

    PubMed

    Liu, Jinting; Gong, Pingyuan; Zhou, Xiaolin

    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 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. PMID:25412229

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

    PubMed

    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. PMID:23195401

  7. The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists.

    PubMed

    Childers, Wayne E; Havran, Lisa M; Asselin, Magda; Bicksler, James J; Chong, Dan C; Grosu, George T; Shen, Zhongqi; Abou-Gharbia, Magid A; Bach, Alvin C; Harrison, Boyd L; Kagan, Natasha; Kleintop, Teresa; Magolda, Ronald; Marathias, Vasilios; Robichaud, Albert J; Sabb, Annmarie L; Zhang, Mei-Yi; Andree, Terrance H; Aschmies, Susan H; Beyer, Chad; Comery, Thomas A; Day, Mark; Grauer, Steven M; Hughes, Zoe A; Rosenzweig-Lipson, Sharon; Platt, Brian; Pulicicchio, Claudine; Smith, Deborah E; Sukoff-Rizzo, Stacy J; Sullivan, Kelly M; Adedoyin, Adedayo; Huselton, Christine; Hirst, Warren D

    2010-05-27

    As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment. PMID:20443629

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

    PubMed

    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. PMID:26315784

  9. Differences among conventional, atypical and novel putative D(2)/5-HT(1A) antipsychotics on catalepsy-associated behaviour in cynomolgus monkeys.

    PubMed

    Auclair, Agnès L; Kleven, Mark S; Barret-Grévoz, Catherine; Barreto, Martine; Newman-Tancredi, Adrian; Depoortère, Ronan

    2009-11-01

    Typical antipsychotics such as haloperidol exert their therapeutic effects via blockade of dopamine (DA) D(2) receptors, leading to extrapyramidal symptoms (EPS) in humans and catalepsy in rodents. In contrast, atypical antipsychotics and new generation D(2)/5-HT(1A) antipsychotics have low cataleptogenic potential. However, there has been no systematic comparative study on the effects of these different classes of antipsychotics in non-human primates, a species displaying a more sophisticated repertoire of behavioural/motor activity than rats. Once weekly, six young adult female non-haloperidol-sensitised cynomolgus monkeys were treated i.m. with a test compound and videotaped to score catalepsy-associated behaviour (CAB: static postures, unusual positions and crouching). Haloperidol, risperidone, olanzapine, nemonapride and remoxipride induced, to different extents, an increase in unusual positions (a response akin to dystonia), some crouching and static postures. In contrast, clozapine, quetiapine, ziprasidone and aripiprazole produced much lower or no unusual positions; clozapine also produced marked increases in static postures and crouching. Among novel D(2)/5-HT(1A) antipsychotics, SLV313 and F15063 augmented the number of unusual positions, albeit at doses 16-63 times higher than those of haloperidol for approximately the same score. SSR181507 and bifeprunox produced moderate static postures, little crouching and negligible unusual positions. These data provide the first comparative analysis in cynomolgus monkeys of EPS liability of conventional, atypical and novel D(2)/5-HT(1A) antipsychotics. They indicate that the latter are less prone than haloperidol to produce CAB, and provide a basis for comparison with rodent catalepsy studies. PMID:19464324

  10. Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe 5-HT Neurons

    PubMed Central

    Montalbano, Alberto; Corradetti, Renato; Mlinar, Boris

    2015-01-01

    G protein-activated inwardly rectifying potassium (GIRK) channels in 5-HT neurons are assumed to be principal effectors of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, but their pharmacology, subunit composition and the role in regulation of 5-HT neuron activity have not been fully elucidated. We sought for a pharmacological tool for assessing the functional role of GIRK channels in 5-HT neurons by characterizing the effects of drugs known to block GIRK channels in the submicromolar range of concentrations. Whole-cell voltage-clamp recording in brainstem slices were used to determine concentration-response relationships for the selected GIRK channel blockers on 5-HT1A autoreceptor-activated inwardly rectifying K+ conductance in rat dorsal raphe 5-HT neurons. 5-HT1A autoreceptor-activated GIRK conductance was completely blocked by the nonselective inwardly rectifying potassium channels blocker Ba2+ (EC50 = 9.4 μM, full block with 100 μM) and by SCH23390 (EC50 = 1.95 μM, full block with 30 μM). GIRK-specific blocker tertiapin-Q blocked 5-HT1A autoreceptor-activated GIRK conductance with high potency (EC50 = 33.6 nM), but incompletely, i.e. ~16% of total conductance resulted to be tertiapin-Q-resistant. U73343 and SCH28080, reported to block GIRK channels with submicromolar EC50s, were essentially ineffective in 5-HT neurons. Our data show that inwardly rectifying K+ channels coupled to 5-HT1A autoreceptors display pharmacological properties generally expected for neuronal GIRK channels, but different from GIRK1-GIRK2 heteromers, the predominant form of brain GIRK channels. Distinct pharmacological properties of GIRK channels in 5-HT neurons should be explored for the development of new therapeutic agents for mood disorders. PMID:26460748

  11. Effects of the serotonin 5-HT(2) antagonist, ritanserin, and the serotonin 5-HT(1A) antagonist, WAY 100635, on cocaine-seeking in rats.

    PubMed

    Schenk, S

    2000-10-01

    Manipulations of serotonergic systems have been shown to modify many of the behavioral effects of cocaine. It was recently demonstrated that serotonin (5-HT) depletions produced by inhibition of tryptophan hydroxylase reduced cocaine-seeking in an animal model. The present study was designed to determine whether pretreatment with specific 5-HT antagonists might also decrease cocaine-seeking. The effect of pretreatment with the 5-HT(2) antagonist, ritanserin (0.0, 1.0, or 10.0 mg/kg), or the 5-HT(1A) antagonist, WAY 100635 (0. 0, 0.1, 0.3, or 1.0 mg/kg), on cocaine (5.0, 10.0, or 20.0 mg/kg)-produced reinstatement of extinguished drug-taking behavior was measured. Although ritanserin was ineffective, WAY 100635 attenuated cocaine-produced reinstatement in a dose-dependent manner. These effects of WAY 100635 appeared to be specific since responding maintained by saccharin self-administration remained high following pretreatment with 0.3 or 1.0 mg/kg WAY 100635. These data suggest a role of 5-HT(1A), but not 5-HT(2), receptors in cocaine-seeking. PMID:11124402

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

    PubMed Central

    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

  13. Serotonin receptor 1A knockout: An animal model of anxiety-related disorder

    PubMed Central

    Ramboz, Sylvie; Oosting, Ronald; Amara, Djamel Aït; Kung, Hank F.; Blier, Pierre; Mendelsohn, Monica; Mann, J. John; Brunner, Dani; Hen, René

    1998-01-01

    To investigate the contribution of individual serotonin (5-hydroxytryptamine; 5-HT) receptors to mood control, we have used homologous recombination to generate mice lacking specific serotonergic receptor subtypes. In the present report, we demonstrate that mice without 5-HT1A receptors display decreased exploratory activity and increased fear of aversive environments (open or elevated spaces). 5-HT1A knockout mice also exhibited a decreased immobility in the forced swim test, an effect commonly associated with antidepressant treatment. Although 5-HT1A receptors are involved in controlling the activity of serotonergic neurons, 5-HT1A knockout mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid, possibly because of an up-regulation of 5-HT1B autoreceptors. Heterozygote 5-HT1A mutants expressed approximately one-half of wild-type receptor density and displayed intermediate phenotypes in most behavioral tests. These results demonstrate that 5-HT1A receptors are involved in the modulation of exploratory and fear-related behaviors and suggest that reductions in 5-HT1A receptor density due to genetic defects or environmental stressors might result in heightened anxiety. PMID:9826725

  14. Mast cell expression of the serotonin1A receptor in guinea pig and human intestine.

    PubMed

    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. PMID:23518679

  15. Mast cell expression of the serotonin1A receptor in guinea pig and human intestine

    PubMed Central

    Wang, Guo-Du; Wang, Xi-Yu; Zou, Fei; Qu, Meihua; Liu, Sumei; Fei, Guijun; Xia, Yun; Needleman, Bradley J.; Mikami, Dean J.

    2013-01-01

    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. PMID:23518679

  16. 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.

    PubMed

    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. PMID:25130282

  17. Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists

    PubMed Central

    Abdala, Ana P.; Bissonnette, John M.; Newman-Tancredi, Adrian

    2014-01-01

    Rett syndrome is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Reduced function of this ubiquitous transcriptional regulator has a devastating effect on the central nervous system. One of the most severe and life-threatening presentations of this syndrome is brainstem dysfunction, which results in autonomic disturbances such as breathing deficits, typified by episodes of breathing cessation intercalated with episodes of hyperventilation or irregular breathing. Defects in numerous neurotransmitter systems have been observed in Rett syndrome both in animal models and patients. Here we dedicate special attention to serotonin due to its role in promoting regular breathing, increasing vagal tone, regulating mood, alleviating Parkinsonian-like symptoms and potential for therapeutic translation. A promising new symptomatic strategy currently focuses on regulation of serotonergic function using highly selective serotonin type 1A (5-HT1A) “biased agonists.” We address this newly emerging therapy for respiratory brainstem dysfunction and challenges for translation with a holistic perspective of Rett syndrome, considering potential mood and motor effects. PMID:24910619

  18. The effect of urapidil, an alpha-1 adrenoceptor antagonist and a 5-HT1A agonist, on the vascular tone of the porcine coronary and pulmonary arteries, the rat aorta and the human pulmonary artery.

    PubMed

    Bopp, Claire; Auger, Cyril; Diemunsch, Pierre; Schini-Kerth, Valérie

    2016-05-15

    Urapidil (Eupressyl(®)) an antihypertensive drug acting as an α1 antagonist and a 5-HT1A agonist, may be of special interest in the treatment of hypertension associated with preeclamptic toxaemia and hypoxia-induced pulmonary arterial vasoconstriction. However, the effect of urapidil on vascular tone has been poorly investigated. Vascular reactivity was evaluated using pulmonary and coronary arteries from 36 pigs, aortae from 22 rats and 9 human pulmonary artery samples suspended in organ chambers. Concentration-relaxation curves either to urapidil, 5-HT, or the 5-HT1A receptor agonist 8-OH-DPAT were constructed after pre-contraction of rings. Pig pulmonary and coronary artery rings were contracted with U46619, a thromboxane mimetic, rat aortic rings with either endothelin-1 or phenylephrine, and human pulmonary artery rings with U46619 or phenylephrine. Urapidil markedly inhibited phenylephrine-induced contractions in rat aortic rings with and without endothelium with a more pronounced effect observed in rings without endothelium. Both 5-HT and 8-OH-DPAT failed to induce relaxation in rat aortic rings with an intact endothelium. 5-HT, but not urapidil and 8-OH-DPAT, induced a concentration-dependent relaxation in the porcine coronary and pulmonary artery rings with an intact endothelium (P<0.05). 5-HT and phenylephrine but not urapidil caused concentration-dependent contractions in human pulmonary artery rings. The present findings, while confirming that urapidil is a potent inhibitor of α1-adrenoceptor-induced contraction, do not support the role of 5-HT1A receptor activation in the control of the vascular tone of the different types of arteries tested in response to urapidil. In addition, they indicate that urapidil seems to preferentially target arteries with endothelial dysfunction. PMID:26957055

  19. Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression

    PubMed Central

    Nugent, Allison C; Carlson, Paul J; Bain, Earle E; Eckelman, William; Herscovitch, Peter; Manji, Husseini; Zarate, Carlos A; Drevets, Wayne C

    2013-01-01

    Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([18F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action. PMID:23926239

  20. Synthesis and structure-activity relationships of a new model of arylpiperazines. Part 7: Study of the influence of lipophilic factors at the terminal amide fragment on 5-HT(1A) affinity/selectivity.

    PubMed

    López-Rodríguez, María L; Ayala, David; Viso, Alma; Benhamú, Bellinda; de La Pradilla, Roberto Fernández; Zarza, Fernando; Ramos, José A

    2004-03-15

    The influence of lipophilic factors at the amide fragment of a new series of (+/-)-7a-alkyl-2-[4-(4-arylpiperazin-1-yl)butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 2 and of (+/-)-7a-alkyl-2-[(4-arylpiperazin-1-yl)methyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 3 has been studied. Variations of logP have been carried out by introducing different hydrocarbonated substituents (R(1)) at the position 7a of the bicyclohydantoin, namely the non-pharmacophoric part. All the new compounds exhibit high potency for the 5-HT(1A) receptor; however, affinities for the alpha(1) receptor are high for compounds 2a-l while compounds 3a-f are selective over this adrenergic receptor. On the other hand, differences in logP do not notably affect the K(i) values for the above receptors. PMID:15018929

  1. Allergic sensitization modifies the pulmonary expression of 5-hydroxytryptamine receptors in guinea pigs.

    PubMed

    Córdoba-Rodríguez, Guadalupe; Vargas, Mario H; Ruiz, Víctor; Carbajal, Verónica; Campos-Bedolla, Patricia; Mercadillo-Herrera, Paulina; Arreola-Ramírez, José Luis; Segura-Medina, Patricia

    2016-03-01

    There is mounting evidence that 5-hydroxytryptamine (5-HT) plays a role in asthma. However, scarce information exists about the pulmonary expression of 5-HT receptors and its modification after allergic sensitization. In the present work, we explored the expression of 5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-ht5a, 5-HT6, and 5-HT7 receptors in lungs from control and sensitized guinea pigs through qPCR and Western blot. In control animals, mRNA from all receptors was detectable in lung homogenates, especially from 5-HT2A and 5-HT4 receptors. Sensitized animals had decreased mRNA expression of 5-HT2A and 5-HT4 receptors and increased that of 5-HT7 receptor. In contrast, they had increased protein expression of 5-HT2A receptor in bronchial epithelium and of 5-HT4 receptor in lung parenchyma. The degree of airway response to the allergic challenge was inversely correlated with mRNA expression of the 5-HT1A receptor. In summary, our results showed that major 5-HT receptor subtypes are constitutively expressed in the guinea pig lung, and that allergic sensitization modifies the expression of 5-HT2A, 5-HT4, and 5-HT7 receptors. PMID:26657047

  2. 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).

    PubMed

    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

  3. Characterization of MDL 73005EF as a 5-HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam.

    PubMed Central

    Moser, P. C.; Tricklebank, M. D.; Middlemiss, D. N.; Mir, A. K.; Hibert, M. F.; Fozard, J. R.

    1990-01-01

    1. With radioligand binding techniques, MDL 73005 EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-az aspiro[4, 5]decane-7,9-dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (greater than 100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5-hydroxytryptamine (5-HT)1A recognition site; it was both more potent and more selective than buspirone in this respect. 2. In rats pretreated with reserpine, 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8-OH-DPAT. 3. In rats trained to discriminate 8-OH-DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose-dependently and completely to the 8-OH-DPAT cue. 4. To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus-maze test and in the water-lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water-lick conflict test but opposite effects in the elevated plus-maze. 8-OH-DPAT also had opposite effects in the elevated plus-maze test to MDL 73005EF and diazepam. 5. The anti-conflict effects of MDL 73005EF were reversed by low doses of the 5-HT1A receptor agonist, 8-OH-DPAT; those of buspirone were neither antagonised nor mimicked by 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1970269

  4. Genetic variation in brain-derived neurotrophic factor val66met allele is associated with altered serotonin-1A receptor binding in human brain.

    PubMed

    Lan, Martin J; Ogden, R Todd; Huang, Yung-yu; Oquendo, Maria A; Sullivan, Gregory M; Miller, Jeffrey; Milak, Matthew; Mann, J John; Parsey, Ramin V

    2014-07-01

    Brain Derived Neurotrophic Factor (BDNF) regulates brain synaptic plasticity. BDNF affects serotonin signaling, increases serotonin levels in brain tissue and prevents degeneration of serotonin neurons. These effects have hardly been studied in human brain. We examined the relationship of the functional val66met polymorphism of the BDNF gene to serotonin 1A (5-HT(1A)) receptor binding in vivo. 50 healthy volunteers (HV) and 50 acutely depressed, unmedicated patients with major depressive disorder (MDD) underwent PET scanning with the 5-HT(1A) receptor ligand, [(11)C]WAY-100635 and a metabolite corrected arterial input function. A linear mixed effects model compared 5-HT(1A) receptor binding potential (BP(F), proportional to the number of available receptors) in 13 brain regions of interest between met allele carriers (met/met and val/met) and noncarriers (val/val) using sex and C-1019G genotype of the 5-HT(1A) receptor promoter functional polymorphism as covariates. There was an interaction between diagnosis and allele (F=4.23, df=1, 94, p=0.042), such that met allele carriers had 17.4% lower BP(F) than non-met carriers in the HV group (t=2.6, df=96, p=0.010), but not in the MDD group (t=-0.4, df=96, p=0.58). These data are consistent with a model where the met allele of the val66met polymorphism causes less proliferation of serotonin synapses, and consequently fewer 5-HT(1A) receptors. In MDD, however, the effect of the val66met polymorphism is not detectable, possibly due to a ceiling effect of over-expression of 5-HT(1A) receptors in mood disorders. PMID:24607934

  5. Receptors that couple to 2 classes of G proteins increase cAMP and activate CFTR expressed in Xenopus oocytes.

    PubMed

    Uezono, Y; Bradley, J; Min, C; McCarty, N A; Quick, M; Riordan, J R; Chavkin, C; Zinn, K; Lester, H A; Davidson, N

    1993-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR), a Cl- channel activated by phosphorylation, was expressed in Xenopus oocytes along with various combinations of several other components of the cAMP signalling pathway. Activation of the coexpressed beta 2 adrenergic receptor increased cAMP and led to CFTR activation. The activation of CFTR (1) requires only short (15 s) exposure to isoproterenol, (2) occurs for agonist concentrations 100-1000 fold lower than those that produce cAMP increases detectable by a radioimmunoassay, (3) requires injection of only 5 pg of receptor cRNA per oocyte, and (4) can be increased further by coexpression of cRNA for adenylyl cyclase type II or III or for Gs alpha. In addition, CFTR activation and cAMP increases by beta 2 activation were enhanced by activation of the coexpressed 5HT1A receptor, which is thought to couple to Gi. The additional activation by the 5HT1A receptor was enhanced by coexpression of adenylyl cyclase type II but not with type III and may proceed via the beta gamma subunits of a G protein. The sensitivity of the assay system is also demonstrated by responses to vasoactive intestinal peptide and to pituitary adenylate cyclase-activating polypeptide in oocytes injected with cerebral cortex mRNA. PMID:7522902

  6. The cardiovascular and renal functional responses to the 5-HT1A receptor agonist flesinoxan in two rat models of hypertension.

    PubMed Central

    Chamienia, A. L.; Johns, E. J.

    1996-01-01

    1. This study investigated the importance of renal sympathetic nerves in regulating sodium and water excretion from the kidneys of stroke prone spontaneously hypertensive and 2K1C Goldblatt hypertensive rats anaesthetized with chloralose/urethane (17.5/300 mg initially and supplemented at regular intervals), and prepared for measurement of renal function. 2. In stroke prone spontaneously hypertensive rats, flesinoxan, 30-1000 micrograms kg-1, i.v., caused graded reductions in blood pressure and heart rate of 74 +/- 5 mmHg and 63 +/- 9 beats min-1, respectively at the highest dose (P < 0.001). Renal blood flow did not change at any dose of drug while glomerular filtration rate fell by some 20% (P < 0.001) at the highest dose of drug, absolute and fractional sodium excretions, approximately doubled at 100 micrograms kg-1, and thereafter fell to below the baseline level at 1000 micrograms kg-1. 3. This pattern of excretory response was abolished following acute renal denervation when flesinoxan caused dose-related reductions in urine flow and sodium excretion, similar to that obtained by a mechanical reduction of renal perfusion pressure. 4. Flesinoxan administration (30-1000 micrograms kg-1, i.v.) into 2K1C Goldblatt hypertensive rats caused a maximum decrease in blood pressure and heart rate (both P < 0.001) of 34 +/- 3 mmHg and 20 +/- 6 beats min-1 and while renal blood flow and glomerular filtration rate were autoregulated, from 160 to 125 mmHg, there were dose-related decreases in urine volume and sodium excretion from the clipped and non-clipped kidneys of approximately 50-60% at the highest dose. 5. These findings suggest that in the stroke prone spontaneously hypertensive rat the renal nerves importantly control sodium and water reabsorption at the level of the tubules, whereas in 2K1C Goldblatt hypertensive rats, they play a minor role. PMID:8864520

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

    ERIC Educational Resources Information Center

    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…

  8. Antipsychotic treatment modulates glutamate transport and NMDA receptor expression.

    PubMed

    Zink, Mathias; Englisch, Susanne; Schmitt, Andrea

    2014-11-01

    Schizophrenia patients often suffer from treatment-resistant cognitive and negative symptoms, both of which are influenced by glutamate neurotransmission. Innovative therapeutic strategies such as agonists at metabotropic glutamate receptors or glycin reuptake inhibitors try to modulate the brain's glutamate network. Interactions of amino acids with monoamines have been described on several levels, and first- and second-generation antipsychotic agents (FGAs, SGAs) are known to exert modulatory effects on the glutamatergic system. This review summarizes the current knowledge on effects of FGAs and SGAs on glutamate transport and receptor expression derived from pharmacological studies. Such studies serve as a control for molecular findings in schizophrenia brain tissue and are clinically relevant. Moreover, they may validate animal models for psychosis, foster basic research on antipsychotic substances and finally lead to a better understanding of how monoaminergic and amino acid neurotransmissions are intertwined. In the light of these results, important differences dependent on antipsychotic substances, dosage and duration of treatment became obvious. While some post-mortem findings might be confounded with multifold drug effects, others are unlikely to be influenced by antipsychotic treatment and could represent important markers of schizophrenia pathophysiology. In similarity to the convergence of toxic and psychotomimetic effects of dopaminergic, serotonergic and anti-glutamatergic substances, the therapeutic mechanisms of SGAs might merge on a yet to be defined molecular level. In particular, serotonergic effects of SGAs, such as an agonism at 5HT1A receptors, represent important targets for further clinical research. PMID:25214389

  9. Larvae of the small white butterfly, Pieris rapae, express a novel serotonin receptor.

    PubMed

    Qi, Yi-Xiang; Xia, Ren-Ying; Wu, Ya-Su; Stanley, David; Huang, Jia; Ye, Gong-Yin

    2014-12-01

    The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in vertebrates and invertebrates. It acts in regulation and modulation of many physiological and behavioral processes through G-protein-coupled receptors. Five 5-HT receptor subtypes have been reported in Drosophila that share high similarity with mammalian 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT7 receptors. We isolated a cDNA (Pr5-HT8 ) from larval Pieris rapae, which shares relatively low similarity to the known 5-HT receptor classes. After heterologous expression in HEK293 cells, Pr5-HT8 mediated increased [Ca(2+)]i in response to low concentrations (< 10 nM) of 5-HT. The receptor did not affect [cAMP]i even at high concentrations (> 10 μM) of 5-HT. Dopamine, octopamine, and tyramine did not influence receptor signaling. Pr5-HT8 was also activated by various 5-HT receptor agonists including 5-methoxytryptamine, (±)-8-Hydroxy-2-(dipropylamino) tetralin, and 5-carboxamidotryptamine. Methiothepin, a non-selective 5-HT receptor antagonist, activated Pr5-HT8 . WAY 10635, a 5-HT1A antagonist, but not SB-269970, SB-216641, or RS-127445, inhibited 5-HT-induced [Ca(2+)]i increases. We infer that Pr5-HT8 represents the first recognized member of a novel 5-HT receptor class with a unique pharmacological profile. We found orthologs of Pr5-HT8 in some insect pests and vectors such as beetles and mosquitoes, but not in the genomes of honeybee or parasitoid wasps. This is likely to be an invertebrate-specific receptor because there were no similar receptors in mammals. We isolated a cDNA (Pr5-HT8) from larval Pieris rapae, which shares relatively low similarity to the known GPCRs. After heterologous expression in HEK293 cells, Pr5-HT8 mediated increased [Ca(2+)]i in response to low concentrations (< 10 nM) of 5-HT and various 5-HT receptor agonists. We found orthologs of Pr5-HT8 in some insect pests and vectors such as beetles and mosquitoes, but not in the genomes of honeybee, parasitoid wasps

  10. Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist

    PubMed Central

    Ryals, Renee C.; Ku, Cristy A.; Fischer, Cody M.; Patel, Rachel C.; Datta, Shreya; Yang, Paul; Wen, Yuquan; Hen, René; Pennesi, Mark E.

    2016-01-01

    Purpose 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. Methods 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. Results 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. Conclusions 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

  11. A developmental characterization of mesolimbocortical serotonergic gene expression changes following early immune challenge.

    PubMed

    Sidor, M M; Amath, A; MacQueen, G; Foster, J A

    2010-12-15

    An immunogenic challenge during early postnatal development leads to long-term changes in behavioural and physiological measures reflecting enhanced emotionality and anxiety. Altered CNS serotonin (5-HT) signalling during the third postnatal week is thought to modify the developing neurocircuitry governing anxiety-like behaviour. Changes in 5-HT signalling during this time window may underlie increased emotionality reported in early immune challenge rodents. Here we examine both the spatial and temporal profile of 5-HT related gene expression, including 5HT1A, 2A, 2C receptors, the 5-HT transporter (5HTT), and tryptophan hydroxylase 2 (TPH2) during early development (postnatal day [P]14, P17, P21, P28) in mice challenged with lipopolysaccharide (LPS) during the first postnatal week. Expression levels were measured using in situ hybridization in regions associated with mediating emotive behaviours: the dorsal raphe (DR), hippocampus, amygdala, and prefrontal cortex (PFC). Increased TPH2 and 5HTT expression in the ventrolateral region of the DR of LPS-mice accompanied decreased expression of ventral DR 5HT1A and dorsal DR 5HTT. In the forebrain, 5HT1A and 2A receptors were increased, whereas 5HT2C receptors were decreased in the hippocampus. Decreased mRNA expression of 5HT2C was detected in the amygdala and PFC of LPS-treated pups; 5HT1A was increased in the PFC. The majority of these changes were restricted to P14-21. These transient changes in 5-HT expression coincide with the critical time window in which 5-HT disturbance leads to permanent modification of anxiety-related behaviours. This suggests that alterations in CNS 5-HT during development may underlie the enhanced emotionality associated with an early immune challenge. PMID:20816924

  12. Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats

    PubMed Central

    Kim, Tae-Woon; Lim, Baek-Vin; Kim, Kijeong; Seo, Jin-Hee; Kim, Chang-Ju

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation. PMID:26331133

  13. Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats.

    PubMed

    Kim, Tae-Woon; Lim, Baek-Vin; Kim, Kijeong; Seo, Jin-Hee; Kim, Chang-Ju

    2015-08-01

    Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation. PMID:26331133

  14. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors

    PubMed Central

    Watson, J; Brough, S; Coldwell, M C; Gager, T; Ho, M; Hunter, A J; Jerman, J; Middlemiss, D N; Riley, G J; Brown, A M

    1998-01-01

    Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors.Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidinyl benzilate vs that of [3H]-Oxotremorine-M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5-HT1 and 5-HT2 receptor subtypes.Carbachol and xanomeline stimulated basal [35S]-GTPγS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline-induced stimulation of [35S]-GTPγS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 μM and was inhibited by the selective 5-HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5-HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors.In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca2+ concentration in cells expressing h5

  15. 5-Hydroxytryptamine 1A and 2B serotonin receptors in neurite outgrowth: involvement of early growth response protein 1.

    PubMed

    Anelli, Tonino; Cardarelli, Silvia; Ori, Michela; Nardi, Irma; Biagioni, Stefano; Poiana, Giancarlo

    2013-01-01

    Neurotransmitters play important roles in neurogenesis; in particular, acetylcholine and serotonin may regulate neurite elongation. Acetylcholine may also activate transcription factors such as early growth response protein 1 (EGR-1), which plays a role in neurite extension. N18TG2 neuroblastoma cells (which do not produce neurotransmitters and constitutively express muscarinic acetylcholine receptors) were transfected with constructs containing the cDNA for choline acetyltransferase, 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2B serotonin receptors to study acetylcholine and serotonin interplay in neurite outgrowth. 5-HT1A receptor stimulation causes a decrease in EGR-1 levels and inhibition of neurite outgrowth; 5-HT2B stimulation, however, has no effect. Muscarinic cholinergic stimulation, on the other end, increases EGR-1 levels and fiber outgrowth. Inhibition of EGR-1 binding reduces fiber outgrowth activity. When both cholinergic and 5-HT1A receptors are stimulated, fiber outgrowth is restored; therefore, acetylcholine counterbalances the inhibitory effect of serotonin on neurite outgrowth. These results suggest that EGR-1 plays a role in the interplay of acetylcholine and serotonin in the regulation of neurite extension during development. PMID:24158140

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

    PubMed Central

    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

  17. Food intake inhibition in rainbow trout induced by activation of serotonin 5-HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.

    PubMed

    Pérez-Maceira, Jorge J; Otero-Rodiño, Cristina; Mancebo, María J; Soengas, José L; Aldegunde, Manuel

    2016-04-01

    In rainbow trout, the food intake inhibition induced by serotonin occurs through 5-HT2C and 5-HT1A receptors, though the mechanisms involved are still unknown. Therefore, we assessed if a direct stimulation of 5-HT2C and 5-HT1A serotonin receptors (resulting in decreased food intake in rainbow trout), affects gene expression of neuropeptides involved in the control of food intake, such as pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), corticotrophin releasing factor (CRF), and agouti-related peptide (AgRP). In a first set of experiments, the injection of the 5-HT2C receptor agonists MK212 (60 μg kg(-1) icv) and WAY 161503 (1 mg kg(-1) ip), and of the 5-HT1A receptor agonist 8-OH-DPAT (1 mg kg(-1) ip and 30 μg kg(-1) icv) induced food intake inhibition. In a second set of experiments, we observed that the injection of MK212 or WAY 161503 (1 and 3 mg kg(-1)) significantly increased hypothalamic POMC mRNA abundance. CART mRNA abundance in hypothalamus was enhanced by treatment with MK212 and unaffected by WAY 161503. The administration of the 5-HT1A receptor agonist 8-OH-DPAT did not induce any significant variation in the hypothalamic POMC or CART mRNA levels. CRF mRNA abundance was only affected by MK212 that increased hypothalamic values. Finally, hypothalamic AgRP mRNA abundance was only evaluated with the agonist 5-HT2C MK212 resulting in no significant effects. The results show that the reduction in food intake mediated by 5-HT2C receptors is associated with increases in hypothalamic POMC, CART and CRF mRNA abundance. PMID:26832922

  18. [The role of brain serotonin in the expression of genetically determined defensive behavior].

    PubMed

    Popova, N K

    2004-06-01

    The review summarizes the results of long-term studies on the role of the brain mediator serotonin and genetic predisposition to various types of defensive behavior. The involvement of the serotonergic brain system in the mechanisms of genetic control of both active and passive defensive responses has been established using silver foxes, Norway rats of S40 selection for low and high aggressiveness to humans, aggressive mice with genetic knockout of monoaminoxidase A, and S40 rats selected for predisposition to passive defensive response of freezing (catalepsy). The changes in the serotonergic 5-HT1A-brain receptors of rats genetically predisposed to different strategies of defensive behavior were similar. However, the activity of the key enzyme of serotonin biosynthesis and the brain structures, in which serotonin metabolism was altered, significantly differed with regard to the preferred strategy. The conclusion was drawn that the 5-HT1A-receptors and enzymes of serotonin metabolism in the brain are involved in implementing genetic control of defensive behavior. Expression of the 5-HT1A-brain receptors was suggested to determine the levels of fear and anxiety and, consequently, the predisposition to defensive behavior, whereas the preferred strategy of defensive response (active or passive defensive) depends on genetically determined features of serotonin metabolism in the brain structures. PMID:15341267

  19. The role of 5-HT₁A receptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: a possible antidepressant mechanism.

    PubMed

    Vines, Aparecida; Delattre, Ana Marcia; Lima, Marcelo M S; Rodrigues, Laís Soares; Suchecki, Deborah; Machado, Ricardo B; Tufik, Sergio; Pereira, Sofia I R; Zanata, Sílvio M; Ferraz, Anete Curte

    2012-01-01

    Epidemiological and dietary studies show that nutritional deficit of omega-3 polyunsaturated fatty acids (ω-3 PUFA) is directly related to the prevalence and severity of depression. Supplementation with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) during critical periods of development (pregnancy and lactation) is essential for cortical maturation, synaptogenesis and myelination, and may also mitigate the risk for cognitive deficits and psychopathologies in young adults. The present study was performed to evaluate the involvement of serotonin (5-HT) receptors, particularly of 5-HT(1A), and hippocampal brain-derived neurotrophic factor (BDNF) expression in the antidepressant effect of ω-3 PUFA supplementation. In Experiment 1, the antidepressant effects of fish oil were assessed by the modified forced swim test in adult rats. The data indicated a robust antidepressant effect produced by this supplementation and that treatment of the rats with WAY 100135 reversed this effect. In Experiment 2, cortical and hippocampal contents of BDNF, 5-HT, dopamine (DA) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC), were determined in animals subjected to the same protocol. Increased BDNF expression in the cortex and hippocampus of both age groups was detected. In 90 day-old rats, 5-HT content in the hippocampus was increased, whereas 5-HIAA formation was diminished in the fish oil group. We suggest the occurrence of a reciprocal involvement of 5-HT(1A) receptors activation and the hippocampal BDNF-increased expression mediated by fish oil supplementation. These data corroborate and expand the notion that supplementation with ω-3 PUFA produces antidepressant effects mediated by an increase in serotonergic neurotransmission, particularly in the hippocampus. This article is part of a Special Issue entitled 'Anxiety and Depression'. PMID:21740919

  20. Changes in social instigation- and food restriction-induced aggressive behaviors and hippocampal 5HT1B mRNA receptor expression in male mice from early weaning.

    PubMed

    Nakamura, Kayo; Kikusui, Takefumi; Takeuchi, Yukari; Mori, Yuji

    2008-03-01

    The time of weaning has numerous effects on neurobehavioral development. Previous findings suggest that the early weaning influences development of aggressive behaviors. Behavioral and neuroendocrine responsiveness to stressors in the adulthood are also influenced by maternal care received early in life, and early-weaned male mice and rats show higher responsiveness to acute stresses than do normally weaned males. Therefore, it is conceivable that early weaning influences stress-related aggressive behaviors. We investigated the effects of early weaning on aggressive behaviors under two stress conditions: social stress (social instigation) and ecological stress (food restriction), both of which augment aggression. Male ICR mice were divided into two groups based on weaning period. Normally weaned mice (weaned PD21) showed twice the baseline level of attack bites after 5 min of social instigation, whereas early-weaned animals (weaned PD14) were not more aggressive following social instigation. However, the early-weaned mice were more aggressive after food restriction stress than were the normally weaned mice, suggesting lower threshold for aggressive behavior after food shortage. We also measured 5HT1A and 5HT1B receptor mRNA expression in the hippocampus which involved in aggression using real-time PCR. Early-weaned mice had lower 5HT1B expression levels than did normally weaned mice; no effect was found for 5HT1A expression. These results suggest that manipulation of weaning time modulates adult aggressive behavior depending on the stressors imposed and that this change may involve the 5HT1B receptor system in the hippocampus. PMID:18022705

  1. [Antidepressants, stressors and the serotonin 1A receptor].

    PubMed

    Kirilly, Eszter; Gonda, Xénia; Bagdy, György

    2015-06-01

    5-HT(1A) receptor is a receptor of surprises. Buspirone, an anxiolytic drug with a then yet unidentified mechanism of action had been marketed for years when it was discovered that it is a 5-HT(1A) partial agonist. Several more years had to pass before it was accepted that this receptor plays the key role in the action mechanism of buspirone. This was followed by further surprises. It was discovered that in spite of its anxiolytic effect buspirone activates the hypothalamic-pituitary-adrenal (HPA) stress axis, furthermore, it increases peripheral noradrenaline and adrenaline concentration via a central mechanism. Thus activation of this receptor leads to ACTH/corticosterone and catecholamine release and also increases beta-endorphine, oxytocin and prolactin secretion while decreasing body temperature, increasing food uptake, eliciting characteristic behavioural responses in rodents and also playing a role in the development of certain types of epilepsy. Human genetic studies revealed the role of 5-HT(1A) receptors in cognitive processes playing a role in the development of depression such as impulsiveness or response to environmental stress. This exceptionally wide spectrum of effects is attributable to the presence of 5-HT1A receptors in serotonergic as well as other, for example glutamatergic, cholinergic, dopaminergic and noradrenergic neurons. The majority of the effects of 5-HT(1A) receptors is manifested via the mediation of Gi proteins through the hyperpolarisation or inhibition of the neuron carrying the receptor. 5-HT(1A) receptors on serotonergic neurons can be found in the somatodendritic area and play a significant role in delaying the effects of antidepressants which is an obvious disadvantage. Therefore the newest serotonergic antidepressants including vilazodone and vortioxetine have been designed to possess 5-HT(1A) receptor partial agonist properties. In the present paper we focus primarily on the role of 5-HT(1A) receptors in stress and

  2. Serotonin receptors are selectively expressed in the avian germ cells and early embryos.

    PubMed

    Stępińska, Urszula; Kuwana, Takashi; Olszańska, Bożenna

    2015-06-01

    The expression of nine serotonin (5-HT) receptor transcripts was studied using reverse transcription polymerase chain reaction (RT-PCR) in germ cells, cleavage and gastrulation stages of Japanese quail, and qPCR for 5-HT3 and 5-HT4 receptors in oocytes and embryos. We show the presence/absence of nine serotonin transcripts known in birds for receptors 5-HT1A, 5-HT1F, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, 5-HT6 and 5-HT7A in avian germ cells and early embryos. The absence of 5-HT3 and 5-HT5A in primordial germ cells and of 5-HT3 and 5-HT7A in sperm is characteristic. All transcripts appeared in oocytes at all stages (except for 5-HT3 and 5-HT5A transcripts) and all were present in cleaving embryos and at gastrulation, except for 5-HT3, which was permanently observed as late as in stage 4. Interestingly, 5-HT3 and 5-HT5A receptors accumulated in 3-mm and F1 oocytes but were degraded at ovulation and started to be re-transcribed in cleavage stage II embryos and beyond. The selective appearance of 5-HT receptors in germ cells and early embryos supports the hypothesis that serotonin may act as a signalling molecule at early stages of germ line and embryo differentiation via individual receptors present during different stages, when specialized communication systems are not yet developed. PMID:24521994

  3. Postnatal Treadmill Exercise Alleviates Prenatal Stress-Induced Anxiety in Offspring Rats by Enhancing Cell Proliferation Through 5-Hydroxytryptamine 1A Receptor Activation

    PubMed Central

    2016-01-01

    Purpose: Stress during pregnancy is a risk factor for the development of anxiety-related disorders in offspring later in life. The effects of treadmill exercise on anxiety-like behaviors and hippocampal cell proliferation were investigated using rats exposed to prenatal stress. Methods: Exposure of pregnant rats to a hunting dog in an enclosed room was used to induce stress. Anxiety-like behaviors of offspring were evaluated using the elevated plus maze test. Immunohistochemistry for the detection of 5-bromo-2ʹ- deoxyuridine and doublecortin (DCX) in the hippocampal dentate gyrus and 5-hydroxytryptamine 1A receptors (5-HT1A) in the dorsal raphe was conducted. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in the hippocampus were evaluated by western blot analysis. Results: Offspring of maternal rats exposed to stress during pregnancy showed anxiety-like behaviors. Offspring also showed reduced expression of BDNF, TrkB, and DCX in the dentate gyrus, decreased cell proliferation in the hippocampus, and reduced 5-HT1A expression in the dorsal raphe. Postnatal treadmill exercise by offspring, but not maternal exercise during pregnancy, enhanced cell proliferation and expression of these proteins. Conclusions: Postnatal treadmill exercise ameliorated anxiety-like behaviors in offspring of stressed pregnant rats, and the alleviating effect of exercise on these behaviors is hypothesized to result from enhancement of cell proliferation through 5-HT1A activation in offspring rats. PMID:27230461

  4. 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception.

    PubMed

    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. PMID:26749090

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

    PubMed Central

    Nakayama, Hiroto; Umeda, Sumiyo; Nibuya, Masashi; Terao, Takeshi; Nisijima, Koichi; Nomura, Soichiro

    2014-01-01

    We propose the possibility of 5-hydroxytryptamine (5-HT)1A 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 through 5-HT1A, and severe serotonin excess induces lethal side effects with hyperthermia through 5-HT2A. Serotonin toxicity via a low dose of paroxetine that is coadministered with perospirone, which acts agonistically on the 5-HT1A receptor and antagonistically on the 5-HT2A receptor, clearly indicated 5-HT1A receptor involvement in mild serotonin toxicity. Careful measures should be adopted to avoid serotonin toxicity following the combined use of SSRIs and 5-HT1A agonists. PMID:24627634

  6. 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

    NASA Astrophysics Data System (ADS)

    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.

  7. Targeting of serotonin 1A receptors to dopaminergic neurons within the parabrachial subdivision of the ventral tegmental area in rat brain.

    PubMed

    Doherty, M D; Pickel, V M

    2001-05-01

    Serotonin (5-hydroxytryptamine [5-HT]) modulates dopamine-related cognitive functions and motor activity through activation of selective receptor subtypes including 5-HT1A. Potential targets for these 5-HT1A-mediated actions of 5-HT include mesocortical and mesolimbic dopaminergic neurons having partially segregated distribution in the parabrachial and paranigral subdivisions of the ventral tegmental area (VTA), respectively. We therefore examined the ultrastructural immunocytochemical localization of the 5-HT1A receptor in the parabrachial (VTApb) and paranigral (VTApn) subdivisions of rat VTA, to determine 1) the functional sites for receptor activation, and 2) the cellular associations between this receptor and dopaminergic neurons identified by their tyrosine hydroxylase (TH) content. In each region, 5-HT1A immunoreactivity was mainly observed in somatodendritic profiles, but it was also present in small unmyelinated axons and in a few axon terminals and glia, suggesting a role for 5-HT1A receptors in presynaptic and glial functions, as well as postsynaptic neuronal activation, in VTA. In somatodendritic profiles, 5-HT1A gold particles were mainly localized to tubulovesicles presumed to be smooth endoplasmic reticulum. In addition, however, in distal dendrites receiving multiple inputs the receptor was targeted to selective postsynaptic junctions, or more randomly distributed on nonsynaptic portions of the plasma membrane. Of the 5-HT1A-labeled dendrites, 64% in VTApb and 44% in VTApn contained TH. These findings suggest a reserve of cytoplasmic 5-HT1A receptors that are mobilized to functional postsynaptic sites on the plasma membrane by afferent input to distal dendrites in the VTA. They also indicate that 5-HT1A activation may affect a larger population of dopaminergic neurons in VTApb compared with VTApn, thus having a potentially greater impact on cognitive functions modulated by mesocortical dopaminergic neurons. PMID:11298363

  8. Stress-Induced Depression Is Alleviated by Aerobic Exercise Through Up-Regulation of 5-Hydroxytryptamine 1A Receptors in Rats

    PubMed Central

    Kim, Tae Woon; Lim, Baek Vin; Baek, Dongjin; Ryu, Dong-Soo; Seo, Jin Hee

    2015-01-01

    Purpose: Stress is associated with depression, which induces many psychiatric disorders. Serotonin, also known as 5-hydroxy-tryptamine (5-HT), acts as a biochemical messenger and regulator in the brain. It also mediates several important physiological functions. Depression is closely associated with an overactive bladder. In the present study, we investigated the effect of treadmill exercise on stress-induced depression while focusing on the expression of 5-HT 1A (5-H1A) receptors in the dorsal raphe. Methods: Stress was induced by applying a 0.2-mA electric foot shock to rats. Each set of electric foot shocks comprised a 6-second shock duration that was repeated 10 times with a 30-second interval. Three sets of electric foot shocks were applied each day for 7 days. For the confirmation of depressive state, a forced swimming test was performed. To visualize the expression of 5-HT and tryptophan hydroxylase (TPH), immunohistochemistry for 5-HT and TPH in the dorsal raphe was performed. Expression of 5-H1A receptors was determined by western blot analysis. Results: A depressive state was induced by stress, and treadmill exercise alleviated the depression symptoms in the stress-induced rats. Expressions of 5-HT, TPH, and HT 1A in the dorsal raphe were reduced by the induction of stress. Treadmill exercise increased 5-HT, TPH, and HT 1A expressions in the stress-induced rats. Conclusions: Treadmill exercise enhanced 5-HT synthesis through the up-regulation of 5-HT1A receptors, and improved the stress-induced depression. In the present study, treadmill exercise improved depression symptoms by enhancing 5-HT1A receptor expression. The present results suggest that treadmill exercise might be helpful for the alleviation of overactive bladder and improve sexual function. PMID:25833478

  9. Age, Sex, and Reproductive Hormone Effects on Brain Serotonin-1A and Serotonin-2A Receptor Binding in a Healthy Population

    PubMed Central

    Moses-Kolko, Eydie L; Price, Julie C; Shah, Nilesh; Berga, Sarah; Sereika, Susan M; Fisher, Patrick M; Coleman, Rhaven; Becker, Carl; Mason, N Scott; Loucks, Tammy; Meltzer, Carolyn C

    2011-01-01

    There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20–80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [11C]WAY100635 and [18F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (VT) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age2, sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004–0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05–0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03–0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low

  10. Age, sex, and reproductive hormone effects on brain serotonin-1A and serotonin-2A receptor binding in a healthy population.

    PubMed

    Moses-Kolko, Eydie L; Price, Julie C; Shah, Nilesh; Berga, Sarah; Sereika, Susan M; Fisher, Patrick M; Coleman, Rhaven; Becker, Carl; Mason, N Scott; Loucks, Tammy; Meltzer, Carolyn C

    2011-12-01

    There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [(11)C]WAY100635 and [(18)F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V(T)) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age(2), sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low

  11. Serotonin receptor expression is dynamic in the liver during the transition period in Holstein dairy cows.

    PubMed

    Laporta, J; Hernandez, L L

    2015-04-01

    Nonneuronal serotonin (5-HT) participates in glucose metabolism, but little is known regarding the actions of 5-HT in the liver during the transition period in dairy cattle. Here, we explore circulating patterns of 5-HT and characterize the hepatic 5-HT receptor and glucose transporter profiles around calving in multiparous Holstein dairy cows (n = 6, average lactation = 4 ± 1.9). Concentrations of serum 5-HT decreased on day -3 compared with -5 and -7 precalving (167.7 ± 80 vs 1511.1 ± 602 ng/mL). 5-HT nadir was on day -1 precalving and remained low postcalving (481.4 ± 49 ng/mL). Plasma glucose concentrations decreased precalving (P = 0.008) and were positively correlated with 5-HT during the precalving period (r = 0.55, P = 0.043). On day 1, postcalving hepatic messenger RNA expression of 5-HT1D, 2B, 3C, 6, and 7 receptors were decreased compared with day -7 (P < 0.048). The 5-HT3A and 5-HT3B decreased on day 7. The 5-HT2A increased on days 1 and 7 compared with -7 (P < 0.05). The 5-HT1F and 5-HT1A receptors were increased 2.5- and 3.8-fold on day 7, respectively, compared with days -7 and 1 (P < 0.046). The 5-HT5A was not detected, and 5-HT4 was detected on days -7 and 1 only. Expression of Glut-2,-5 and SGLT1 were decreased on days 1 and 7 compared with -7 (P < 0.05), whereas Glut-1 was increased on day 7 compared with -7 (P < 0.05). These results indicate that 5-HT could be important for liver glucose homeostasis possibly through receptor mediated signaling at specific times. Additional research is needed to further explore the functional role of these receptors in the liver during the transition from pregnancy to lactation. PMID:25528206

  12. Monoallelic Expression of Olfactory Receptors

    PubMed Central

    Monahan, Kevin; Lomvardas, Stavros

    2016-01-01

    The sense of smell collects vital information about the environment by detecting a multitude of chemical odorants. Breadth and sensitivity are provided by a huge number of chemosensory receptor proteins, including more than 1,400 olfactory receptors (ORs). Organizing the sensory information generated by these receptors so that it can be processed and evaluated by the central nervous system is a major challenge. This challenge is overcome by monogenic and monoallelic expression of OR genes. The single OR expressed by each olfactory sensory neuron determines the neuron’s odor sensitivity and the axonal connections it will make to downstream neurons in the olfactory bulb. The expression of a single OR per neuron is accomplished by coupling a slow chromatin-mediated activation process to a fast negative-feedback signal that prevents activation of additional ORs. Singular OR activation is likely orchestrated by a network of interchromosomal enhancer interactions and large-scale changes in nuclear architecture. PMID:26359778

  13. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system.

    PubMed

    Lee, Minkyung; Ryu, Young Hoon; Cho, Won Gil; Kang, Yeo Wool; Lee, Soo Jin; Jeon, Tae Joo; Lyoo, Chul Hyoung; Kim, Chul Hoon; Kim, Dong Goo; Lee, Kyochul; Choi, Tae Hyun; Choi, Jae Yong

    2015-09-01

    Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats: [(18) F]FP-CIT for DA transporters and [(18) F]Mefway for serotonin 1A (5-HT(1A)) receptors. Here, 6-OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5-HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R(2)  = 0.79, P = 0.003). In 6-OHDA lesioned rats, binding values for 5-HT(1A) receptors was 22% lower than the sham operated group. This decrement of 5-HT(1A) receptor binding was also correlated with the severity of depression (R(2)  = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. PMID:26089169

  14. Serotonin1A-receptor-dependent signaling proteins in mouse hippocampus

    PubMed Central

    Li, Lin; Whittle, Nigel; Klug, Stefanie; Chen, Wei-Qiang; Singewald, Nicolas; Toth, Miklos; Lubec, Gert

    2009-01-01

    The serotonin1A receptor (5-HT1A R) knock-out mouse (KO) is a widely used animal model for anxiety and cognitive function and regulation of signaling cascades by this receptor has been reported. We aimed to determine individual representatives of signaling cascades in order to screen 5-HT1A R-dependent signaling proteins (SPs). Hippocampal proteins from wild type and 5-HT1A R KO mice were extracted, run on two-dimensional gel electrophoresis, proteins were identified by MALDI and nano-ESI-LC-MS/MS and SPs were quantified by specific software. Nucleoside diphosphate kinase A (NDK A, synonym: nm23), Dual specificity mitogen-activated protein kinase kinase 1 (MAPKK1, synonym: MEK), Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PP-1G), Septin-5, were reduced in the KO mice. Novel phosphorylation sites at T386 on MAPKK1 and at S225 and Y265 on Septin-5 were observed. MAPKK1 and PP-1G are known 5-HT1A R-dependent signaling compounds and are in agreement with receptor knock-out and septin-5 is involved in serotonin transport, although regulation by 5-HT1A R has not been reported. 5-HT1A R – dependent levels for NDK A have not been demonstrated so far and we herewith propose a role for NDK A in 5-HT1A R signaling. Reduced SP levels along with findings of two novel phosphorylation sites may be relevant for interpretation of previous and the design of future studies on this receptor system. PMID:19607848

  15. Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats.

    PubMed

    Conti, Melissa M; Ostock, Corinne Y; Lindenbach, David; Goldenberg, Adam A; Kampton, Elias; Dell'isola, Rich; Katzman, Aaron C; Bishop, Christopher

    2014-02-01

    Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and -naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT(1A) receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels. PMID:24067924

  16. Role of serotonin 1A receptors in the median raphe nucleus on the behavioral consequences of forced swim stress.

    PubMed

    Almeida, P V G; Trovo, M C; Tokumoto, A M; Pereira, A C; Padovan, C M

    2013-12-01

    Despite the intense research on the neurobiology of stress, the role of serotonin (5-HT)1A receptors still remains to be elucidated. In the hippocampus, post-synaptic 5-HT1A receptors activation induces anxiolytic effects in animals previously exposed to stressful situations. However, little is known about somatodendritic 5-HT1A receptors in the median raphe nucleus (MRN). Therefore, the aim of this study was to investigate the role of 5-HT1A receptors located in the MRN in rats exposed to forced swim stress. After recovering from surgery, rats were forced to swim for 15 min in a cylinder. Intra-MRN injections of saline, 8-OH-DPAT (3 nmol/0.2 µL) and/or WAY-100635 (0.3 nmol/0.2 µL) were performed immediately before or after pre-exposure or 24 h later (immediately before test). Non-stressed rats received the same treatment 24 h or 10 min before test. Our data showed that 8-OH-DPAT increased latency to display immobility while decreasing time spent immobile in almost all experimental conditions. These effects were not prevented by previous treatment with WAY-100635. No effects of different treatments were described in non-stressed animals. Taken together, our data suggest that in addition to activation of 5-HT1A, 5-HT7 receptors may also be involved in the behavioural consequences of exposure to swim stress. PMID:24162801

  17. Higher density of serotonin-1A receptors in the hippocampus and cerebral cortex of alcohol-preferring P rats

    SciTech Connect

    Wong, D.T.; Threlkeld, P.G. ); Lumeng, L.; Li, Ting-Kai )

    1990-01-01

    Saturable ({sup 3}H)-80HDPAT binding to 5HT-1A receptors in membranes prepared from hippocampus and frontal cerebral cortex of alcohol-preferring (P) rats and of alcohol-nonpreferring (NP) rats has been compared. The B{sub max} values or densities of recognition sites for 5HT-1A receptors in both brain areas of the P rats are 38 and 44 percent lower in the P rats than in the NP rats. The corresponding K{sub D} values are 38 and 44 percent lower in the P rats than in the NP rats, indicating higher affinities of the recognition sites for the 5HT-1A receptors in hippocampus and cerebral cortex of the P rats. These findings indicate either an enrichment of 5HT-1A receptor density during selective breeding for alcohol preference or an upregulation of 5HT-1A receptors of 5HT found in these brain areas of P rats as compared with the NP rats.

  18. Serotonin Receptors in Rat Jugular Vein: Presence and Involvement in the Contraction

    PubMed Central

    Gaskell, Geri L.; Szasz, Theodora; Thompson, Janice M.; Watts, Stephanie W.

    2010-01-01

    observed mRNA expression for the 5-HT2A, 5-HT2B, and 5-HT7 receptors, whereas no significant mRNA expression was found for 5-HT1A, 5-HT1B, and 5-HT1D receptors. These results support the 5-HT2A receptor as the main subtype targeted by 5-HT to contract the RJV. PMID:20378714

  19. The role of spinal serotonin receptor and alpha adrenoceptor on the antiallodynic effects induced by intrathecal milnacipran in chronic constriction injury rats.

    PubMed

    Nakamura, Takehiro; Ikeda, Tetsuya; Takeda, Ryuichiro; Igawa, Kaori; Naono-Nakayama, Rumi; Sakoda, Sumio; Nishimori, Toshikazu; Ishida, Yasushi

    2014-09-01

    Milnacipran, a reuptake inhibitor of noradrenaline (NA) and serotonin (5-HT), elicits an antiallodynic effect in rats with neuropathic pain; however, the role of NA and 5-HT receptors in the induction of the antiallodynic effect of milnacipran remains unclear. Thus, we examined the effects of prazosin as an α1 adrenoceptor antagonist, yohimbine as an α2 adrenoceptor antagonist, metergoline as a 5-HT1, 5-HT2 and 5-HT7 receptor antagonist, cyanopindolol as a 5-HT1A/1B receptor antagonist, ketanserin as a 5-HT2 receptor antagonist, and ondansetoron as a 5-HT3 receptor antagonist on the antiallodynic effect of milnacipran in neuropathic rats with chronic constriction injury (CCI). The CCI rats expressed mechanical and thermal allodynia, which was attenuated by intrathecal injection of milnacipran. Yohimbine, but not prazosin, reversed the milnacipran-induced antiallodynic effect. The antiallodynic effect of milnacipran was also reversed by metergoline, ketanserin and ondansetron, while cyanopindolol reversed the antiallodynic effect on mechanical, but not thermal stimulation. Furthermore, c-Fos expression in lamina I/II of the spinal dorsal horn was enhanced by thermal stimulation and the enhanced expression of c-Fos was suppressed by milnacipran. This effect of milnacipran was reversed by yohimbine, metergoline, katanserin and ondansetron, but not prazosin. These results indicate that the effect of milnacipran on mechanical and thermal allodynia and c-Fos expression is elicited through the α2 adrenoceptor, but not α1 adrenoceptor, and 5-HT2 and 5-HT3 receptors; furthermore, the 5-HT1A/1B receptor is involved in mechanical allodynia, but not thermal allodynia. PMID:24876059

  20. Hormone activation of baculovirus expressed progesterone receptors.

    PubMed

    Elliston, J F; Beekman, J M; Tsai, S Y; O'Malley, B W; Tsai, M J

    1992-03-15

    Human and chicken progesterone receptors (A form) were overproduced in a baculovirus expression system. These recombinant progesterone receptors were full-length bound progesterone specifically and were recognized by monoclonal antibodies, AB52 and PR22, specific for human and chicken progesterone receptor, respectively. In gel retardation studies, binding of recombinant human and chicken progesterone receptors to their progesterone response element (PRE) was specific and was enhanced in the presence of progesterone. Binding of human progesterone receptor to the PRE was also enhanced in the presence of the antiprogestin, RU486, but very little effect was observed in the presence of estradiol, dexamethasone, testosterone, and vitamin D. In our cell-free transcription system, human progesterone receptor induced transcription in a receptor-dependent and hormone-activable manner. Receptor-stimulated transcription required the presence of the PRE in the test template and could be specifically inhibited by excess PRE oligonucleotides. Furthermore, chicken progesterone receptor also induced in vitro transcription in a hormone-activable manner. These results demonstrate that steroid receptors overexpressed in a baculovirus expression system are functional and exhibit steroid-responsive binding and transcription. These observations support our present understanding of the mechanism of steroid receptor-regulated gene expression and provide a technological format for studies of the role of hormone and antihormone in altering gene expression. PMID:1544902

  1. Involvement of 5-HT₇ receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents.

    PubMed

    Westrich, Ligia; Haddjeri, Nasser; Dkhissi-Benyahya, Ouria; Sánchez, Connie

    2015-02-01

    Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 μM vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents. PMID:25446573

  2. Human neuroepithelial cells express NMDA receptors.

    PubMed

    Sharp, Christopher D; Fowler, M; Jackson, T H; Houghton, J; Warren, A; Nanda, A; Chandler, I; Cappell, B; Long, A; Minagar, A; Alexander, J S

    2003-11-13

    L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1) cerebral endothelial barrier and 2) cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells) have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR) expression via immunohistochemistry and murine neuroepithelial cell line (V1) were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease. PMID:14614784

  3. Effect of long-term actual spaceflight on the expression of key genes encoding serotonin and dopamine system

    NASA Astrophysics Data System (ADS)

    Popova, Nina; Shenkman, Boris; Naumenko, Vladimir; Kulikov, Alexander; Kondaurova, Elena; Tsybko, Anton; Kulikova, Elisabeth; Krasnov, I. B.; Bazhenova, Ekaterina; Sinyakova, Nadezhda

    The effect of long-term spaceflight on the central nervous system represents important but yet undeveloped problem. The aim of our work was to study the effect of 30-days spaceflight of mice on Russian biosatellite BION-M1 on the expression in the brain regions of key genes of a) serotonin (5-HT) system (main enzymes in 5-HT metabolism - tryptophan hydroxylase-2 (TPH-2), monoamine oxydase A (MAO A), 5-HT1A, 5-HT2A and 5-HT3 receptors); b) pivotal enzymes in DA metabolism (tyrosine hydroxylase, COMT, MAO A, MAO B) and D1, D2 receptors. Decreased expression of genes encoding the 5-HT catabolism (MAO A) and 5-HT2A receptor in some brain regions was shown. There were no differences between “spaceflight” and control mice in the expression of TPH-2 and 5-HT1A, 5-HT3 receptor genes. Significant changes were found in genetic control of DA system. Long-term spaceflight decreased the expression of genes encoding the enzyme in DA synthesis (tyrosine hydroxylase in s.nigra), DA metabolism (MAO B in the midbrain and COMT in the striatum), and D1 receptor in hypothalamus. These data suggested that 1) microgravity affected genetic control of 5-HT and especially the nigrostriatal DA system implicated in the central regulation of muscular tonus and movement, 2) the decrease in the expression of genes encoding key enzyme in DA synthesis, DA degradation and D1 receptor contributes to the movement impairment and dyskinesia produced by the spaceflight. The study was supported by Russian Foundation for Basic Research grant № 14-04-00173.

  4. Characterization of the Distance Relationship Between Localized Serotonin Receptors and Glia Cells on Fluorescence Microscopy Images of Brain Tissue.

    PubMed

    Jacak, Jaroslaw; Schaller, Susanne; Borgmann, Daniela; Winkler, Stephan M

    2015-08-01

    We here present two new methods for the characterization of fluorescent localization microscopy images obtained from immunostained brain tissue sections. Direct stochastic optical reconstruction microscopy images of 5-HT1A serotonin receptors and glial fibrillary acidic proteins in healthy cryopreserved brain tissues are analyzed. In detail, we here present two image processing methods for characterizing differences in receptor distribution on glial cells and their distribution on neural cells: One variant relies on skeleton extraction and adaptive thresholding, the other on k-means based discrete layer segmentation. Experimental results show that both methods can be applied for distinguishing classes of images with respect to serotonin receptor distribution. Quantification of nanoscopic changes in relative protein expression on particular cell types can be used to analyze degeneration in tissues caused by diseases or medical treatment. PMID:26173412

  5. Brain Serotonin Receptors and Transporters: Initiation vs. Termination of Escalated Aggression

    PubMed Central

    Takahashi, Aki; Quadros, Isabel M.; de Almeida, Rosa M. M.; Miczek, Klaus A.

    2013-01-01

    Rationale Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. Objective We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. Results New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Conclusions Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment. PMID:20938650

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

    PubMed Central

    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

  7. Developmental expression of retinoic acid receptors (RARs)

    PubMed Central

    Dollé, Pascal

    2009-01-01

    Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the 'retinoid X' or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors’ expression patterns. PMID:19471585

  8. OPIATE EXPOSURE AND WITHDRAWAL DYNAMICALLY REGULATE mRNA EXPRESSION IN THE SEROTONERGIC DORSAL RAPHE NUCLEUS

    PubMed Central

    Lunden, Jason; Kirby, Lynn G.

    2013-01-01

    Previous results from our lab suggest that hypofunctioning of the serotonergic (5-HT) dorsal raphe nucleus (DRN) is involved in stress-induced opiate reinstatement. To further investigate the effects of morphine dependence and withdrawal on the 5-HT DRN system, we measured gene expression at the level of mRNA in the DRN during a model of morphine dependence, withdrawal and post withdrawal stress exposure in rats. Morphine pellets were implanted for 72h and then either removed or animals were injected with naloxone to produce spontaneous or precipitated withdrawal, respectively. Animals exposed to these conditions exhibited withdrawal symptoms including weight loss, wet dog shakes and jumping behavior. Gene expression for brain-derived neurotrophic factor (BDNF), TrkB, corticotrophin releasing-factor (CRF)-R1, CRF-R2, GABAA-α1, μ-opioid receptor (MOR), 5-HT1A, tryptophan hydroxylase2 and the 5-HT transporter was then measured using quantitative real-time PCR at multiple time-points across the model of morphine exposure, withdrawal and post withdrawal stress. Expression levels of BDNF, TrkB and CRF-R1 mRNA were decreased during both morphine exposure and following seven days of withdrawal. CRF-R2 mRNA expression was elevated after seven days of withdrawal. 5-HT1A receptor mRNA expression was decreased following 3 hours of morphine exposure, while TPH2 mRNA expression was decreased after seven days of withdrawal with swim stress. There were no changes in the expression of GABAA-α1, MOR or 5-HT transporter mRNA. Collectively these results suggest that alterations in neurotrophin support, CRF-dependent stress signaling, 5-HT synthesis and release may underlie 5-HT DRN hypofunction that can potentially lead to stress-induced opiate relapse. PMID:24055683

  9. Activation of 5-hyrdoxytryptamine 7 receptors within the rat nucleus tractus solitarii modulates synaptic properties.

    PubMed

    Matott, Michael P; Kline, David D

    2016-03-15

    Serotonin (5-HT) is a potent neuromodulator with multiple receptor types within the cardiorespiratory system, including the nucleus tractus solitarii (nTS) - the central termination site of visceral afferent fibers. The 5-HT7 receptor facilitates cardiorespiratory reflexes through its action in the brainstem and likely in the nTS. However, the mechanism and site of action for these effects is not clear. In this study, we examined the expression and function of 5-HT7 receptors in the nTS of Sprague-Dawley rats. 5-HT7 receptor mRNA and protein were identified across the rostrocaudal extent of the nTS. To determine 5-HT7 receptor function, we examined nTS synaptic properties following 5-HT7 receptor activation in monosynaptic nTS neurons in the in vitro brainstem slice preparation. Application of 5-HT7 receptor agonists altered tractus solitarii evoked and spontaneous excitatory postsynaptic currents which were attenuated with a selective 5-HT7 receptor antagonist. 5-HT7 receptor-mediated changes in excitatory postsynaptic currents were also altered by block of 5-HT1A and GABAA receptors. Interestingly, 5-HT7 receptor activation also reduced the amplitude but not frequency of GABAA-mediated inhibitory currents. Together these results indicate a complex role for 5-HT7 receptors in the nTS that mediate its diverse effects on cardiorespiratory parameters. PMID:26779891

  10. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors).

    PubMed

    Stahl, Stephen M

    2015-04-01

    Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites--or nodes--where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks. PMID:25831967

  11. Cannabinoid-receptor expression in human leukocytes.

    PubMed

    Bouaboula, M; Rinaldi, M; Carayon, P; Carillon, C; Delpech, B; Shire, D; Le Fur, G; Casellas, P

    1993-05-15

    Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS), probably through the cannabinoid receptor, which has recently been cloned in rat and human. While numerous reports have also described effects of cannabinoids on the immune system, the observation of both mRNA and cannabinoid receptor has hitherto been exclusively confined to the brain, a reported detection in the testis being the sole example of its presence at the periphery. Here we report the expression of the cannabinoid receptor on human immune tissues using a highly sensitive polymerase-chain-reaction-based method for mRNA quantification. We show that, although present in a much lower abundance than in brain, cannabinoid receptor transcripts are found in human spleen, tonsils and peripheral blood leukocytes. The distribution pattern displays important variations of the mRNA level for the cannabinoid receptor among the main human blood cell subpopulations. The rank order of mRNA levels in these cells is B cells > natural killer cells > or = polymorphonuclear neutrophils > or = T8 cells > monocytes > T4 cells. Cannabinoid-receptor mRNA, which is also found in monocytic, as well as T and B leukemia cell lines but not in Jurkat cells, presents a great diversity of expression on these cells as well, B-cell lines expressing a much higher level than T-cell lines. The cannabinoid receptor PCR products from leukocytes and brain are identical both in size and sequence suggesting a strong similarity between central and peripheral cannabinoid receptors. The expression of this receptor was demonstrated on membranes of the myelomonocytic U937 cells using the synthetic cannabinoid [3H]CP-55940 as ligand. The Kd determined from Scatchard analysis was 0.1 nM and the Bmax for membranes was 525 fmol/mg protein. The demonstration of cannabinoid-receptor expression at both mRNA and protein levels on human leukocytes provides a molecular basis for cannabinoid action on these cells. PMID

  12. Activation of the serotonin 1A receptor alters the temporal characteristics of auditory responses in the inferior colliculus.

    PubMed

    Hurley, Laura M

    2007-11-21

    Serotonin, like other neuromodulators, acts on a range of receptor types, but its effects also depend on the functional characteristics of the neurons responding to receptor activation. In the inferior colliculus (IC), an auditory midbrain nucleus, activation of a common serotonin (5-HT) receptor type, the 5-HT 1A receptor, depresses auditory-evoked responses in many neurons. Whether these effects occur differentially in different types of neurons is unknown. In the current study, the effects of iontophoretic application of the 5-HT 1A agonist 8-OH-DPAT on auditory responses were compared with the characteristic frequencies (CFs), recording depths, and control first-spike latencies of the same group of IC neurons. The 8-OH-DPAT-evoked change in response significantly correlated with first-spike latency across the population, so that response depressions were more prevalent in longer-latency neurons. The 8-OH-DPAT-evoked change in response did not correlate with CF or with recording depth. 8-OH-DPAT also altered the temporal characteristics of spike trains in a subset of neurons that fired multiple spikes in response to brief stimuli. For these neurons, activation of the 5-HT 1A receptor suppressed lagging spikes proportionally more than initial spikes. These results suggest that the 5-HT 1A receptor, by affecting the timing of the responses of both individual neurons and the neuron population, shifts the temporal profile of evoked activity within the IC. PMID:17916336

  13. Sinonasal Leiomyoma With Estrogen Receptor Expression.

    PubMed

    Kim, Jong Seung; Shin, Jin Yong; Kwon, Sam Hyun

    2015-09-01

    Leiomyoma is an extremely rare tumor in sinonasal area. The reason for this is due to minimal amount of the smooth muscle in the area. The origin of this tumor is not clear and its etiology has not been proven in the literature. A 58-year-old woman who experienced nasal obstruction and epiphora visited our clinic. A huge mass was noted in right nasal cavity originating from the lacrimal bone area. The authors conducted endoscopic sinus surgery and obtained the specimen. Immunochemistry showed leiomyoma in the nasal cavity, which expressed estrogen receptor. There was no progesterone receptor expressed. The authors describe a sinonasal leiomyoma with estrogen receptors, not ever reported in previous article. PMID:26355987

  14. Widespread ectopic expression of olfactory receptor genes

    PubMed Central

    Feldmesser, Ester; Olender, Tsviya; Khen, Miriam; Yanai, Itai; Ophir, Ron; Lancet, Doron

    2006-01-01

    Background Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication of such ectopic expression. Results We analyzed the expression of hundreds of human and mouse OR transcripts, via EST and microarray data, in several dozens of human and mouse tissues. Different tissues had specific, relatively small OR gene subsets which had particularly high expression levels. In testis, average expression was not particularly high, and very few highly expressed genes were found, none corresponding to ORs previously implicated in sperm chemotaxis. Higher expression levels were more common for genes with a non-OR genomic neighbor. Importantly, no correlation in expression levels was detected for human-mouse orthologous pairs. Also, no significant difference in expression levels was seen between intact and pseudogenized ORs, except for the pseudogenes of subfamily 7E which has undergone a human-specific expansion. Conclusion The OR superfamily as a whole, show widespread, locus-dependent and heterogeneous expression, in agreement with a neutral or near neutral evolutionary model for transcription control. These results cannot reject the possibility that small OR subsets might play functional roles in different tissues, however considerable care should be exerted when offering a functional interpretation for ectopic OR expression based only on transcription information. PMID:16716209

  15. A Characterization of the Manduca sexta Serotonin Receptors in the Context of Olfactory Neuromodulation

    PubMed Central

    Dacks, Andrew M.; Reale, Vincenzina; Pi, Yeli; Zhang, Wujie; Dacks, Joel B.; Nighorn, Alan J.; Evans, Peter D.

    2013-01-01

    Neuromodulation, the alteration of individual neuron response properties, has dramatic consequences for neural network function and is a phenomenon observed across all brain regions and taxa. However, the mechanisms underlying neuromodulation are made complex by the diversity of neuromodulatory receptors expressed within a neural network. In this study we begin to examine the receptor basis for serotonergic neuromodulation in the antennal lobe of Manduca sexta. To this end we cloned all four known insect serotonin receptor types from Manduca (the Ms5HTRs). We used phylogenetic analyses to classify the Ms5HTRs and to establish their relationships to other insect serotonin receptors, other insect amine receptors and the vertebrate serotonin receptors. Pharmacological assays demonstrated that each Ms5HTR was selective for serotonin over other endogenous amines and that serotonin had a similar potency at all four Ms5HTRs. The pharmacological assays also identified several agonists and antagonists of the different Ms5HTRs. Finally, we found that the Ms5HT1A receptor was expressed in a subpopulation of GABAergic local interneurons suggesting that the Ms5HTRs are likely expressed heterogeneously within the antennal lobe based on functional neuronal subtype. PMID:23922709

  16. Differential expression of vasoactive mediators in microparticle-challenged lungs of chickens that differ in susceptibility to pulmonary arterial hypertension.

    PubMed

    Hamal, Krishna R; Wideman, Robert F; Anthony, Nicholas B; Erf, Gisela F

    2010-01-01

    Pulmonary hypertension syndrome (PHS; ascites) in fast growing meat-type chickens (broilers) is characterized by the onset of idiopathic pulmonary arterial hypertension (IPAH) leading to right-sided congestive heart failure and terminal ascites. Intravenous microparticle (MP) injection is a tool used by poultry geneticists to screen for the broilers that are resistant (RES) or susceptible (SUS) to IPAH in a breeding population. MPs occlude pulmonary arterioles and initiate focal inflammation, causing local tissues and responding leukocytes to release vasoactive mediators such as serotonin (5-HT), endothelin-1 (ET-1), and nitric oxide (NO). RT-PCR was used to examine the differences between RES and SUS broilers in terms of gene expression of ET-1, ET receptor types A and B (ET(A) and ET(B)), the serotonin transporter (SERT), serotonin receptors (5-HT(1A), 5-HT(2A), 5-HT(1B), 5-HT(2B)), endothelial NO synthase (eNOS), and inducible NOS (iNOS) in the lungs of these broilers before (0 h) and after (2, 6, 12, 24, and 48 h) MP injection. In SUS broilers MP injection elicited higher (P < 0.05) pulmonary expression of 5-HT(1A), 5-HT(2B), and ET-1, which promote vasoconstriction and proliferation of pulmonary arterial smooth muscle cells (PASMC). In RES broilers the MP injection elicited higher expression of eNOS, iNOS, and ET(B), which promote vasodilation and inhibit PASMC proliferation. These observations support the hypothesis that the resistance of broiler chickens to IPAH may be due to the higher expression of vasoactive mediators that favor enhanced vasodilation and attenuated vasoconstriction during MP injection challenges to the pulmonary vasculature. PMID:19907003

  17. Grafted Human Embryonic Progenitors Expressing Neurogenin-2 Stimulate Axonal Sprouting and Improve Motor Recovery after Severe Spinal Cord Injury

    PubMed Central

    Perrin, Florence E.; Lonjon, Nicolas; Serre, Angeline; Prieto, Monica; Mallet, Jacques; Privat, Alain

    2010-01-01

    Background Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats. Methods and Principal Findings With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery. Conclusions and Significance Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for

  18. IL-21 Receptor Expression in Human Tendinopathy

    PubMed Central

    Campbell, Abigail L.; Smith, Nicola C.; Reilly, James H.; Kerr, Shauna C.; Leach, William J.; Fazzi, Umberto G.; Rooney, Brian P.; Murrell, George A. C.; Millar, Neal L.

    2014-01-01

    The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward an early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly upregulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression, these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy. PMID:24757284

  19. A Small-Animal Pharmacokinetic/Pharmacodynamic PET Study of Central Serotonin 1A Receptor Occupancy by a Potential Therapeutic Agent for Overactive Bladder

    PubMed Central

    Nakatani, Yosuke; Suzuki, Michiyuki; Tokunaga, Masaki; Maeda, Jun; Sakai, Miyuki; Ishihara, Hiroki; Yoshinaga, Takashi; Takenaka, Osamu; Zhang, Ming-Rong; Suhara, Tetsuya; Higuchi, Makoto

    2013-01-01

    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. PMID:24086433

  20. Kinin receptor expression during Staphylococcus aureus infection

    PubMed Central

    Bengtson, Sara H.; Phagoo, Stephen B.; Norrby-Teglund, Anna; Påhlman, Lisa; Mörgelin, Matthias; Zuraw, Bruce L.; Leeb-Lundberg, L. M. Fredrik; Herwald, Heiko

    2006-01-01

    An inappropriate host response to invading bacteria is a critical parameter that often aggravates the outcome of an infection. Staphylococcus aureus is a major human Gram-positive pathogen that causes a wide array of community- and hospital-acquired diseases ranging from superficial skin infections to severe conditions such as staphylococcal toxic shock. Here we find that S aureus induces inflammatory reactions by modulating the expression and response of the B1 and B2 receptors, respectively. This process is initiated by a chain of events, involving staphylococcal-induced cytokine release from monocytes, bacteria-triggered contact activation, and conversion of bradykinin to its metabolite desArg9bradykinin. The data of the present study implicate an important and previously unknown role for kinin receptor regulation in S aureus infections. PMID:16735595

  1. Strain-dependent variations in visceral sensitivity: relationship to stress, anxiety and spinal glutamate transporter expression.

    PubMed

    Moloney, R D; Dinan, T G; Cryan, J F

    2015-04-01

    Responses to painful stimuli differ between populations, ethnic groups, sexes and even among individuals of a family. However, data regarding visceral pain are still lacking. Thus, we investigated differences in visceral nociception across inbred and outbred mouse strains using colorectal distension. Anxiety and depression-like behaviour were assessed using the open field and forced swim test as well as the corticosterone stress response. Possible mechanistic targets [excitatory amino acid transporter (EAAT-1), brain-derived neurotrophic factor (BDNF) and 5HT1A receptor] were also assessed using quantitative real-time polymerase chain reaction. Adult, male, inbred and outbred mouse strains were used in all assays (inbred strains; CBA/J Hsd, C3H/HeNHsd, BALB/c OlaHsd, C57 BL/6JOlaHsd, DBA/2J RccHsd, CAST/EiJ, SM/J, A/J OlaHsd, 129P2/OlaHsd, FVB/NHan Hsd and outbred strains: Swiss Webster, CD-1). mRNA expression levels of EAAT-1, BDNF and 5HT1A receptor (HTR1A) were quantified in the lumbosacral spinal cord, amygdala and hippocampus. A significant effect of strain was found in visceral sensitivity, anxiety and depressive-like behaviours. Strain differences were also seen in both baseline and stress-induced corticosterone levels. CBA/J mice consistently exhibited heightened visceral sensitivity, anxiety behaviour and depression-like behaviour which were associated with decreased spinal EAAT-1 and hippocampal BDNF and HTR1A. Our results show the CBA/J mouse strain as a novel mouse model to unravel the complex mechanisms of brain-gut axis disorders such as irritable bowel syndrome, in particular the underlying mechanisms of visceral hypersensitivity, for which there is great need. Furthermore, this study highlights the importance of genotype and the consequences for future development of transgenic strains in pain research. PMID:25851919

  2. The D1 receptor-mediated effects of the ergoline derivative LEK-8829 in rats with unilateral 6-hydroxydopamine lesions.

    PubMed Central

    Zivin, M.; Sprah, L.; Sket, D.

    1996-01-01

    1. Previous experiments have suggested a potential atypical antipsychotic activity of the ergoline derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2 = 1.11) and a moderate affinity to D1 receptors. In vivo experiments showed antagonism of dopamine and 5-hydroxytryptamine (5-HT) receptor-linked behaviours. 2. In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6-hydroxydopamine (6-OHDA), were used to determine the effects of LEK-8829 on turning behaviour and on striatal c-fos mRNA levels. 3. The administration of LEK-8829 induced a long lasting contralateral turning behaviour that was dose-dependent. It was found that the specific D1 receptor antagonist SCH-23390 but not the D2 receptor antagonist haloperidol or 5-HT1A antagonist pindolol, dose-dependently inhibited the turning behaviour induced by LEK-8829. 4. In an attempt to clarify the D1:D2 receptor interactions involved in the action of LEK-8829 in the 6OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH-23390 pretreatment on striatal c-fos mRNA expression induced either by LEK-8829 or by the typical antipsychotic haloperidol. 5. LEK-8829 induced a bilateral striatal c-fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH-23390. In contrast, haloperidol-induced striatal c-fos mRNA expression was limited to the innervated striatum and was not blocked by SCH-23390. 6. Our data demonstrate an intrinsic activity of LEK-8829 on D1 receptors that is potentiated in the dopamine-depleted striatum. We conclude, therefore, that the putative atypical antipsychotic LEK-8829 may prove useful as an experimental tool for the study of D1:D2 receptor interactions and could have beneficial

  3. Activation of 5-HT₁A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease.

    PubMed

    Sun, Yi-Na; Wang, Tao; Wang, Yong; Han, Ling-Na; Li, Li-Bo; Zhang, Yu-Ming; Liu, Jian

    2015-08-01

    Although the medial subdivision of the central nucleus of the amygdala (CeM) and serotonin-1A (5-HT1A) receptors are involved in the regulation of anxiety, their roles in Parkinson's disease (PD)-associated anxiety are still unknown. Here we assessed the importance of CeM 5-HT1A receptors for anxiety in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). The lesion induced anxiety-like behaviors, increased the firing rate and burst-firing pattern of CeM γ-aminobutyric acid (GABA) neurons, as well as decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), amygdala and ventral part of hippocampus (vHip). Intra-CeM injection of the selective 5-HT1A receptor agonist 8-OH-DPAT produced anxiolytic effects in the lesioned rats, and decreased the firing rate of CeM GABAergic neurons in two groups of rats. Compared to sham-operated rats, the duration of the inhibitory effect on the firing rate of GABAergic neurons was shortened in the lesioned rats. The injection increased DA levels in the mPFC and amygdala in two groups of rats and the vHip in the lesioned rats, and increased 5-HT level in the lesioned rats, whereas it decreased NA levels in the mPFC in two groups of rats and the vHip in the lesioned rats. Moreover, the mean density of 5-HT1A receptor and GABA double-labeled neurons in the CeM was reduced after the lesioning. These results suggest that activation of CeM 5-HT1A receptor produces anxiolytic effects in the 6-OHDA-lesioned rats, which involves decreased firing rate of the GABAergic neurons, and changed monoamine levels in the limbic and limbic-related brain regions. PMID:25797491

  4. Expression and function of ryanodine receptors in nonexcitable cells.

    PubMed

    Bennett, D L; Cheek, T R; Berridge, M J; De Smedt, H; Parys, J B; Missiaen, L; Bootman, M D

    1996-03-15

    We have used reverse transcriptase-polymerase chain reaction to investigate the expression of ryanodine receptors in several excitable and nonexcitable cell types. Consistent with previous reports, we detected ryanodine receptor expression in brain, heart, and skeletal muscle. In addition, we detected ryanodine receptor expression in various other excitable cells including PC 12 and A7r5 cells. Several muscle cell lines (BC3H1, C2C12, L6, and Sol8) weakly expressed ryanodine receptor when undifferentiated but strongly expressed type 1 and type 3 ryanodine receptor isoforms when differentiated into a muscle phenotype. Only 2 (HeLa and LLC-PK1 cells) out of 11 nonexcitable cell types examined expressed ryanodine receptors. Expression of ryanodine receptors at the protein level in these cells was confirmed using [3H]ryanodine binding. We also investigated the function of ryanodine receptors in Ca2+ signaling in HeLa cells using single-cell Fura-2 imaging. Neither caffeine nor ryanodine caused a detectable elevation of cytoplasmic Ca2+ in single HeLa cells. However, ryanodine caused a significant decrease in the amplitude of Ca 2+ signals evoked by repetitive stimulation with ATP. These studies show that ryanodine receptors are expressed in some nonexcitable cell types and furthermore suggest that the ryanodine receptors may be involved in a subtle regulation of intracellular Ca2+ responses. PMID:8626432

  5. Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT₁A receptors and stressful experiences.

    PubMed

    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. PMID:25701682

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

    PubMed

    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. PMID:24477871

  7. Quantification of the Serotonin 1A Receptor Using PET: Identification of a Potential Biomarker of Major Depression in Males.

    PubMed

    Kaufman, Joshua; Sullivan, Gregory M; Yang, Jie; Ogden, R Todd; Miller, Jeffrey M; Oquendo, Maria A; Mann, J John; Parsey, Ramin V; DeLorenzo, Christine

    2015-06-01

    Multiple lines of research have implicated the serotonin 1A (5-HT1A) receptor in major depressive disorder (MDD). Despite this, quantification of 5-HT1A is yet to yield a clinically relevant MDD biomarker. One reason may be that reported sex differences in the serotonergic system confound the comparison between diagnostic groups. Therefore, this study sought to determine whether differences in 5-HT1A binding between depressed and control subjects are affected by sex. Using positron emission tomography (PET), serotonin 1A binding was quantified in 50 patients with MDD (34 female, 16 male) and 57 healthy controls (32 female, 25 male). The subjects' 5-HT1A density (BPF, equal to the product of the density of available receptors and tracer affinity), was determined by using the PET tracer [carbonyl-C-11]-WAY-100635, a selective 5-HT1A antagonist. Results indicated that male MDD subjects had a 67.0% higher BPF across 13 brain regions compared with male controls (df=103, p<0.0001). The greatest difference between MDD subjects and controls was in the raphe (132%, p=0.000). Furthermore, by using a threshold, male controls can be distinguished from depressed males with high sensitivity and specificity (both >80%). In females, the separation between diagnostic groups yields much lower sensitivity and specificity. This data therefore suggests a specific biosignature for MDD in males. Identification of such a biosignature could provide a deeper understanding of depression pathology, help identify those at highest risk, and aid in the development of new therapies. Further, these findings suggest that combining male and female cohorts may not be optimal for some MDD studies. PMID:25578798

  8. Quantification of the Serotonin 1A Receptor Using PET: Identification of a Potential Biomarker of Major Depression in Males

    PubMed Central

    Kaufman, Joshua; Sullivan, Gregory M; Yang, Jie; Ogden, R Todd; Miller, Jeffrey M; Oquendo, Maria A; Mann, J John; Parsey, Ramin V; DeLorenzo, Christine

    2015-01-01

    Multiple lines of research have implicated the serotonin 1A (5-HT1A) receptor in major depressive disorder (MDD). Despite this, quantification of 5-HT1A is yet to yield a clinically relevant MDD biomarker. One reason may be that reported sex differences in the serotonergic system confound the comparison between diagnostic groups. Therefore, this study sought to determine whether differences in 5-HT1A binding between depressed and control subjects are affected by sex. Using positron emission tomography (PET), serotonin 1A binding was quantified in 50 patients with MDD (34 female, 16 male) and 57 healthy controls (32 female, 25 male). The subjects' 5-HT1A density (BPF, equal to the product of the density of available receptors and tracer affinity), was determined by using the PET tracer [carbonyl-C-11]-WAY-100635, a selective 5-HT1A antagonist. Results indicated that male MDD subjects had a 67.0% higher BPF across 13 brain regions compared with male controls (df=103, p<0.0001). The greatest difference between MDD subjects and controls was in the raphe (132%, p=0.000). Furthermore, by using a threshold, male controls can be distinguished from depressed males with high sensitivity and specificity (both >80%). In females, the separation between diagnostic groups yields much lower sensitivity and specificity. This data therefore suggests a specific biosignature for MDD in males. Identification of such a biosignature could provide a deeper understanding of depression pathology, help identify those at highest risk, and aid in the development of new therapies. Further, these findings suggest that combining male and female cohorts may not be optimal for some MDD studies. PMID:25578798

  9. Profiling Eph receptor expression in cells and tissues

    PubMed Central

    Noberini, Roberta; Rubio de la Torre, Elena; Pasquale, Elena B.

    2012-01-01

    The Eph receptor tyrosine kinase family includes many members, which are often expressed together in various combinations and can promiscuously interact with multiple ephrin ligands, generating intricate networks of intracellular signals that control physiological and pathological processes. Knowing the entire repertoire of Eph receptors and ephrins expressed in a biological sample is important when studying their biological roles. Moreover, given the correlation between Eph receptor/ephrin expression and cancer pathogenesis, their expression patterns could serve important diagnostic and prognostic purposes. However, profiling Eph receptor and ephrin expression has been challenging. Here we describe a novel and straightforward approach to catalog the Eph receptors present in cultured cells and tissues. By measuring the binding of ephrin Fc fusion proteins to Eph receptors in ELISA and pull-down assays, we determined that a mixture of four ephrins is suitable for isolating both EphA and EphB receptors in a single pull-down. We then used mass spectrometry to identify the Eph receptors present in the pull-downs and estimate their relative levels. This approach was validated in cultured human cancer cell lines, human tumor xenograft tissue grown in mice, and mouse brain tissue. The new mass spectrometry approach we have developed represents a useful tool for the identification of the spectrum of Eph receptors present in a biological sample and could also be extended to profiling ephrin expression. PMID:22568954

  10. Treadmill exercise enhances NMDA receptor expression in schizophrenia mice

    PubMed Central

    Park, Joon-Ki; Lee, Sam-Jun; Kim, Tae-Won

    2014-01-01

    Schizophrenia is a serious psychiatric disorder with several symptoms including cognitive dysfunction. Although the causes of schizophrenia are still unclear, there is a strong suspicion that the abnormality in N-methyl-D-aspartate (NMDA) receptor may contribute to schizophrenia symptoms. In the present study, the effect of treadmill exercise on the NMDA receptor expression was evaluated using MK-801-induced schizophrenia mice. Immunohistochemistry for expressions of NMDA receptor tyrosine hydroxylase (TH) was conducted. Western blot for brain-derived neurotrophic factor (BDNF) was also performed. In the present results, the mice in the MK-801-treated group displayed reduced NMDA receptor expression. Enhanced TH expression and suppressed BDNF expression were also observed in the MK-801-treated mice. Treadmill exercise improved NMDA receptor expression in the MK-801-induced schizophrenia mice. Treadmill exercise also suppressed TH expression and enhanced BDNF expression in the MK-801-induced schizophrenia mice. The present study showed that down-regulation of NMDA receptor demonstrated schizophrenia-like parameters, meanwhile treadmill running improved schizophrenia-related parameters through enhancing NMDA receptor expression. PMID:24678500

  11. Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala

    PubMed Central

    Jensen, Morten; Ratner, Cecilia; Rudenko, Olga; Christiansen, Søren H.; Skov, Louise J.; Hundahl, Cecilie; Woldbye, David P.D.

    2016-01-01

    Background: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly. Methods: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. Results: We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff–induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression. Conclusions: Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system. PMID:26578081

  12. Vitamin D Receptor Expression in Vitiligo

    PubMed Central

    Doss, Reham William; El-Rifaie, Abdel-Aziz; Gohary, Yasser M; Rashed, Laila A

    2015-01-01

    Background: Vitiligo is a progressive depigmenting disorder characterized by loss of functional melanocytes from the epidermis. The etiopathogenesis of vitiligo is still unclear. Vitamin D has stimulatory effects on melanocytes and acts through its nuclear Vitamin D receptor (VDR) on target cells. Aims and Objectives: The purpose of this study was to declare the role of Vitamin D in the pathogenesis of vitiligo. Materials and Methods: This case-control study included 30 vitiligo patients and 30 age, gender-matched healthy controls. Blood samples were withdrawn from the study subjects, and the serum 25(OH) D level was determined by an enzyme-linked immunosorbent assay technique. Serum 25(OH) D levels were divided into: Normal or sufficient (≥30 ng/ml), insufficient (< 30-> 20ng/ml), and deficient (≤20 ng/ml) levels. Skin biopsies were obtained from the depigmented lesions and clinically normal skin of vitiligo patients and from the controls, and VDR gene expression was determined using real-time polymerase chain reaction. Results: Only 10 patients with vitiligo (33.3%) had sufficient serum 25(OH) D levels (≥30 ng/ml), 12 patients (40%) had insufficient levels, and 8 patients (26.7%) had deficient levels. On the other hand, most of the controls (96.7%) had sufficient levels. The mean serum 25(OH) D level in patients was significantly decreased compared to controls (P < 0.001). The VDR-mRNA expression was also significantly decreased in lesional and nonlesional skin of patients compared to controls (P < 0.001, P < 0.001, respectively). Conclusion: Vitamin D deficiency influences the extent of vitiligo and could contribute to the pathogenesis of vitiligo through its immunomodulatory role and its role in melanogenesis. PMID:26677265

  13. Expression of the Endocannabinoid Receptors in Human Fascial Tissue

    PubMed Central

    Fede, C.; Albertin, G.; Petrelli, L.; Sfriso, M.M.; Biz, C.; Caro, R. De; Stecco, C.

    2016-01-01

    Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues. Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia. However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established. Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2. Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts. This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments. Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation. PMID:27349320

  14. Expression of the endocannabinoid receptors in human fascial tissue.

    PubMed

    Fede, C; Albertin, G; Petrelli, L; Sfriso, M M; Biz, C; De Caro, R; Stecco, C

    2016-01-01

    Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues. Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia. However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established. Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2. Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts. This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments. Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation. PMID:27349320

  15. Expression of prostanoid receptors in human lower segment pregnant myometrium.

    PubMed

    Leonhardt, Andreas; Glaser, Alexander; Wegmann, Markus; Hackenberg, Reinhard; Nüsing, Rolf M

    2003-11-01

    Prostanoids, especially prostaglandin (PG) E(2), are important mediators of uterine relaxation and contractions during gestation and parturition. Inhibitors of PG formation as well as PG analogues are used to modulate uterine tonus. So far, only limited data are available regarding the expression of prostanoid receptors in human pregnant myometrium. In the present study, the expression of the receptors for PGE(2) (EP1, EP2, EP3, EP4), PGF(2alpha) (FP), prostacyclin (IP), and thromboxane A(2) (TP) in human pregnant myometrium was studied by RT-PCR, in situ hybridization and immunohistochemistry. Myometrial tissue was obtained from five women at term and not in labour and from two women who delivered preterm. Tissue specimens were excised from the upper edge of the transverse lower uterine segment incision. In all tissues analysed, EP1, EP2, EP3, EP4, FP, TP and IP receptor mRNA and protein was detected. mRNA expression for PGD(2) (DP) receptor was not detected in the majority of tissue specimens. EP1, EP2, EP4, IP, TP and FP receptor protein was detected on myometrial smooth muscle cells, whereas EP3 receptor protein was only expressed by stromal and endothelial cells. In situ hybridization experiments yielded similar results. The expression of the EP2 receptor mRNA was inversely related to gestational age. We suggest that the contractile effect of PGE(2) at term is probably mediated directly by the EP1 receptor expressed in myometrial smooth muscle cells and indirectly by the EP3 receptor expressed in stromal cells and a decrease in EP2 receptor expression. PMID:14580364

  16. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    PubMed Central

    Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S.; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.

    2014-01-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands. PMID:25426041

  17. Dopamine receptor-mediated regulation of neuronal "clock" gene expression.

    PubMed

    Imbesi, M; Yildiz, S; Dirim Arslan, A; Sharma, R; Manev, H; Uz, T

    2009-01-23

    Using a transgenic mice model (i.e. "clock" knockouts), clock transcription factors have been suggested as critical regulators of dopaminergic behaviors induced by drugs of abuse. Moreover, it has been shown that systemic administration of psychostimulants, such as cocaine and methamphetamine regulates the striatal expression of clock genes. However, it is not known whether dopamine receptors mediate these regulatory effects of psychostimulants at the cellular level. Primary striatal neurons in culture express dopamine receptors as well as clock genes and have been successfully used in studying dopamine receptor functioning. Therefore, we investigated the role of dopamine receptors on neuronal clock gene expression in this model using specific receptor agonists. We found an inhibitory effect on the expression of mClock and mPer1 genes with the D2-class (i.e. D2/D3) receptor agonist quinpirole. We also found a generalized stimulatory effect on the expression of clock genes mPer1, mClock, mNPAS2 (neuronal PAS domain protein 2), and mBmal1 with the D1-class (i.e. D1) receptor agonist SKF38393. Further, we tested whether systemic administration of dopamine receptor agonists causes similar changes in striatal clock gene expression in vivo. We found quinpirole-induced alterations in mPER1 protein levels in the mouse striatum (i.e. rhythm shift). Collectively, our results indicate that the dopamine receptor system may mediate psychostimulant-induced changes in clock gene expression. Using striatal neurons in culture as a model, further research is needed to better understand how dopamine signaling modulates the expression dynamics of clock genes (i.e. intracellular signaling pathways) and thereby influences neuronal gene expression, neuronal transmission, and brain functioning. PMID:19017537

  18. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor

    PubMed Central

    Walker, Christopher S; Eftekhari, Sajedeh; Bower, Rebekah L; Wilderman, Andrea; Insel, Paul A; Edvinsson, Lars; Waldvogel, Henry J; Jamaluddin, Muhammad A; Russo, Andrew F; Hay, Debbie L

    2015-01-01

    Objective The trigeminovascular system plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal system. Methods Receptor expression was determined using Taqman G protein-coupled receptor arrays and immunohistochemistry in trigeminal ganglia (TG) and the spinal trigeminal complex of the brainstem in rat and human. Receptor pharmacology was quantified using sensitive signaling assays in primary rat TG neurons. Results mRNA and histological expression analysis in rat and human samples revealed the presence of two CGRP-responsive receptors (AMY1: calcitonin receptor/receptor activity-modifying protein 1 [RAMP1]) and the CGRP receptor (calcitonin receptor-like receptor/RAMP1). In support of this finding, quantification of agonist and antagonist potencies revealed a dual population of functional CGRP-responsive receptors in primary rat TG neurons. Interpretation The unexpected presence of a functional non-canonical CGRP receptor (AMY1) at neural sites important for craniofacial pain has important implications for targeting the CGRP axis in migraine. PMID:26125036

  19. Expression of prostanoid receptors in human ductus arteriosus.

    PubMed

    Leonhardt, Andreas; Glaser, Alexander; Wegmann, Markus; Schranz, Dietmar; Seyberth, Hannsjörg; Nüsing, Rolf

    2003-02-01

    1. Prostaglandins play a major role in maintaining ductal patency in utero. Ductal tone is regulated by both locally released and circulating vasodilatory prostaglandins. In infants with ductus arteriosus-dependent congenital heart disease, ductal patency is maintained by intravenous administration of prostaglandin (PG) E(1). Little information is available regarding the expression of prostaglandin receptors in man. 2. By means of RT-PCR and immunohistochemistry we studied the expression of the PGI(2) receptor (IP), the four different PGE(2) receptors (EP1, EP2, EP3 and EP4), and the receptors for thromboxane (Tx) A(2) (TP), PGD(2) (DP) and PGF(2alpha) (FP) in the ductus arteriosus of three newborn infants with ductus arteriosus-dependent congenital heart disease and intravenous infusion of PGE(1) and of one 8 month old child with a patent ductus arteriosus. 3. The EP3, EP4, FP, IP and TP receptor were markedly expressed at the mRNA and protein level, whereas the EP2 receptor was weakly expressed and the EP1 receptor was detected in two out of four tissue specimens only. The DP receptor was not detected in any of the samples. The most pronounced expression, which was located in the media of the ductus arteriosus, was observed for the EP4 and TP receptors followed by IP and FP receptor protein. 4. These data indicate that ductal patency during the infusion of PGE(1) in infants with ductus arteriosus-dependent congenital heart disease might be mediated by the EP4 and IP receptor. The data further suggest that a heterogeneous population of prostanoid receptors may contribute to the regulation of ductus arteriosus tone in humans. PMID:12598419

  20. Serotonin 5-HT2 Receptors Induce a Long-Lasting Facilitation of Spinal Reflexes Independent of Ionotropic Receptor Activity

    PubMed Central

    Shay, Barbara L.; Sawchuk, Michael; Machacek, David W.; Hochman, Shawn

    2009-01-01

    Dorsal root-evoked stimulation of sensory afferents in the hemisected in vitro rat spinal cord produces reflex output, recorded on the ventral roots. Transient spinal 5-HT2C receptor activation induces a long-lasting facilitation of these reflexes (LLFR) by largely unknown mechanisms. Two Sprague-Dawley substrains were used to characterize network properties involved in this serotonin (5-HT) receptor-mediated reflex plasticity. Serotonin more easily produced LLFR in one substrain and a long-lasting depression of reflexes (LLDR) in the other. Interestingly, LLFR and LLDR were bidirectionally interconvertible using 5-HT2A/2C and 5-HT1A receptor agonists, respectively, regardless of substrain. LLFR was predominantly Aβ afferent fiber mediated, consistent with prominent 5-HT2C receptor expression in the Aβ fiber projection territories (deeper spinal laminae). Reflex facilitation involved an unmasking of polysynaptic pathways and an increased receptive field size. LLFR emerged even when reflexes were evoked three to five times/h, indicating an activity independent induction. Both the NMDA and AMPA/kainate receptor-mediated components of the reflex could be facilitated, and facilitation was dependent on 5-HT receptor activation alone, not on coincident reflex activation in the presence of 5-HT. Selective blockade of GABAA and/or glycine receptors also did not prevent reflex amplification and so are not required for LLFR. Indeed, a more robust response was seen after blockade of spinal inhibition, indicating that inhibitory processes serve to limit reflex amplification. Overall we demonstrate that the serotonergic system has the capacity to induce long-lasting bidirectional changes in reflex strength in a manner that is nonassociative and independent of evoked activity or activation of ionotropic excitatory and inhibitory receptors. PMID:16033939

  1. Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA.

    PubMed

    Hasler, F; Studerus, E; Lindner, K; Ludewig, S; Vollenweider, F X

    2009-11-01

    Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system. PMID:18635693

  2. Hypothyroidism affects D2 receptor-mediated breathing without altering D2 receptor expression.

    PubMed

    Schlenker, Evelyn H; Del Rio, Rodrigo; Schultz, Harold D

    2014-03-01

    Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age-matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a peripheral D2 receptor agonist), increased oxygen consumption and body temperature in awake air-exposed hypothyroid female hamsters and stimulated their ventilation before and following exposure to hypoxia. Carmoxirole depressed frequency of breathing in euthyroid hamsters prior to, during and following hypoxia exposures and stimulated it in the hypothyroid hamsters following hypoxia. Although hypothyroidism did not affect expression of D2 receptors, it influenced central D2 modulation of breathing in a disparate manner relative to euthyroid hamsters. PMID:24434437

  3. Odor memories regulate olfactory receptor expression in the sensory periphery.

    PubMed

    Claudianos, Charles; Lim, Julianne; Young, Melanie; Yan, Shanzhi; Cristino, Alexandre S; Newcomb, Richard D; Gunasekaran, Nivetha; Reinhard, Judith

    2014-05-01

    Odor learning induces structural and functional modifications throughout the olfactory system, but it is currently unknown whether this plasticity extends to the olfactory receptors (Or) in the sensory periphery. Here, we demonstrate that odor learning induces plasticity in olfactory receptor expression in the honeybee, Apis mellifera. Using quantitative RT-PCR analysis, we show that six putative floral scent receptors were differentially expressed in the bee antennae depending on the scent environment that the bees experienced. Or151, which we characterized using an in vitro cell expression system as a broadly tuned receptor binding floral odorants such as linalool, and Or11, the specific receptor for the queen pheromone 9-oxo-decenoic acid, were significantly down-regulated after honeybees were conditioned with the respective odorants in an olfactory learning paradigm. Electroantennogram recordings showed that the neural response of the antenna was similarly reduced after odor learning. Long-term odor memory was essential for inducing these changes, suggesting that the molecular mechanisms involved in olfactory memory also regulate olfactory receptor expression. Our study demonstrates for the first time that olfactory receptor expression is experience-dependent and modulated by scent conditioning, providing novel insight into how molecular regulation at the periphery contributes to plasticity in the olfactory system. PMID:24628891

  4. Endotoxin suppresses rat hepatic low-density lipoprotein receptor expression.

    PubMed Central

    Liao, W; Rudling, M; Angelin, B

    1996-01-01

    Endotoxin induces hyperlipidaemia in experimental animals. In the current study, we investigated whether endotoxin alters hepatic low-density lipoprotein (LDL) receptor expression in rats. Endotoxin treatment suppressed hepatic LDL receptor expression in a dose- and time-dependent manner. Eighteen hours after intraperitoneal injection of increasing amounts of endotoxin, LDL receptor and its mRNA levels were determined by ligand blot and solution hybridization respectively. LDL receptor expression was inhibited by about 70% at a dose of 500 micrograms/100 g body weight. However, LDL receptor mRNA levels were markedly increased in all endotoxin-treated groups at this time point (by 83-136%; P < 0.001). Time-course experiments showed that LDL receptor expression was already reduced by 48% 4 h after endotoxin injection and was maximally reduced (by 63-65%) between 8 and 18 h. Changes in hepatic LDL receptor mRNA showed a different pattern. By 4 h after endotoxin injection, LDL receptor mRNA had decreased by 78% (P < 0.001). However, by 8 h after endotoxin injection, LDL receptor mRNA had returned to levels similar to controls, and 18 and 24 h after endotoxin injection, they were increased by about 60% (P < 0.05). Separation of plasma lipoproteins by FPLC demonstrated that endotoxin-induced changes in plasma triacylglycerols and cholesterol were due to accumulation of plasma apolipoprotein B-containing lipoproteins among very-low-density lipoprotein, intermediate-density lipoprotein and LDL. It is concluded that endotoxin suppresses hepatic LDL receptor expression in vivo in rats. PMID:8611169

  5. Giant vesicles functionally expressing membrane receptors for an insect pheromone.

    PubMed

    Hamada, Satoshi; Tabuchi, Masashi; Toyota, Taro; Sakurai, Takeshi; Hosoi, Tomohiro; Nomoto, Tomonori; Nakatani, Kei; Fujinami, Masanori; Kanzaki, Ryohei

    2014-03-18

    To date, biochemical approaches to membrane receptors have been limited to the following methods: knockout or overexpression of membrane receptors by gene introduction and genome engineering or extraction of membrane receptor-surfactant complexes from innate cells and their introduction into model biomembranes. Here, we describe the development of a third method involving gene expression using cell-free in situ protein synthesis inside model biomembrane capsules. We verified this method by synthesizing olfactory receptors from the silkmoth Bombyx mori inside giant vesicles and found that they were excited in the presence of their ligand the Bombyx mori sex pheromone. PMID:24509495

  6. Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice.

    PubMed

    Halberstadt, Adam L; Koedood, Liselore; Powell, Susan B; Geyer, Mark A

    2011-11-01

    Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT(2C) receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT(2A) receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT(1A) antagonist WAY-100635 but were not altered by the selective 5-HT(2C) antagonist SB 242,084 or by 5-HT(2A) receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT(2C) and 5-HT(1A) receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6-9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT(2A) sites but is inactive at the 5-HT(1A) receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin

  7. Mistargeting hippocampal axons by expression of a truncated Eph receptor

    PubMed Central

    Yue, Yong; Chen, Zhi-Yong; Gale, Nick W.; Blair-Flynn, Jan; Hu, Tian-Jing; Yue, Xin; Cooper, Margaret; Crockett, David P.; Yancopoulos, George D.; Tessarollo, Lino; Zhou, Renping

    2002-01-01

    Topographic mapping of axon terminals is a general principle of neural architecture that underlies the interconnections among many neural structures. The Eph family tyrosine kinase receptors and their ligands, the ephrins, have been implicated in the formation of topographic projection maps. We show that multiple Eph receptors and ligands are expressed in the hippocampus and its major subcortical projection target, the lateral septum, and that expression of a truncated Eph receptor in the mouse brain results in a pronounced alteration of the hippocamposeptal topographic map. Our observations provide strong support for a critical role of Eph family guidance factors in regulating ontogeny of hippocampal projections. PMID:12124402

  8. Serotonin (5-HT) and 5-HT2A receptor agonists suppress lipolysis in primary rat adipose cells.

    PubMed

    Hansson, Björn; Medina, Anya; Fryklund, Claes; Fex, Malin; Stenkula, Karin G

    2016-05-27

    Serotonin (5-HT) is a biogenic monoamine that functions both as a neurotransmitter and a circulating hormone. Recently, the metabolic effects of 5-HT have gained interest and peripheral 5-HT has been proposed to influence lipid metabolism in various ways. Here, we investigated the metabolic effects of 5-HT in isolated, primary rat adipose cells. Incubation with 5-HT suppressed β-adrenergically stimulated glycerol release and decreased phosphorylation of protein kinase A (PKA)-dependent substrates, hormone sensitive lipase (Ser563) and perilipin (Ser522). The inhibitory effect of 5-HT on lipolysis enhanced the anti-lipolytic effect of insulin, but sustained in the presence of phosphodiesterase inhibitors, OPC3911 and isobuthylmethylxanthine (IBMX). The relative expression of 5-HT1A, -2B and -4 receptor class family were significantly higher in adipose tissue compared to adipose cells, whereas 5-HT1D, -2A and -7 were highly expressed in isolated adipose cells. Similar to 5-HT, 5-HT2 receptor agonists reduced lipolysis while 5-HT1 receptor agonists rather decreased non-stimulated and insulin-stimulated glucose uptake. Together, these data provide evidence of a direct effect of 5-HT on adipose cells, where 5-HT suppresses lipolysis and glucose uptake, which could contribute to altered systemic lipid- and glucose metabolism. PMID:27109474

  9. Nested expression domains for odorant receptors in zebrafish olfactory epithelium.

    PubMed

    Weth, F; Nadler, W; Korsching, S

    1996-11-12

    The mapping of high-dimensional olfactory stimuli onto the two-dimensional surface of the nasal sensory epithelium constitutes the first step in the neuronal encoding of olfactory input. We have used zebrafish as a model system to analyze the spatial distribution of odorant receptor molecules in the olfactory epithelium by quantitative in situ hybridization. To this end, we have cloned 10 very divergent zebrafish odorant receptor molecules by PCR. Individual genes are expressed in sparse olfactory receptor neurons. Analysis of the position of labeled cells in a simplified coordinate system revealed three concentric, albeit overlapping, expression domains for the four odorant receptors analyzed in detail. Such regionalized expression should result in a corresponding segregation of functional response properties. This might represent the first step of spatial encoding of olfactory input or be essential for the development of the olfactory system. PMID:8917589

  10. Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

    PubMed

    Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

    2015-06-01

    By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. PMID:25924828

  11. Cloning, constitutive activity and expression profiling of two receptors related to relaxin receptors in Drosophila melanogaster.

    PubMed

    Van Hiel, Matthias B; Vandersmissen, Hans Peter; Proost, Paul; Vanden Broeck, Jozef

    2015-06-01

    Leucine-rich repeat containing G protein-coupled receptors (LGRs) comprise a cluster of transmembrane proteins, characterized by the presence of a large N-terminal extracellular domain. This receptor group can be classified into three subtypes. Belonging to the subtype C LGRs are the mammalian relaxin receptors LGR7 (RXFP1) and LGR8 (RXFP2), which mediate important reproductive and other processes. We identified two related receptors in the genome of the fruit fly and cloned their open reading frames into an expression vector. Interestingly, dLGR3 demonstrated constitutive activity at very low doses of transfected plasmid, whereas dLGR4 did not show any basal activity. Both receptors exhibited a similar expression pattern during development, with relatively high transcript levels during the first larval stage. In addition, both receptors displayed higher expression in male adult flies as compared to female flies. Analysis of the tissue distribution of both receptor transcripts revealed a high expression of dLGR3 in the female fat body, while the expression of dLGR4 peaked in the midgut of both the wandering and adult stage. PMID:25064813

  12. Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.

    PubMed

    Peñas-Cazorla, Raúl; Vilaró, M Teresa

    2015-11-01

    Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists. PMID:25183542

  13. Nuclear receptor SHP inhibition of Dnmt1 expression via ERRγ.

    PubMed

    Zhang, Yuxia; Wang, Li

    2011-05-01

    We describe a transcriptional mechanism regulating the expression of Dnmt1 by nuclear receptors. We show that ERRγ functions as a transcriptional activator of mouse and human Dnmt1 expression by direct binding to its response elements (ERE1/ERE2) in the dnmt1/DNMT1 promoters. The induction of Dnmt1 by ERRγ is repressed by SHP through SHP inhibition of ERRγ transactivity, diminishing ERRγ recruitment to the Dnmt1 promoter, and altering the conformation of local chromatin from an active mode by ERRγ to an inactive mode. Our study provides the first evidence for nuclear receptor mediated regulation of Dnmt1 expression through ERRγ and SHP crosstalk. PMID:21459093

  14. Nuclear receptor SHP inhibition of Dnmt1 expression via ERRγ

    PubMed Central

    Zhang, Yuxia; Wang, Li

    2011-01-01

    We describe a transcriptional mechanism regulating the expression of Dnmt1 by nuclear receptors. We show that ERRγ functions as a transcriptional activator of mouse and human Dnmt1 expression by direct binding to its response elements (ERE1/ERE2) in the dnmt1/DNMT1 promoters. The induction of Dnmt1 by ERRγ is repressed by SHP through SHP inhibition of ERRγ transactivity, diminishing ERRγ recruitment to the Dnmt1 promoter, and altering the conformation of local chromatin from an active mode by ERRγ to an inactive mode. Our study provides the first evidence for nuclear receptor mediated regulation of Dnmt1 expression through ERRγ and SHP crosstalk. PMID:21459093

  15. Aberrant expression of hormone receptors in adrenal Cushing's syndrome.

    PubMed

    Christopoulos, Stavroula; Bourdeau, Isabelle; Lacroix, André

    2004-01-01

    In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has emerged. The ectopic or aberrant expression of G-protein-coupled hormone receptors in the adrenal cortex was found to play a central role in the regulation of cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some unilateral adrenal adenomas. Various aberrant receptors, functionally coupled to steroidogenesis, have been reported: GIP, vasopressin, beta-adrenergic, LH/hCG, and serotonin receptors have been best characterized, but angiotensin, leptin, glucagon, IL-1 and TSH receptors have also been described. The molecular mechanisms responsible for the aberrant expression of these receptors are currently unknown. One or many of these aberrant receptors are present in most cases of AIMAH and in some cases of adrenal adenomas with overt or sub-clinical secretion of cortisol. Clinical protocols to screen for such aberrant receptors have been developed and should be performed in all patients with AIMAH. The identification of such aberrant regulation of steroidogenesis in AIMAH provides the novel opportunity to treat some of these patients with pharmacological agents that either suppress the endogenous ligand or block the aberrant receptor, thus avoiding bilateral adrenalectomy. PMID:16010457

  16. Stable Expression and Characterization of an Optimized Mannose Receptor

    PubMed Central

    Vigerust, David J; Vick, Sherell; Shepherd, Virginia L

    2015-01-01

    The mannose receptor (MR) is a macrophage surface receptor that recognizes pathogen associated molecular patterns (PAMPs) from a diverse array of bacterial, fungal and viral pathogens. Functional studies of the MR are hampered by the scarcity of human cell lines that express the receptor. Current model systems available for the study of MR biology often demonstrate low levels of expression and do not retain many of the classical MR properties. Although several laboratories have reported transient and stable expression of MR from plasmids, preliminary data from our laboratory suggests that these plasmids produce a protein that lacks critical domains and is often not stable over time. In this current report we describe the generation and characterization of a novel human codon-optimized system for transient and stable MR expression. Rare codons and sequences that contribute to mRNA instability were modified to produce mRNA that is qualitatively and quantitatively improved. Confocal imaging of the transient and stably expressed optimized receptor demonstrates a distribution consistent with previous reports. To demonstrate the functional characteristics of the optimized receptor, we further show that the introduction of codon-optimized MR plasmid can confer MR-associated phagocytosis of S. aureus to non-phagocytic HeLa cells. We show that three molecules participate in the engagement and internalization of S. aureus. MR was found to colocalize with Toll-like receptor 2 (TLR2) and Rab5 following exposure to pHrodo-stained S. aureus, suggesting cooperation among the three molecules to engage and internalize the bacterial particle. This study describes a transfection capable, optimized MR receptor with functional characteristics similar to the wild type receptor and further demonstrates a new system for the continued study of MR biology and function. PMID:26581716

  17. Repertoire of Chemokine Receptor Expression in the Female Genital Tract

    PubMed Central

    Patterson, Bruce K.; Landay, Alan; Andersson, Jan; Brown, Clark; Behbahani, Homira; Jiyamapa, Dan; Burki, Zareefa; Stanislawski, Donna; Czerniewski, Mary Ann; Garcia, Patricia

    1998-01-01

    Sexually transmitted diseases, genital ulcer disease, and progesterone therapy increase susceptibility to lentivirus transmission. Infection of cells by human immunodeficiency virus (HIV) is dependent on expression of specific chemokine receptors known to function as HIV co-receptors. Quantitative kinetic reverse transcription-polymerase chain reaction was developed to determine the in vivo expression levels of CCR5, CXCR4, CCR3, CCR2b, and the cytomegalovirus-encoded US28 in peripheral blood mononuclear cells and cervical biopsies from 12 women with and without sexually transmitted diseases, genital ulcer disease, and progesterone-predominant conditions. Our data indicate that CCR5 is the major HIV co-receptor expressed in the female genital tract, and CXCR4 is the predominantly expressed HIV co-receptor in peripheral blood. CCR5 mRNA expression in the ectocervix was 10-fold greater than CXCR4, 20-fold greater than CCR2b, and 100-fold greater than CCR3. In peripheral blood, CXCR4 expression was 1.5-fold greater than CCR5, 10-fold greater than CCR2b, and 15-fold greater than CCR3. US28 was not expressed in cervical tissue despite expression in peripheral blood mononuclear cells from five individuals. CCR5 was significantly increased (p < 0.02) in biopsies from women with sexually transmitted diseases and others who were progesterone predominant. In vitro studies demonstrate that progesterone increases CCR5, CXCR4, and CCR3 expression and decreases CCR2b expression in lymphocytes and monocytes/macrophages. Characterization of chemokine receptors at the tissue level provides important information in identifying host determinants of HIV-1 transmission. PMID:9708808

  18. Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium

    PubMed Central

    Shabir, Saqib; Cross, William; Kirkwood, Lisa A.; Pearson, Joanna F.; Appleby, Peter A.; Walker, Dawn; Eardley, Ian

    2013-01-01

    In addition to its role as a physical barrier, the urothelium is considered to play an active role in mechanosensation. A key mechanism is the release of transient mediators that activate purinergic P2 receptors and transient receptor potential (TRP) channels to effect changes in intracellular Ca2+. Despite the implied importance of these receptors and channels in urothelial tissue homeostasis and dysfunctional bladder disease, little is known about their functional expression by the human urothelium. To evaluate the expression and function of P2X and P2Y receptors and TRP channels, the human ureter and bladder were used to separate urothelial and stromal tissues for RNA isolation and cell culture. RT-PCR using stringently designed primer sets was used to establish which P2 and TRP species were expressed at the transcript level, and selective agonists/antagonists were used to confirm functional expression by monitoring changes in intracellular Ca2+ and in a scratch repair assay. The results confirmed the functional expression of P2Y4 receptors and excluded nonexpressed receptors/channels (P2X1, P2X3, P2X6, P2Y6, P2Y11, TRPV5, and TRPM8), while a dearth of specific agonists confounded the functional validation of expressed P2X2, P2X4, P2Y1, P2Y2, TRPV2, TRPV3, TRPV6 and TRPM7 receptors/channels. Although a conventional response was elicited in control stromal-derived cells, the urothelial cell response to well-characterized TRPV1 and TRPV4 agonists/antagonists revealed unexpected anomalies. In addition, agonists that invoked an increase in intracellular Ca2+ promoted urothelial scratch repair, presumably through the release of ATP. The study raises important questions about the ligand selectivity of receptor/channel targets expressed by the urothelium. These pathways are important in urothelial tissue homeostasis, and this opens the possibility of selective drug targeting. PMID:23720349

  19. Estrogen and Progesterone hormone receptor expression in oral cavity cancer

    PubMed Central

    Biegner, Thorsten; Teriete, Peter; Hoefert, Sebastian; Krimmel, Michael; Munz, Adelheid; Reinert, Siegmar

    2016-01-01

    Background Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible. Material and Methods Estrogen Receptor alpha (ERα) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERα and PR expression. Results ERα expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERα positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERα and PR. Conclusions ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC. Key words:Oral squamous cell carcinoma, estrogen receptor, progesterone receptor, hormone receptor. PMID:27475696

  20. Expression of Angiotensin II Receptor-1 in Human Articular Chondrocytes

    PubMed Central

    Kawakami, Yuki; Matsuo, Kosuke; Murata, Minako; Yudoh, Kazuo; Nakamura, Hiroshi; Shimizu, Hiroyuki; Beppu, Moroe; Inaba, Yutaka; Saito, Tomoyuki; Kato, Tomohiro; Masuko, Kayo

    2012-01-01

    Background. Besides its involvement in the cardiovascular system, the renin-angiotensin-aldosterone (RAS) system has also been suggested to play an important role in inflammation. To explore the role of this system in cartilage damage in arthritis, we investigated the expression of angiotensin II receptors in chondrocytes. Methods. Articular cartilage was obtained from patients with osteoarthritis, rheumatoid arthritis, and traumatic fractures who were undergoing arthroplasty. Chondrocytes were isolated and cultured in vitro with or without interleukin (IL-1). The expression of angiotensin II receptor types 1 (AT1R) and 2 (AT2R) mRNA by the chondrocytes was analyzed using reverse transcription-polymerase chain reaction (RT-PCR). AT1R expression in cartilage tissue was analyzed using immunohistochemistry. The effect of IL-1 on AT1R/AT2R expression in the chondrocytes was analyzed by quantitative PCR and flow cytometry. Results. Chondrocytes from all patient types expressed AT1R/AT2R mRNA, though considerable variation was found between samples. Immunohistochemical analysis confirmed AT1R expression at the protein level. Stimulation with IL-1 enhanced the expression of AT1R/AT2R mRNA in OA and RA chondrocytes. Conclusions. Human articular chondrocytes, at least partially, express angiotensin II receptors, and IL-1 stimulation induced AT1R/AT2R mRNA expression significantly. PMID:23346400

  1. β-Adrenergic receptor expression in vascular tumors.

    PubMed

    Chisholm, Karen M; Chang, Kay W; Truong, Mai T; Kwok, Shirley; West, Rob B; Heerema-McKenney, Amy E

    2012-11-01

    Propranolol has recently emerged as an effective therapy for infantile hemangiomas causing regression. The β-adrenergic receptor (AR) antagonist is thought to cause vasoconstriction by its effect on nitric oxide, block angiogenesis by its effect on vascular endothelial growth factor (VEGF), and induce apoptosis. In a prior report, we identified expression of β2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma that responded to propranolol treatment. We now explore the expression of βARs on a variety of vascular lesions utilizing a tissue microarray containing 141 lesions, including infantile hemangiomas, angiosarcomas, hemangiomas, hemangioendotheliomas, and various vascular malformations. The array was immunostained for B2-AR, B2-ARP, and β3-AR (B3-AR), and the results scored for the intensity of endothelial cell expression as negative, weak positive, or strong positive. All phases of infantile hemangiomas had strong expression of all three receptors, with the exception of only weak expression of B2-ARP in the proliferative phase infantile hemangioma. Strong expression of all three receptors was present in many hemangiomas, hemangioendotheliomas, and vascular malformations. Absent to weak expression of all three receptors was seen in glomus tumor, hobnail hemangioendothelioma, pyogenic granuloma, and reactive vascular proliferations. This is the first study to report β-AR expression in a variety of vascular lesions. Although immunohistochemical expression of the receptors does not necessarily indicate that similar pathways of responsiveness to β-blockade are present, it does raises the possibility that β-blockade could potentially affect apoptosis and decrease responsiveness to VEGF. Additional study is warranted, as therapeutic options are limited for some patients with these lesions. PMID:22743651

  2. Developmental changes in NMDA receptor expression in the platyfish brain

    NASA Technical Reports Server (NTRS)

    Flynn, K. M.; Schreibman, M. P.; Magliulo-Cepriano, L.

    1997-01-01

    We have examined the distribution of the N-methyl-D-aspartate (NMDA) receptor in the brain of a freshwater teleost using an antibody against the R1 subunit of the receptor (NMDAR1). The primary site of localization was the nucleus olfactoretinalis (NOR), a significant gonadotropin releasing hormone (GnRH)-containing brain nucleus. The number of cells expressing NMDAR1 in this nucleus was dependent upon developmental stage, with pubescent and mature animals displaying significantly more stained cells than immature and senescent animals. This is the first reported observation of age- and maturity-related NMDA receptor association with GnRH-containing brain areas.

  3. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    SciTech Connect

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. )

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  4. TAM Receptors in Leukemia: Expression, Signaling, and Therapeutic Implications

    PubMed Central

    Brandão, Luis; Migdall-Wilson, Justine; Eisenman, Kristen; Graham, Douglas K.

    2016-01-01

    In the past 30 years there has been remarkable progress in the treatment of leukemia and lymphoma. However, current treatments are largely ineffective against relapsed leukemia and, in the case of pediatric patients, are often associated with severe long-term toxicities. Thus, there continues to be a critical need for the development of effective biologically targeted therapies. The TAM family of receptor tyrosine kinases—Tyro3, Axl, and Mer—plays an important role in normal hematopoiesis, including natural killer cell maturation, macrophage function, and platelet activation and signaling. Furthermore, TAM receptor activation leads to upregulation of pro-survival and proliferation signaling pathways, and aberrant TAM receptor expression contributes to cancer development, including myeloid and lymphoid leukemia. This review summarizes the role of TAM receptors in leukemia. We outline TAM receptor expression patterns in different forms of leukemia, describe potential mechanisms leading to their overexpression, and delineate the signaling pathways downstream of receptor activation that have been implicated in leukemogenesis. Finally, we discuss the current research focused on inhibitors against these receptors in an effort to develop new therapeutic strategies for leukemia. PMID:22150307

  5. Multiple melanocortin receptors are expressed in bone cells

    NASA Technical Reports Server (NTRS)

    Zhong, Qing; Sridhar, Supriya; Ruan, Ling; Ding, Ke-Hong; Xie, Ding; Insogna, Karl; Kang, Baolin; Xu, Jianrui; Bollag, Roni J.; Isales, Carlos M.

    2005-01-01

    Melanocortin receptors belong to the seven transmembrane domain, G-protein coupled family of receptors. There are five members of this receptor family labeled MC1R-MC5R. These receptors are activated by fragments derived from a larger molecule, proopiomelanocortin (POMC) and include ACTH, alpha beta and gamma-MSH and beta-endorphin. Because of in vitro and in vivo data suggesting direct effects of these POMC molecules on bone and bone turnover, we examined bone and bone derived cells for the presence of the various members of the melanocortin receptor family. We report that the five known melanocortin receptors are expressed to varying degrees in osteoblast-like and osteoclastic cells. POMC fragments increased proliferation and expression of a variety of genes in osteoblastic cells. Furthermore, POMC mRNA was detected in osteoclastic cells. These data demonstrate that POMC-derived peptide hormones acting through high affinity melanocortin receptors have specific effects on bone cells. Thus, in addition to the indirect effects of POMC-derived hormones on bone turnover through their modulation of steroid hormone secretion, POMC fragments may have direct and specific effects on bone cell subpopulations.

  6. mu opiate receptor: cDNA cloning and expression.

    PubMed Central

    Wang, J B; Imai, Y; Eppler, C M; Gregor, P; Spivak, C E; Uhl, G R

    1993-01-01

    mu opiate receptors recognize morphine with high affinity. A 2.1-kb rat brain cDNA whose predicted translation product displays 63% identity with recently described delta and kappa opiate receptor sequences was identified through polymerase chain reaction and cDNA homology approaches. This cDNA recognizes a 10.5-kb mRNA that is expressed in thalamic neurons. COS-cell expression confers naloxonazine-, Na(+)-, and GTP-sensitive binding of mu but not delta or kappa opioid ligands. Expressing cells bind morphine, [D-Ala2,N-methyl-Phe4,glyol5]enkephalin (DAMGO), and [D-Ala2,D-Leu5]enkephalin (DADLE) with nanomolar or subnanomolar affinities, defining a mu opiate receptor that avidly recognizes analgesic and euphoric opiate drugs and opioid peptides. Images Fig. 1 Fig. 3 PMID:8234282

  7. Purification of a rat neurotensin receptor expressed in Escherichia coli.

    PubMed Central

    Tucker, J; Grisshammer, R

    1996-01-01

    A truncated rat neurotensin receptor (NTR), expressed in Escherichia coli with the maltose-binding protein fused to its N-terminus and the 13 amino acid Bio tag fused to its C-terminus, was purified to apparent homogeneity in two steps by use of the monomeric avidin system followed by a novel neurotensin column. This purification protocol was developed by engineering a variety of affinity tags on to the C-terminus of NTR. Surprisingly, expression levels varied considerably depending on the C-terminal tag used. Functional expression of NTR was highest (800 receptors/cell) when thioredoxin was placed between the receptor C-terminus and the tag, indicating a stabilizing effect of the thioredoxin moiety. Several affinity chromatography methods were tested for purification. NTR with the in vivo-biotinylated Bio tag was purified with the highest efficiency compared with NTR with the Strep tag or a hexa-histidine tail. Co-expression of biotin ligase improved considerably the in vivo biotinylation of the Bio tag and, therefore, the overall purification yield. Proteolysis of the NTR fusion protein was prevented by removing a protease-sensitive site discovered at the N-terminus of NTR. The ligand binding properties of the purified receptor were similar to those of the membrane-bound protein and the native receptor. The scale-up of this purification scheme, to provide sufficient protein for biophysical studies, is in progress. PMID:8760379

  8. Pharmacological evidence for the mediation of the panicolytic effect of fluoxetine by dorsal periaqueductal gray matter μ-opioid receptors.

    PubMed

    Roncon, Camila Marroni; Almada, Rafael Carvalho; Maraschin, Jhonatan Christian; Audi, Elisabeth Aparecida; Zangrossi, Hélio; Graeff, Frederico Guilherme; Coimbra, Norberto Cysne

    2015-12-01

    Previously reported results have shown that the inhibitory effect of fluoxetine on escape behavior, interpreted as a panicolytic-like effect, is blocked by pretreatment with either the opioid receptor antagonist naloxone or the 5-HT1A receptor (5-HT1A-R) antagonist WAY100635 via injection into the dorsal periaqueductal gray matter (dPAG). Additionally, reported evidence indicates that the μ-opioid receptor (MOR) interacts with the 5-HT1A-R in the dPAG. In the present work, pretreatment of the dPAG with the selective MOR blocker CTOP antagonized the anti-escape effect of chronic fluoxetine (10 mg/kg, i.p., daily, for 21 days), as measured in the elevated T-maze (ETM) test, indicating mediation of this effect by the MOR. In addition, the combined administration of sub-effective doses of the selective MOR agonist DAMGO (intra-dPAG) and sub-effective doses of chronic as well as subchronic (7 days) fluoxetine increased avoidance and escape latencies, suggesting that the activation of MORs may facilitate and accelerate the effects of fluoxetine. The current observation that MORs located in the dPAG mediate the anti-escape effect of fluoxetine may open new perspectives for the development of more efficient and fast-acting panic-alleviating drugs. PMID:26320545

  9. Sex-dependent adaptive changes in serotonin-1A autoreceptor function and anxiety in Deaf1-deficient mice.

    PubMed

    Luckhart, Christine; Philippe, Tristan J; Le François, Brice; Vahid-Ansari, Faranak; Geddes, Sean D; Béïque, Jean-Claude; Lagace, Diane C; Daigle, Mireille; Albert, Paul R

    2016-01-01

    The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6-BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5-HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor-mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light-dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men. PMID:27488351

  10. Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development

    PubMed Central

    Maciag, Dorota; Coppinger, David; Paul, Ian A.

    2006-01-01

    Neonatal (postnatal days 8-21) exposure of rats to the selective serotonin reuptake inhibitor (SSRI), citalopram, results in persistent changes in behavior including decreased sexual activity in adult animals. We hypothesized that this effect was a consequence of abnormal stimulation of serotonergic receptors 5- HT1A or/and 5-HT1B as a result of increased synaptic availability of serotonin during a critical period of development. We examined whether neonatal exposure to a 5-HT1A (8OH-DPAT) and/or a 5-HT1B (CGS 12066B) receptor agonist can mimic the effect of neonatal exposure to citalopram on adult sexual behavior. Results showed that neonatal treatment with 5-HT1B receptor agonist robustly impaired sexual behavior similar to the effect of citalopram whereas exposure to 5-HT1A receptor agonist only moderately influenced male sexual activity in adult animals. These data support the hypothesis that stimulation of serotonin autoreceptors during development contributes to the adult sexual deficit in rats neonatally exposed to citalopram. PMID:17101120

  11. Nicotinic receptor Alpha7 expression during mouse adrenal gland development.

    PubMed

    Gahring, Lorise C; Myers, Elizabeth; Palumbos, Sierra; Rogers, Scott W

    2014-01-01

    The nicotinic acetylcholine receptor alpha 7 (α7) is a ligand-activated ion channel that contributes to a diversity of cellular processes involved in development, neurotransmission and inflammation. In this report the expression of α7 was examined in the mouse developing and adult adrenal gland that expresses a green fluorescent protein (GFP) reporter as a bi-cistronic extension of the endogenous α7 transcript (α7(G)). At embryonic day 12.5 (E12.5) α7(G) expression was associated with the suprarenal ganglion and precursor cells of the adrenal gland. The α7(G) cells are catecholaminergic chromaffin cells as reflected by their progressive increase in the co-expression of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) that is complete by E18.5. In the adult, α7(G) expression is limited to a subset of chromaffin cells in the adrenal medulla that cluster near the border with the adrenal cortex. These chromaffin cells co-express α7(G), TH and DBH, but they lack phenylethanolamine N-methyltransferase (PNMT) consistent with only norepinephrine (NE) synthesis. These cell groups appear to be preferentially innervated by pre-ganglionic afferents identified by the neurotrophin receptor p75. No afferents identified by beta-III tubulin, neurofilament proteins or p75 co-expressed α7(G). Occasional α7(G) cells in the pre-E14.5 embryos express neuronal markers consistent with intrinsic ganglion cells and in the adult some α7(G) cells co-express glutamic acid decarboxylase. The transient expression of α7 during adrenal gland development and its prominent co-expression by a subset of NE chromaffin cells in the adult suggests that the α7 receptor contributes to multiple aspects of adrenal gland development and function that persist into adulthood. PMID:25093893

  12. Expression of somatostatin receptor genes and acetylcholine receptor development in rat skeletal muscle during postnatal development.

    PubMed

    Peng, M; Conforti, L; Millhorn, D E

    1998-05-01

    Our laboratory reported previously that somatostatin (SST) is transiently expressed in rat motoneurons during the first 14 days after birth. We investigated the possibility that the SST receptor (SSTR) is expressed in skeletal muscle. We found that two of the five subtypes of SSTR (SSTR3 and SSTR4) are expressed in skeletal muscle with a time course that correlates with the transient expression of SST in motoneurons. In addition, SSTR2A is expressed from birth to adulthood in skeletal muscle. Both SSTR2A and SSTR4 are also expressed in L6 cells, a skeletal muscle cell line. Somatostatin acting through its receptors has been shown to stimulate tyrosine phosphatase activity in a number of different tissues. We found that several proteins (50, 65, 90, 140, 180 and 200 kDa) exhibited a reduced degree of tyrosine phosphorylation following SST treatment. Inhibition of tyrosine phosphatase activity with sodium orthovanadate increased expression of the nicotinic acetyl-choline receptor (nAChR) epsilon subunit mRNA by three fold. Somatostatin reversed the elevated epsilon mRNA following orthovanadate treatment. These findings show that SSTR is expressed in skeletal muscle and that SST acting via the SSTR regulates tyrosine phosphorylation and expression of the epsilon subunit of the AChR in the rat skeletal muscle. PMID:9852305

  13. Characterization of urokinase receptor expression by human placental trophoblasts.

    PubMed

    Zini, J M; Murray, S C; Graham, C H; Lala, P K; Karikó, K; Barnathan, E S; Mazar, A; Henkin, J; Cines, D B; McCrae, K R

    1992-06-01

    The processes of implantation and placentation are both dependent on the invasion and remodeling of the uterine endometrium and vasculature by trophoblasts. Because the secretion and autocrine binding of urokinase (uPA) appears to be a common mechanism used by cells to facilitate plasmin-dependent tissue invasion, we measured the production of uPA and expression of uPA receptors by trophoblasts. Prourokinase bound specifically, reversibly, and with high affinity to cultured trophoblasts, via the uPA epidermal growth factor-like domain. Trophoblasts derived from two first-trimester placentae bound more prourokinase than cells isolated from term placentae. Furthermore, in vitro differentiation of cultured cytotrophoblasts into syncytiotrophoblasts was associated with diminished expression of urokinase receptors and a parallel decrease in the cellular content of uPA receptor mRNA. Trophoblasts also secreted prourokinase and plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2). Although prourokinase was secreted in amounts sufficient to endogenously saturate trophoblast uPA receptors, trophoblasts secreted greater amounts of PAI-1 and PAI-2 than uPA, and no net plasminogen activator activity was detected in trophoblast conditioned medium. In contrast, plasminogen added directly to cultured trophoblasts was readily converted to plasmin. Although the invasion and remodeling of uterine tissues by trophoblasts is a complex process dependent on several proteases of varying specificity, our findings suggest that the expression and modulation of urokinase receptors on the trophoblast cell surface may play an important role in this process. PMID:1316787

  14. Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors.

    PubMed

    Goitia, Belén; Rivero-Echeto, María Celeste; Weisstaub, Noelia V; Gingrich, Jay A; Garcia-Rill, Edgar; Bisagno, Verónica; Urbano, Francisco J

    2016-02-01

    Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 μM) and high (100 μM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 μM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 μM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 μM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre-synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G-protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and

  15. Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses

    PubMed Central

    Xavier, Andre Machado; Anunciato, Aparecida Kataryna Olimpio; Rosenstock, Tatiana Rosado; Glezer, Isaias

    2016-01-01

    Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC’s effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive. PMID:27148162

  16. Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses.

    PubMed

    Xavier, Andre Machado; Anunciato, Aparecida Kataryna Olimpio; Rosenstock, Tatiana Rosado; Glezer, Isaias

    2016-01-01

    Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC's effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive. PMID:27148162

  17. Detection of CXCR2 cytokine receptor surface expression using immunofluorescence.

    PubMed

    Lam, Clarissa; Pavel, Mahmud Arif; Kashyap, Parul; Salehi-Najafabadi, Zahra; Valentino, Victoria; Yu, Yong

    2014-01-01

    The interleukin-8 (IL-8, CXCL8) chemokine, also known as the neutrophil chemotactic factor, is a cytokine that plays a key role in inflammatory response, cell proliferation, migration, and survival. IL-8 expression is increased not only in inflammatory disorders, but also in many types of cancer, including prostate cancer. IL-8 acts as a ligand for the C-X-C chemokine receptor 2 (CXCR2) protein present on the cell plasma membrane. Binding of the IL-8 ligand to the CXCR2 receptor results in an intracellular signaling pathway mediated by GTP binding proteins coupled to the receptor itself. Knowledge of the CXCR2 expression levels facilitates the understanding of the role and function of IL-8. In this chapter, we describe a protocol that uses the immunofluorescence method and confocal microscopy to analyze the CXCR2 surface expression in human prostate cancer cells. However, this protocol is easily adaptable to analyze the surface expression of other cytokine receptors in different cell types. PMID:24908306

  18. Problem-Solving Test: Expression Cloning of the Erythropoietin Receptor

    ERIC Educational Resources Information Center

    Szeberenyi, Jozsef

    2008-01-01

    Terms to be familiar with before you start to solve the test: cytokines, cytokine receptors, cDNA library, cDNA synthesis, poly(A)[superscript +] RNA, primer, template, reverse transcriptase, restriction endonucleases, cohesive ends, expression vector, promoter, Shine-Dalgarno sequence, poly(A) signal, DNA helicase, DNA ligase, topoisomerases,…

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

    PubMed Central

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

    2014-01-01

    Rationale 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. Objectives This study compares behavioral effects and mechanisms of action of these substituted phenethylamines with those of hallucinogens and a stimulant. Methods 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. Results 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. Conclusions 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 hallucinogenlike discriminative stimulus effects. Additionally, the 5-HT2A inositol phosphate pathway may

  20. Evaluation of leptin receptor expression on buffalo leukocytes.

    PubMed

    De Matteis, Giovanna; Grandoni, Francesco; Scatà, Maria Carmela; Catizone, Angela; Reale, Anna; Crisà, Alessandra; Moioli, Bianca

    2016-09-01

    Experimental evidences support a direct role for leptin in immunity. Besides controlling food intake and energy expenditure, leptin was reported to be involved in the regulation of the immune system in ruminants. The aim of this work was to highlight the expression of leptin receptor (LEPR) on Bubalus bubalis immune cells using a multi-approach assessment: flow cytometry, confocal microscopy and gene expression analysis. Flow cytometric analysis of LEPR expression showed that peripheral blood monocytes were the predominant cells expressing LEPR. This result was corroborated by confocal microscopy and RT-PCR analysis. Moreover, among lymphocytes, LEPR was mainly expressed by B lymphocytes and Natural Killer cells. Evidence of LEPR expression on buffalo blood leukocytes showed to be a good indicator of the responsivity of these cells to leptin, so confirming the involvement of leptin in buffalo immune response. PMID:27436440

  1. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy.

    PubMed

    Smith, Terry J

    2015-03-01

    Thyroid-associated ophthalmopathy (TAO) is a vexing and undertreated ocular component of Graves disease in which orbital tissues undergo extensive remodelling. My colleagues and I have introduced the concept that fibrocytes expressing the haematopoietic cell antigen CD34 (CD34(+) fibrocytes), which are precursor cells of bone-marrow-derived monocyte lineage, express the TSH receptor (TSHR). These cells also produce several other proteins whose expression was traditionally thought to be restricted to the thyroid gland. TSHR-expressing fibrocytes in which the receptor is activated by its ligand generate extremely high levels of several inflammatory cytokines. Acting in concert with TSHR, the insulin-like growth factor 1 receptor (IGF-1R) expressed by orbital fibroblasts and fibrocytes seems to be necessary for TSHR-dependent cytokine production, as anti-IGF-1R blocking antibodies attenuate these proinflammatory actions of TSH. Furthermore, circulating fibrocytes are highly abundant in patients with TAO and seem to infiltrate orbital connective tissues, where they might transition to CD34(+) fibroblasts. My research group has postulated that the infiltration of fibrocytes into the orbit, their unique biosynthetic repertoire and their proinflammatory and profibrotic phenotype account for the characteristic properties exhibited by orbital connective tissues that underlie susceptibility to TAO. These insights, which have emerged in the past few years, might be of use in therapeutically targeting pathogenic orbit-infiltrating fibrocytes selectively by utilizing novel biologic agents that interfere with TSHR and IGF-1R signalling. PMID:25560705

  2. Expression of serotonin receptor genes in cranial ganglia.

    PubMed

    Maeda, Naohiro; Ohmoto, Makoto; Yamamoto, Kurumi; Kurokawa, Azusa; Narukawa, Masataka; Ishimaru, Yoshiro; Misaka, Takumi; Matsumoto, Ichiro; Abe, Keiko

    2016-03-23

    Taste cells release neurotransmitters to gustatory neurons to transmit chemical information they received. Sweet, umami, and bitter taste cells use ATP as a neurotransmitter. However, ATP release from sour taste cells has not been observed so far. Instead, they release serotonin when they are activated by sour/acid stimuli. Thus it is still controversial whether sour taste cells use ATP, serotonin, or both. By reverse transcription-polymerase chain reaction and subsequent in situ hybridization (ISH) analyses, we revealed that of 14 serotonin receptor genes only 5-HT3A and 5-HT3B showed significant/clear signals in a subset of neurons of cranial sensory ganglia in which gustatory neurons reside. Double-fluorescent labeling analyses of ISH for serotonin receptor genes with wheat germ agglutinin (WGA) in cranial sensory ganglia of pkd1l3-WGA mice whose sour neural pathway is visualized by the distribution of WGA originating from sour taste cells in the posterior region of the tongue revealed that WGA-positive cranial sensory neurons rarely express either of serotonin receptor gene. These results suggest that serotonin receptors expressed in cranial sensory neurons do not play any role as neurotransmitter receptor from sour taste cells. PMID:26854841

  3. Prevention of 5-hydroxytryptamine2C receptor RNA editing and alternate splicing in C57BL/6 mice activates the hypothalamic-pituitary-adrenal axis and alters mood

    PubMed Central

    Bombail, Vincent; Qing, Wei; Chapman, Karen E; Holmes, Megan C

    2014-01-01

    The 5-hydroxytryptamine2C (5-HT)2C receptor is widely implicated in the aetiology of affective and eating disorders as well as regulation of the hypothalamo-pituitary-adrenal axis. Signalling through this receptor is regulated by A-to-I RNA editing, affecting three amino acids in the protein sequence, with unedited transcripts encoding a receptor (INI) that, in vitro, is hyperactive compared with edited isoforms. Targeted alteration (knock-in) of the Htr2c gene to generate ‘INI’ mice with no alternate splicing, solely expressing the full-length unedited isoform, did not produce an overt metabolic phenotype or altered anxiety behaviour, but did display reduced depressive-like and fear-associated behaviours. INI mice exhibited a hyperactive hypothalamo-pituitary-adrenal axis, with increased nadir plasma corticosterone and corticotrophin-releasing hormone expression in the hypothalamus but responded normally to chronic stress and showed normal circadian activity and activity in a novel environment. The circadian patterns of 5-HT2C receptor mRNA and mbii52, a snoRNA known to regulate RNA editing and RNA splicing of 5-HT2C receptor pre-mRNA, were altered in INI mice compared with wild-type control mice. Moreover, levels of 5-HT1A receptor mRNA were increased in the hippocampus of INI mice. These gene expression changes may underpin the neuroendocrine and behavioural changes observed in INI mice. However, the phenotype of INI mice was not consistent with a globally hyperactive INI receptor encoded by the unedited transcript in the absence of alternate splicing. Hence, the in vivo outcome of RNA editing may be neuronal cell type specific. PMID:25257581

  4. Dopamine receptor expression and function in corticotroph pituitary tumors.

    PubMed

    Pivonello, Rosario; Ferone, Diego; de Herder, Wouter W; Kros, Johan M; De Caro, Maria Laura Del Basso; Arvigo, Marica; Annunziato, Lucio; Lombardi, Gaetano; Colao, Annamaria; Hofland, Leo J; Lamberts, Steven W J

    2004-05-01

    The role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D(2) receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion and the in vivo effect of short-term cabergoline treatment on cortisol secretion. D(2) expression was evaluated by receptor-ligand binding, immunohistochemistry, and RT-PCR. A 50% or more decrease in daily urinary cortisol levels was considered a significant clinical response. At receptor-ligand binding, specific binding of [(125)I]epidepride was found in 80% of cases. At immunohistochemistry, specific D(2) immunostaining was found in 75% of cases. D(2) expression was found in 83.3% of cases (D(2long) in 40%, D(2short) in 20%, and both in 40%) by RT-PCR. Significant in vitro inhibition of ACTH secretion was found in 100% of D(2)-positive cases, but not in 100% of D(2)-negative cases by either bromocriptine or cabergoline. A significant in vivo inhibition of cortisol secretion after 3-month cabergoline treatment was found in 60%, although a normalization of cortisol secretion was found in 40% of cases. All cabergoline-responsive cases were associated with D(2) expression, whereas all noncabergoline-responsive cases but one were not associated with D(2) expression. In conclusion, functional D(2) receptors were expressed in approximately 80% of corticotroph pituitary tumors. The effectiveness of cabergoline in normalizing cortisol secretion in 40% of cases supports its therapeutic use in the management of Cushing's disease. PMID:15126577

  5. Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues.

    PubMed

    Cheung, C P; Yu, Shan; Wong, K B; Chan, L W; Lai, Fernand M M; Wang, Xianghong; Suetsugi, Masatomo; Chen, Shiuan; Chan, Franky L

    2005-03-01

    Estrogen receptor-related receptors (ERRs; alpha, beta, gamma) are orphan nuclear receptors and constitutively active without binding to estrogen. Like estrogen receptors (ERs), ERRs bind to estrogen receptor elements and estrogen receptor element-related repeats. Growing evidence suggests that ERRs can cross-talk with ERs in different cell types via competition for DNA sites and coactivators. We hypothesize that ERRs might play regulatory roles in normal and neoplastic prostatic cells by sharing similar ER-mediated pathways or acting independently. In this study, we investigated mRNA and protein expression patterns of three ERR members in normal human prostate epithelial cells, established cell lines, cancer xenografts, and prostatic tissues. Additionally, effects of transient transfection of ERRs on prostatic cell proliferation and ER expression were also examined. RT-PCR showed that ERRalpha and ERRgamma transcripts were detected in most cell lines and xenografts, whereas ERRbeta was detected in normal epithelial cells and few immortalized cell lines but not in most cancer lines. Similar results were demonstrated in clinical prostatic specimens. Western blottings and immunohistochemistry confirmed similar expression patterns that ERR proteins were detected as nuclear proteins in epithelial cells, whereas their expressions became reduced or undetected in neoplastic prostatic cells. Transient transfection confirmed that ERRs were expressed in prostatic cells as nuclear proteins and transcriptionally active in the absence of estradiol. Transfection results showed that overexpression of ERRs inhibited cell proliferation and repressed ERalpha transcription in PC-3 cells. Our study shows that ERRs, which are coexpressed with ERs in prostatic cells, could regulate cell growth and modulate ER-mediated pathways via interference on ERalpha transcription in prostatic cells. PMID:15598686

  6. Transgenic silkworms expressing human insulin receptors for evaluation of therapeutically active insulin receptor agonists.

    PubMed

    Matsumoto, Yasuhiko; Ishii, Masaki; Ishii, Kenichi; Miyaguchi, Wataru; Horie, Ryo; Inagaki, Yoshinori; Hamamoto, Hiroshi; Tatematsu, Ken-ichiro; Uchino, Keiro; Tamura, Toshiki; Sezutsu, Hideki; Sekimizu, Kazuhisa

    2014-12-12

    We established a transgenic silkworm strain expressing the human insulin receptor (hIR) using the GAL4/UAS system. Administration of human insulin to transgenic silkworms expressing hIR decreased hemolymph sugar levels and facilitated Akt phosphorylation in the fat body. The decrease in hemolymph sugar levels induced by injection of human insulin in the transgenic silkworms expressing hIR was blocked by co-injection of wortmannin, a phosphoinositide 3-kinase inhibitor. Administration of bovine insulin, an hIR ligand, also effectively decreased sugar levels in the transgenic silkworms. These findings indicate that functional hIRs that respond to human insulin were successfully induced in the transgenic silkworms. We propose that the humanized silkworm expressing hIR is useful for in vivo evaluation of the therapeutic activities of insulin receptor agonists. PMID:25449269

  7. Transient Receptor Potential Canonical 1 (TRPC1) Channels as Regulators of Sphingolipid and VEGF Receptor Expression

    PubMed Central

    Asghar, Muhammad Yasir; Magnusson, Melissa; Kemppainen, Kati; Sukumaran, Pramod; Löf, Christoffer; Pulli, Ilari; Kalhori, Veronica; Törnquist, Kid

    2015-01-01

    The identity of calcium channels in the thyroid is unclear. In human follicular thyroid ML-1 cancer cells, sphingolipid sphingosine 1-phosphate (S1P), through S1P receptors 1 and 3 (S1P1/S1P3), and VEGF receptor 2 (VEGFR2) stimulates migration. We show that human thyroid cells express several forms of transient receptor potential canonical (TRPC) channels, including TRPC1. In TRPC1 knockdown (TRPC1-KD) ML-1 cells, the basal and S1P-evoked invasion and migration was attenuated. Furthermore, the expression of S1P3 and VEGFR2 was significantly down-regulated. Transfecting wild-type ML-1 cells with a nonconducting TRPC1 mutant decreased S1P3 and VEGFR2 expression. In TRPC1-KD cells, receptor-operated calcium entry was decreased. To investigate whether the decreased receptor expression was due to attenuated calcium entry, cells were incubated with the calcium chelator BAPTA-AM (1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). In these cells, and in cells where calmodulin and calmodulin-dependent kinase were blocked pharmacologically, S1P3 and VEGFR2 expression was decreased. In TRPC1-KD cells, both hypoxia-inducible factor 1α expression and the secretion and activity of MMP2 and MMP9 were attenuated, and proliferation was decreased in TRPC1-KD cells. This was due to a prolonged G1 phase of the cell cycle, a significant increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27, and a decrease in the expression of cyclin D2, cyclin D3, and CDK6. Transfecting TRPC1 to TRPC1-KD cells rescued receptor expression, migration, and proliferation. Thus, the expression of S1P3 and VEGFR2 is mediated by a calcium-dependent mechanism. TRPC1 has a crucial role in this process. This regulation is important for the invasion, migration, and proliferation of thyroid cancer cells. PMID:25971967

  8. Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors.

    PubMed

    Chiodi, Valentina; Ferrante, Antonella; Ferraro, Luca; Potenza, Rosa Luisa; Armida, Monica; Beggiato, Sarah; Pèzzola, Antonella; Bader, Michael; Fuxe, Kjell; Popoli, Patrizia; Domenici, Maria Rosaria

    2016-03-01

    Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2 A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2 A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2 A Rs, the effects mediated by CB1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A2A and CB1 receptors and providing a strategy to dissect the involvement of A2 A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2 A Rs and CB1 Rs, playing a fundamental role in the regulation of striatal functions. We studied A2A -CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A ). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A -CB1

  9. Steroid Receptor Coactivator-2 Expression in Brain and Physical Associations with Steroid Receptors

    PubMed Central

    Yore, Mackensie A.; Im, DaEun; Webb, Lena K.; Zhao, Yingxin; Chadwick, Joseph G.; Molenda-Figueira, Heather A.; Haidacher, Sigmund J.; Denner, Larry; Tetel, Marc J.

    2010-01-01

    Estradiol and progesterone bind to their respective receptors in the hypothalamus and hippocampus to influence a variety of behavioral and physiological functions, including reproduction and cognition. Work from our lab and others has shown that the nuclear receptor coactivators, steroid receptor coactivator-1 (SRC-1) and SRC-2, are essential for efficient estrogen receptor (ER) and progestin receptor (PR) transcriptional activity in brain and for hormone-dependent behaviors. While the expression of SRC-1 in brain has been studied extensively, little is known about the expression of SRC-2 in brain. In the present studies, we found that SRC-2 was highly expressed throughout the hippocampus, amygdala and hypothalamus, including the medial preoptic area (MPOA), ventral medial nucleus (VMN), arcuate nucleus (ARC), bed nucleus of the stria terminalis, supraoptic nucleus and suprachiasmatic nucleus. In order for coactivators to function with steroid receptors, they must be expressed in the same cells. Indeed, SRC-2 and ERα were coexpressed in many cells in the MPOA, VMN and ARC, all brain regions known to be involved in female reproductive behavior and physiology. While in vitro studies indicate that SRC-2 physically associates with ER and PR, very little is known about receptor-coactivator interactions in brain. Therefore, we used pull-down assays to test the hypotheses that SRC-2 from hypothalamic and hippocampal tissue physically associate with ER and PR subtypes in a ligand-dependent manner. SRC-2 from both brain regions interacted with ERα bound to agonist, but not in the absence of ligand or in the presence of the selective ER modulator, tamoxifen. Analysis by mass spectrometry confirmed these ligand-dependent interactions between ERα and SRC-2 from brain. In dramatic contrast, SRC-2 from brain showed little to no interaction with ERβ. Interestingly, SRC-2 from both brain regions interacted with PR-B, but not PR-A, in a ligand-dependent manner. Taken together

  10. Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.

    PubMed Central

    Rao, N K; Shi, G P; Chapman, H A

    1995-01-01

    Binding of urokinase to the glycolipid-anchored urokinase receptor (uPAR) has been implicated in macrophage differentiation. However, no biochemical markers of differentiation have yet been directly linked to uPAR occupancy. As extensive changes in proteolytic profile characterize monocytic differentiation, we have examined the role of uPAR occupancy on protease expression by differentiating phagocytes. Antibodies to either urokinase or to uPAR that prevent receptor binding inhibited induction of cathepsin B in cultured monocytes and both cathepsin B and 92-kD gelatinase mRNA and protein in phorbol diester-stimulated myeloid cells. Mannosamine, an inhibitor of glycolipid anchor assembly, also blocked protease expression. Anti-catalytic urokinase antibodies, excess inactive urokinase, or aprotinin had no effect, indicating that receptor occupancy per se regulated protease expression. Antibodies to the integrins CD11a and CD29 or to the glycolipid-anchored proteins CD14 and CD55 also had no effect. Protease induction was independent of matrix attachment. Antibodies to urokinase or uPAR affected neither the decrease in cathepsin G nor the increase in tumor necrosis factor-alpha in phorbol ester-stimulated cells. These data establish that uPAR is a multifunctional receptor, not only promoting pericellular proteolysis and matrix attachment, but also effecting cysteine- and metallo-protease expression during macrophage differentiation. Images PMID:7615819

  11. Triggering Receptor Expressed on Myeloid Cells in Cutaneous Melanoma.

    PubMed

    Nguyen, Austin Huy; Koenck, Carleigh; Quirk, Shannon K; Lim, Victoria M; Mitkov, Mario V; Trowbridge, Ryan M; Hunter, William J; Agrawal, Devendra K

    2015-10-01

    The tumor microenvironment plays an important role in the progression of melanoma, the prototypical immunologic cutaneous malignancy. The triggering receptor expressed on myeloid cells (TREM) family of innate immune receptors modulates inflammatory and innate immune signaling. It has been investigated in various neoplastic diseases, but not in melanoma. This study examines the expression of TREM-1 (a proinflammatory amplifier) and TREM-2 (an anti-inflammatory modulator and phagocytic promoter) in human cutaneous melanoma and surrounding tissue. Indirect immunofluorescence staining was performed on skin biopsies from 10 melanoma patients and staining intensity was semiquantitatively scored. Expression of TREM-1 and TREM-2 was higher in keratinocytes than melanoma tissue (TREM-1: p < 0.01; TREM-2: p < 0.01). Whereas TREM-2 was the dominant isoform expressed in normal keratinocytes, TREM-1 expression predominated in melanoma tissue (TREM-1 to TREM-2 ratio: keratinocytes = 0.78; melanoma = 2.08; p < 0.01). The increased TREM ratio in melanoma tissue could give rise to a proinflammatory and protumor state of the microenvironment. This evidence may be suggestive of a TREM-1/TREM-2 paradigm in which relative levels dictate inflammatory and immune states, rather than absolute expression of one or the other. Further investigation regarding this paradigm is warranted and could carry prognostic or therapeutic value in treatment for melanoma. PMID:26184544

  12. Effects of housing and muricidal behavior on serotonergic receptors and interactions with novel anxiolytic drugs.

    PubMed

    McMillen, B A; Chamberlain, J K; DaVanzo, J P

    1988-01-01

    Mouse killing by rats represents a predatory behavior that can be modified by drugs from several different therapeutic classes and by environmental conditions. Buspirone and gepirone, non-benzodiazepine anxiolytics that stimulate serotonergic receptors (5HT1a) and inhibit isolation-induced intraspecies aggression, were tested for inhibition of muricidal behavior by isolated rats. Neither buspirone (3.0 mg/kg s.c.) nor gepirone (from 5.0 to 40 mg/kg) inhibited muricide. Additional rats were housed, either aggregated or isolated, and tested for muricidal behavior 9 times over 5 weeks to establish which animals were muricidal: thus, there were 4 groups of rats: muricidal or non-muricidal under either isolated or aggregated housing condition. [3H]-Spiperone was used to determine striatal D2 receptor Bmax and Kd and prefrontal cortex D2 and 5HT2 receptor binding. There were no changes across the four groups. Binding of [3H]-5-hydroxytryptamine (5HT) to 5HT1a receptors decreased in septum of both groups of isolated rats and binding to 5HT1b receptors decreased 50% in hippocampus of isolated and aggregated muricidal rats. Binding of [3H]-5HT to either receptor was unchanged in amygdaloid area and hypothalamus across all groups. Thus, stimulating pre- and postsynaptic 5HT1a receptors does not alter muricidal behavior and changes in 5HT1 receptor binding occurs in limited areas. Whether this limited change in hippocampal 5HT1b binding is important for establishing muricidal behavior is unclear; however the direction of the change is consistent with reports that decreased serotonergic activity increases predatory behavior. PMID:2894404

  13. Expression of Estrogen Receptor α in the Mouse Cerebral Cortex

    PubMed Central

    Dietrich, Alicia K.; Humphreys, Gwendolyn I.; Nardulli, Ann M.

    2015-01-01

    Although estrogen receptor alpha (ERα) and 17β-estradiol play critical roles in protecting the cerebral cortex from ischemia-induced damage, there has been some controversy about the expression of ERα in this region of the brain. We have examined ERα mRNA and protein levels in the cerebral cortices of female mice at postnatal days 5 and 17 and at 4, 13, and 18 months of age. We found that although ERα transcript levels declined from postnatal day 5 through 18 months of age, ERα protein levels remained stable. Importantly, expression of the E2-regulated progesterone receptor gene was sustained in younger and in older females suggesting that age-related changes in estrogen responsiveness in the cerebral cortex are not due to the absence of ERα protein. PMID:25700604

  14. Serotonergic receptor mechanisms underlying antidepressant-like action in the progesterone withdrawal model of hormonally induced depression in rats.

    PubMed

    Li, Yan; Raaby, Kasper F; Sánchez, Connie; Gulinello, Maria

    2013-11-01

    Hormonally induced mood disorders such as premenstrual dysphoric disorder (PMDD) are characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. Studies demonstrated rodent models of progesterone withdrawal (PWD) have a high level of constructive and descriptive validity to model hormonally-induced mood disorders in women. Here we evaluate the effects of several classes of antidepressants in PWD female Long-Evans rats using the forced swim test (FST) as a measure of antidepressant activity. The study included fluoxetine, duloxetine, amitriptyline and an investigational multimodal antidepressant, vortioxetine (5-HT(3), 5-HT(7) and 5-HT(1D) receptor antagonist; 5-HT(1B) receptor partial agonist; 5-HT(1A) receptor agonist; inhibitor of the serotonin transporter (SERT)). After 14 days of administration, amitriptyline and vortioxetine significantly reduced immobility in the FST whereas fluoxetine and duloxetine were ineffective. After 3 injections over 48 h, neither fluoxetine nor duloxetine reduced immobility, whereas amitriptyline and vortioxetine significantly reduced FST immobility during PWD. When administered acutely during PWD, the 5-HT(1A) receptor agonist, flesinoxan, significantly reduced immobility, whereas the 5-HT(1A) receptor antagonist, WAY-100635, increased immobility. The 5-HT(3) receptor antagonist, ondansetron, significantly reduced immobility, whereas the 5-HT(3) receptor agonist, SR-57227, increased immobility. The 5-HT(7) receptor antagonist, SB-269970, was inactive, although the 5-HT(7) receptor agonist, AS-19, significantly increased PWD-induced immobility. None of the compounds investigated (ondansetron, flesinoxan and SB-269970) improved the effect of fluoxetine during PWD. These data indicate that modulation of specific 5-HT receptor subtypes is critical for manipulating FST immobility in this model of hormone-induced depression. PMID:24016840

  15. Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival12

    PubMed Central

    Jönsson, Jenny-Maria; Skovbjerg Arildsen, Nicolai; Malander, Susanne; Måsbäck, Anna; Hartman, Linda; Nilbert, Mef; Hedenfalk, Ingrid

    2015-01-01

    Background and Aims: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer. Methods: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer in an independent data set, hypothesizing that the expression levels and prognostic impact may differ between the subtypes. Results: Expression of PR or AR protein was associated with improved 5-year progression-free (P = .001 for both) and overall survival (P < .001 for both, log-rank test). ERα and ERβ did not provide prognostic information. Patients whose tumors coexpressed PR and AR had the most favorable prognosis, and this effect was retained in multivariable analyses. Analyses of the corresponding genes using an independent data set revealed differences among the molecular subtypes, but no clear relationship between high coexpression of PGR and AR and prognosis. Conclusions: A favorable outcome was seen for patients whose tumors coexpressed PR and AR. Gene expression data suggested variable effects in the different molecular subtypes. These findings demonstrate a prognostic role for PR and AR in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer. PMID:26500033

  16. Cell-Free Expression of G Protein-Coupled Receptors.

    PubMed

    Segers, Kenneth; Masure, Stefan

    2015-01-01

    The large-scale production of recombinant G protein-coupled receptors (GPCRs) is one of the major bottlenecks that hamper functional and structural studies of this important class of integral membrane proteins. Heterologous overexpression of GPCRs often results in low yields of active protein, usually due to a combination of several factors, such as low expression levels, protein insolubility, host cell toxicity, and the need to use harsh and often denaturing detergents (e.g., SDS, LDAO, OG, and DDM, among others) to extract the recombinant receptor from the host cell membrane. Many of these problematic issues are inherently linked to cell-based expression systems and can therefore be circumvented by the use of cell-free systems. In this unit, we provide a range of protocols for the production of GPCRs in a cell-free expression system. Using this system, we typically obtain GPCR expression levels of ∼1 mg per ml of reaction mixture in the continuous-exchange configuration. Although the protocols in this unit have been optimized for the cell-free expression of GPCRs, they should provide a good starting point for the production of other classes of membrane proteins, such as ion channels, aquaporins, carrier proteins, membrane-bound enzymes, and even large molecular complexes. PMID:26237676

  17. Chemokine receptor expression by inflammatory T cells in EAE

    PubMed Central

    Mony, Jyothi Thyagabhavan; Khorooshi, Reza; Owens, Trevor

    2014-01-01

    Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20 receptor CCR6 has been reported to be selectively expressed by CD4+ T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4+ T cells produced IFNγ in flow cytometric cytokine assays, whereas less than 1% produced IL-17. About 1% of CD4+ T cells produced both cytokines. CCR6 was expressed by Th1, Th1+17 and by Th17 cells, but not by CD8+ T cells. CD8+ T cells expressed CXCR3, which was also expressed by CD4+ T cells, with no correlation to cytokine profile. Messenger RNA for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6+ and CXCR3+ CD4+ T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8+ T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double immunofluorescence. Consistent with flow cytometry data some but not all CD4+ T cells expressed CCR6 within infiltrates. CD4-negative CCR6+ cells included macrophage/microglial cells. Thus we have for the first time directly studied CD4+ and CD8+ T cells in the CNS of mice with peak EAE, and determined IFNγ and IL17 expression by cells expressing CCR6 and CXCR3. We show that neither CCR6 or CXCR3 align with CD4 T cell subsets, and Th1 or mixed Th1+17 predominate in EAE. PMID:25071447

  18. Spatiotemporal expression of Nogo-66 receptor after focal cerebral ischemia

    PubMed Central

    Cao, Yue; Dong, Ya-xian; Xu, Jie; Chu, Guo-liang; Yang, Zhi-hua; Liu, Yan-ming

    2016-01-01

    NgR, the receptor for the neurite outgrowth inhibitor Nogo-66, plays a critical role in the plasticity and regeneration of the nervous system after injury such as ischemic stroke. In the present study, we used immunohistochemistry to investigate the regional expression of NgR in rat brain following middle cerebral artery occlusion (MCAO). NgR protein expression was not observed in the center of the lesion, but was elevated in the marginal zone compared with control and sham-operated rats. The cerebral cortex and hippocampus (CA1, CA2, and CA3) showed the greatest expression of NgR. Furthermore, NgR expression was higher in the ipsilesional hemisphere than on the control side in the same coronal section. Although time-dependent changes in NgR expression across brain regions had their own characteristics, the overall trend complied with the following rules: NgR expression changes with time showed two peaks and one trough; the first peak in expression appeared between 1 and 3 days after MCAO; expression declined at 5 days; and the second peak occurred at 28 days. PMID:26981102

  19. Molecular Background of Estrogen Receptor Gene Expression in Endometriotic Cells.

    PubMed

    Izawa, Masao; Taniguchi, Fuminori; Harada, Tasuku

    2016-07-01

    The molecular background of estrogen receptor (ER) expression is important to understand the pathophysiology of the high estrogen environment in endometriosis. However, the molecular details have not been fully understood. The objective of this study is to evaluate the molecular background of ERα and ERβ messenger RNA (mRNA) expression in endometriotic cells. The following summarizes our observations: (1) ERα mRNA expression in endometriotic cells was estimated to be approximately one-tenth of that in endometrial cells. (2) Three mRNAs, which include 3 different 5'-untranslated exons tagged to an open reading frame of wild-type ERα, were detected. (3) Expression of ERβ mRNA depends mostly on 0N promoter and includes 2 open reading frames: one for a wild-type ERβ1 and another for a splice variant ERβ2. (4) Expression of ERβ1 mRNA was approximately 40-fold higher than that in endometrial cells. (5) Expression of ERβ2 mRNA was almost at a comparable level of the ERβ1. 9 (6) ERα and ERβ mRNAs are equivalently expressed in endometriotic cells. These observations show the molecular background of ER mRNA expression in endometriotic cells and provide a clue to further understanding the estrogen-dependent pathophysiology leading to clinical application in endometriosis. PMID:26704524

  20. Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

    PubMed Central

    Teodorov, E.; Ferrari, M.F.R.; Fior-Chadi, D.R.; Camarini, R.; Felício, L.F.

    2012-01-01

    The periaqueductal gray (PAG) has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc) or 0.9% saline (up to 1 mL/kg) and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05) because a lower percentage of U69593 group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR). A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05) and lactating female rats (P < 0.01), with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid system in female

  1. Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors.

    PubMed

    Alhaider, A A; Hamon, M; Wilcox, G L

    1993-11-01

    The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin). PMID:7507056

  2. Toll-Like Receptor Gene Expression during Trichinella spiralis Infection

    PubMed Central

    Kim, Sin; Park, Mi Kyung; Yu, Hak Sun

    2015-01-01

    In Trichinella spiralis infection, type 2 helper T (Th2) cell-related and regulatory T (Treg) cell-related immune responses are the most important immune events. In order to clarify which Toll-like receptors (TLRs) are closely associated with these responses, we analyzed the expression of mouse TLR genes in the small intestine and muscle tissue during T. spiralis infection. In addition, the expression of several chemokine- and cytokine-encoding genes, which are related to Th2 and Treg cell mediated immune responses, were analyzed in mouse embryonic fibroblasts (MEFs) isolated from myeloid differentiation factor 88 (MyD88)/TIR-associated proteins (TIRAP) and Toll receptor-associated activator of interferons (TRIF) adapter protein deficient and wild type (WT) mice. The results showed significantly increased TLR4 and TLR9 gene expression in the small intestine after 2 weeks of T. spiralis infection. In the muscle, TLR1, TLR2, TLR5, and TLR9 gene expression significantly increased after 4 weeks of infection. Only the expression of the TLR4 and TLR9 genes was significantly elevated in WT MEF cells after treatment with excretory-secretory (ES) proteins. Gene expression for Th2 chemokine genes were highly enhanced by ES proteins in WT MEF cells, while this elevation was slightly reduced in MyD88/TIRAP-/- MEF cells, and quite substantially decreased in TRIF-/- MEF cells. In contrast, IL-10 and TGF-β expression levels were not elevated in MyD88/TIRAP-/- MEF cells. In conclusion, we suggest that TLR4 and TLR9 might be closely linked to Th2 cell and Treg cell mediated immune responses, although additional data are needed to convincingly prove this observation. PMID:26323841

  3. Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression.

    PubMed

    Girer, Nathaniel G; Murray, Iain A; Omiecinski, Curtis J; Perdew, Gary H

    2016-07-15

    The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor α (PPARα), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist-activated AHR impairs PPARα-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARα-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling. PMID:27226639

  4. Toll-Like Receptor Gene Expression during Trichinella spiralis Infection.

    PubMed

    Kim, Sin; Park, Mi Kyung; Yu, Hak Sun

    2015-08-01

    In Trichinella spiralis infection, type 2 helper T (Th2) cell-related and regulatory T (Treg) cell-related immune responses are the most important immune events. In order to clarify which Toll-like receptors (TLRs) are closely associated with these responses, we analyzed the expression of mouse TLR genes in the small intestine and muscle tissue during T. spiralis infection. In addition, the expression of several chemokine- and cytokine-encoding genes, which are related to Th2 and Treg cell mediated immune responses, were analyzed in mouse embryonic fibroblasts (MEFs) isolated from myeloid differentiation factor 88 (MyD88)/TIR-associated proteins (TIRAP) and Toll receptor-associated activator of interferons (TRIF) adapter protein deficient and wild type (WT) mice. The results showed significantly increased TLR4 and TLR9 gene expression in the small intestine after 2 weeks of T. spiralis infection. In the muscle, TLR1, TLR2, TLR5, and TLR9 gene expression significantly increased after 4 weeks of infection. Only the expression of the TLR4 and TLR9 genes was significantly elevated in WT MEF cells after treatment with excretory-secretory (ES) proteins. Gene expression for Th2 chemokine genes were highly enhanced by ES proteins in WT MEF cells, while this elevation was slightly reduced in MyD88/TIRAP(-/-) MEF cells, and quite substantially decreased in TRIF(-/-) MEF cells. In contrast, IL-10 and TGF-β expression levels were not elevated in MyD88/TIRAP(-/-) MEF cells. In conclusion, we suggest that TLR4 and TLR9 might be closely linked to Th2 cell and Treg cell mediated immune responses, although additional data are needed to convincingly prove this observation. PMID:26323841

  5. An Expression Refinement Process Ensures Singular Odorant Receptor Gene Choice.

    PubMed

    Abdus-Saboor, Ishmail; Al Nufal, Mohammed J; Agha, Maha V; Ruinart de Brimont, Marion; Fleischmann, Alexander; Shykind, Benjamin M

    2016-04-25

    Odorant receptor (OR) gene choice in mammals is a paradigmatic example of monogenic and monoallelic transcriptional selection, in which each olfactory sensory neuron (OSN) chooses to express one OR allele from over 1,000 encoded in the genome [1-3]. This process, critical for generation of the circuit from nose to brain [4-6], is thought to occur in two steps: a slow initial phase that randomly activates a single OR allele, followed by a rapid feedback that halts subsequent expression [7-14]. Inherent in this model is a finite failure rate wherein multiple OR alleles may be activated prior to feedback suppression [15, 16]. Confronted with more than one receptor, the neuron would need to activate a refinement mechanism to eliminate multigenic OR expression and resolve unique neuronal identity [16], critical to the generation of the circuit from nose to olfactory bulb. Here we used a genetic approach in mice to reveal a new facet of OR regulation that corrects adventitious activation of multiple OR alleles, restoring monogenic OR expression and unique neuronal identity. Using the tetM71tg model system, in which the M71 OR is expressed in >95% of mature OSNs and potently suppresses the expression of the endogenous OR repertoire [10], we provide clear evidence of a post-selection refinement (PSR) process that winnows down the number of ORs. We further demonstrate that PSR efficiency is linked to OR expression level, suggesting an underlying competitive process and shedding light on OR gene switching and the fundamental mechanism of singular OR choice. PMID:27040780

  6. Cyclic AMP-receptor protein activates aerobactin receptor IutA expression in Vibrio vulnificus.

    PubMed

    Kim, Choon-Mee; Kim, Seong-Jung; Shin, Sung-Heui

    2012-04-01

    The ferrophilic bacterium Vibrio vulnificus can utilize the siderophore aerobactin of Escherichia coli for iron acquisition via its specific receptor IutA. This siderophore piracy by V. vulnificus may contribute to its survival and proliferation, especially in mixed bacterial environments. In this study, we examined the effects of glucose, cyclic AMP (cAMP), and cAMP-receptor protein (Crp) on iutA expression in V. vulnificus. Glucose dose-dependently repressed iutA expression. A mutation in cya encoding adenylate cyclase required for cAMP synthesis severely repressed iutA expression, and this change was recovered by in trans complementing cya or the addition of exogenous cAMP. Furthermore, a mutation in crp encoding Crp severely repressed iutA expression, and this change was recovered by complementing crp. Accordingly, glucose deprivation under iron-limited conditions is an environmental signal for iutA expression, and Crp functions as an activator that regulates iutA expression in response to glucose availability. PMID:22538662

  7. Insulin decreases atherosclerosis by inducing endothelin receptor B expression

    PubMed Central

    Park, Kyoungmin; Mima, Akira; Li, Qian; Rask-Madsen, Christian; He, Pingnian; Mizutani, Koji; Katagiri, Sayaka; Maeda, Yasutaka; Wu, I-Hsien; Khamaisi, Mogher; Preil, Simone Rordam; Maddaloni, Ernesto; Sørensen, Ditte; Rasmussen, Lars Melholt; Huang, Paul L.; King, George L.

    2016-01-01

    Endothelial cell (EC) insulin resistance and dysfunction, caused by diabetes, accelerates atherosclerosis. It is unknown whether specifically enhancing EC-targeted insulin action can decrease atherosclerosis in diabetes. Accordingly, overexpressing insulin receptor substrate-1 (IRS1) in the endothelia of Apoe−/− mice (Irs1/Apoe−/−) increased insulin signaling and function in the aorta. Atherosclerosis was significantly reduced in Irs1/ApoE−/− mice on diet-induced hyperinsulinemia and hyperglycemia. The mechanism of insulin’s enhanced antiatherogenic actions in EC was related to remarkable induction of NO action, which increases endothelin receptor B (EDNRB) expression and intracellular [Ca2+]. Using the mice with knockin mutation of eNOS, which had Ser1176 mutated to alanine (AKI), deleting the only known mechanism for insulin to activate eNOS/NO pathway, we observed that IRS1 overexpression in the endothelia of Aki/ApoE−/− mice significantly decreased atherosclerosis. Interestingly, endothelial EDNRB expression was selectively reduced in intima of arteries from diabetic patients and rodents. However, endothelial EDNRB expression was upregulated by insulin via P13K/Akt pathway. Finally EDNRB deletion in EC of Ldlr−/− and Irs1/Ldlr−/− mice decreased NO production and accelerated atherosclerosis, compared with Ldlr−/− mice. Accelerated atherosclerosis in diabetes may be reduced by improving insulin signaling selectively via IRS1/Akt in the EC by inducing EDNRB expression and NO production. PMID:27200419

  8. Expression of metabotropic glutamate receptor 4 in osteosarcoma

    PubMed Central

    WANG, SHUO; WEI, XING; CHEN, BINGYAO; ZHAO, MIN; SONG, GUANGZE; ZHANG, ZENGLIANG; LI, NAN

    2016-01-01

    Metabotropic glutamate receptor 4 (mGluR4) has been associated with the pathogenesis of osteosarcoma. The aim of this study was to investigate mGluR4 expression and its clinical significance in osteosarcoma patients. mGluR4 expression was investigated using immunohistochemistry (IHC) in 58 osteosarcomas and 32 giant-cell tumors of bone. The correlations between mGluR4 expression and clinicopathological characteristics were analyzed with the Chi-squared test and survival curves were generated using the Kaplan-Meier method. The IHC results demonstrated that 20.69% (12/58) of the osteosarcomas and 43.75% (14/32) of the giant-cell tumors were mGluR4-positive. The statistical analysis revealed that mGluR4 expression was correlated with gender, age, Enneking stage and tumor volume in osteosarcomas (P<0.05). In the multivariate stepwise Cox regression analysis, Enneking stage was found to be statistically significantly associated with survival (P<0.05) and the survival analysis demonstrated that the survival probability was significantly higher in patients with higher mGluR4 expression compared with those with lower expression (P<0.05). Therefore, mGluR4 expression may be used to estimate the prognosis of osteosarcoma patients. PMID:26870360

  9. Targeting the expression of integrin receptors in tumors

    NASA Astrophysics Data System (ADS)

    Bloch, Sharon; Liang, Kexian; Dorshow, Richard B.; Ye, Yunpeng; Achilefu, Samuel I.

    2004-06-01

    Expression of integrin αvβ3 is upregulated in a number of cancers including colon, pancreas, lung and breast. Additionally, αvβ3 integrin expression has been linked to tumor metastasis and targeting this cell surface protein could provide a viable approach to image and evaluate the metastatic potential of tumors. Accordingly, we evaluated the selective retention of some near infrared (NIR) fluorescent probes in nude mice bearing A549 lung cancer xenograft that express αvβ3 integrin. Our preliminary results indicate that a novel NIR probe designed to target this integrin selectively accumulated in A549 tumor while other non-integrin specific probes were not retained in the tumor. Blocking studies show that tumor uptake of the probe is mediated by αvβ3 integrin receptor.

  10. (18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier.

    PubMed

    Liow, Jeih-San; Zoghbi, Sami S; Hu, Shuo; Hall, Matthew D; Hines, Christina S; Shetty, H Umesha; Araneta, Maria D; Page, Emily M; Pike, Victor W; Kreisl, William C; Herscovitch, Peter; Gottesman, Michael M; Theodore, William H; Innis, Robert B

    2016-09-01

    Efflux transporters at the blood-brain barrier can decrease the entry of drugs and increase the removal of those molecules able to bypass the transporter. We previously hypothesized that (18)F-FCWAY, a radioligand for the serotonin 5-HT1A receptor, is a weak substrate for permeability glycoprotein (P-gp) based on its very early peak and rapid washout from human brain. To determine whether (18)F-FCWAY is a substrate for P-gp, breast cancer resistance protein (BCRP), and multidrug resistance protein (MRP1) - the three most prevalent efflux transporters at the blood-brain barrier - we performed three sets of experiments. In vitro, we conducted fluorescence-activated cell sorting (FACS) flow cytometry studies in cells over-expressing P-gp, BCRP, and MRP1 treated with inhibitors specific to each transporter and with FCWAY. Ex vivo, we measured (18)F-FCWAY concentration in plasma and brain homogenate of transporter knockout mice using γ-counter and radio-HPLC. In vivo, we conducted positron emission tomography (PET) studies to assess changes in humans who received (18)F-FCWAY during an infusion of tariquidar (2-4mg/kg iv), a potent and selective P-gp inhibitor. In vitro studies showed that FCWAY allowed fluorescent substrates to get into the cell by competitive inhibition of all three transporters at the cell membrane. Ex vivo measurements in knockout mice indicate that (18)F-FCWAY is a substrate only for P-gp and not BCRP. In vivo, tariquidar increased (18)F-FCWAY brain uptake in seven of eight subjects by 60-100% compared to each person's baseline. Tariquidar did not increase brain uptake via some peripheral mechanism, given that it did not significantly alter concentrations in plasma of the parent radioligand (18)F-FCWAY or its brain-penetrant radiometabolite (18)F-FC. These results show that (18)F-FCWAY is a weak substrate for efflux transport at the blood-brain barrier; some radioligand can enter brain, but its removal is hastened by P-gp. Although (18)F-FCWAY is

  11. Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation

    PubMed Central

    2011-01-01

    Background Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. Methods The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Results Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic

  12. Molecular Cooperativity Governs Diverse and Monoallelic Olfactory Receptor Expression

    NASA Astrophysics Data System (ADS)

    Xing, Jianhua; Tian, Xiaojun; Zhang, Hang; Sannerud, Jens

    Multiple-objective optimization is common in biological systems. In the mammalian olfactory system, each sensory neuron stochastically expresses only one out of up to thousands of olfactory receptor (OR) gene alleles; at organism level the types of expressed ORs need to be maximized. The molecular mechanism of this Nobel-Prize winning puzzle remains unresolved after decades of extensive studies. Existing models focus only on monoallele activation, and cannot explain recent observations in mutants, especially the reduced global diversity of expressed ORs in G9a/GLP knockouts. In this work we integrated existing information on OR expression, and proposed an evolutionarily optimized three-layer regulation mechanism, which includes zonal segregation, epigenetic and enhancer competition coupled to a negative feedback loop. This model not only recapitulates monoallelic OR expression, but also elucidates how the olfactory system maximizes and maintains the diversity of OR expression. The model is validated by several experimental results, and particularly underscores cooperativity and synergy as a general design principle of multi-objective optimization in biology. The work is supported by the NIGMS/DMS Mathematical Biology program.

  13. Downregulation of transferrin receptor surface expression by intracellular antibody

    SciTech Connect

    Peng Jilin; Wu Sha; Zhao Xiaoping; Wang Min; Li Wenhan; Shen Xin; Liu Jing; Lei Ping; Zhu Huifen; Shen Guanxin . E-mail: guanxin_shen@yahoo.com.cn

    2007-03-23

    To deplete cellular iron uptake, and consequently inhibit the proliferation of tumor cells, we attempt to block surface expression of transferrin receptor (TfR) by intracellular antibody technology. We constructed two expression plasmids (scFv-HAK and scFv-HA) coding for intracellular single-chain antibody against TfR with or without endoplasmic reticulum (ER) retention signal, respectively. Then they were transfected tumor cells MCF-7 by liposome. Applying RT-PCR, Western blotting, immunofluorescence microscopy and immunoelectron microscope experiments, we insure that scFv-HAK intrabody was successfully expressed and retained in ER contrasted to the secreted expression of scFv-HA. Flow cytometric analysis confirmed that the TfR surface expression was markedly decreased approximately 83.4 {+-} 2.5% in scFv-HAK transfected cells, while there was not significantly decrease in scFv-HA transfected cells. Further cell growth and apoptosis characteristics were evaluated by cell cycle analysis, nuclei staining and MTT assay. Results indicated that expression of scFv-HAK can dramatically induce cell cycle G1 phase arrest and apoptosis of tumor cells, and consequently significantly suppress proliferation of tumor cells compared with other control groups. For First time this study demonstrates the potential usage of anti-TfR scFv-intrabody as a growth inhibitor of TfR overexpressing tumors.

  14. Sulfonylurea Receptor 1 Expression in Human Cerebral Infarcts

    PubMed Central

    Mehta, Rupal I.; Ivanova, Svetlana; Tosun, Cigdem; Castellani, Rudy J.; Gerzanich, Volodymyr

    2013-01-01

    Abstract In animal models of stroke, sulfonylurea receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neutrophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea receptor 1 immunoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction. PMID:23965746

  15. Sulfonylurea receptor 1 expression in human cerebral infarcts.

    PubMed

    Mehta, Rupal I; Ivanova, Svetlana; Tosun, Cigdem; Castellani, Rudy J; Gerzanich, Volodymyr; Simard, J Marc

    2013-09-01

    In animal models of stroke, sulfonylurea receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neutrophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea receptor 1 immunoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction. PMID:23965746

  16. Simvastatin enhances bone morphogenetic protein receptor type II expression

    SciTech Connect

    Hu Hong; Sung, Arthur; Zhao, Guohua; Shi, Lingfang; Qiu Daoming; Nishimura, Toshihiko; Kao, Peter N. . E-mail: peterkao@stanford.edu

    2006-01-06

    Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4 kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function.

  17. Gene Expression Switching of Receptor Subunits in Human Brain Development

    PubMed Central

    Bar-Shira, Ossnat; Maor, Ronnie; Chechik, Gal

    2015-01-01

    Synaptic receptors in the human brain consist of multiple protein subunits, many of which have multiple variants, coded by different genes, and are differentially expressed across brain regions and developmental stages. The brain can tune the electrophysiological properties of synapses to regulate plasticity and information processing by switching from one protein variant to another. Such condition-dependent variant switch during development has been demonstrated in several neurotransmitter systems including NMDA and GABA. Here we systematically detect pairs of receptor-subunit variants that switch during the lifetime of the human brain by analyzing postmortem expression data collected in a population of donors at various ages and brain regions measured using microarray and RNA-seq. To further detect variant pairs that co-vary across subjects, we present a method to quantify age-corrected expression correlation in face of strong temporal trends. This is achieved by computing the correlations in the residual expression beyond a cubic-spline model of the population temporal trend, and can be seen as a nonlinear version of partial correlations. Using these methods, we detect multiple new pairs of context dependent variants. For instance, we find a switch from GLRA2 to GLRA3 that differs from the known switch in the rat. We also detect an early switch from HTR1A to HTR5A whose trends are negatively correlated and find that their age-corrected expression is strongly positively correlated. Finally, we observe that GRIN2B switch to GRIN2A occurs mostly during embryonic development, presumably earlier than observed in rodents. These results provide a systematic map of developmental switching in the neurotransmitter systems of the human brain. PMID:26636753

  18. Differential Expression of Motilin Receptor in Various Parts of Gastrointestinal Tract in Dogs

    PubMed Central

    He, Yu; Wang, Hui; Yang, DongYan; Wang, ChengYan; Yang, LanLan; Jin, Chunxiang

    2015-01-01

    Objectives. The presence of motilin receptor in the GI tract of different animal species has been verified. However, the quantitation of motilin receptor expression in different regions of the GI tract remains unclear. The aim of this study was to investigate the expression of motilin receptor in the GI tract and semiquantitatively compare the expression difference in different GI regions in dogs. Methods. Antrum, duodenum, jejunum, ileum, proximal colon, middle colon, and distal colon were obtained from various parts of the GI tract of six sacrificed dogs. The distribution of motilin receptor was determined by immunohistochemistry. The expression levels of motilin receptor mRNA in different regions were measured by RT-PCR. Results. Motilin receptor was expressed throughout the GI tract in dogs. Multiple comparisons of the mean motilin receptor mRNA expression among various regions were significant (P < 0.05). Motilin receptor mRNA was extensively expressed in duodenum, followed by ileum, jejunum, proximal colon, antrum, middle colon, and distal colon. Immunohistochemistry revealed that motilin receptor immunoreactivity was observed only in the enteric nervous system. Conclusion. Motilin receptor is expressed differentially along the GI tract in dogs. The significantly high expression of motilin receptor mRNA is found in the duodenum. PMID:25918525

  19. Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia.

    PubMed

    Lee, Ki Seok; Zhang, Youping; Asgar, Jamila; Auh, Q-Schick; Chung, Man-Kyo; Ro, Jin Y

    2016-09-01

    The involvement of testosterone in pain, inflammation, and analgesia has been reported, but the role of androgen receptor (AR), a steroid receptor for testosterone, is not well understood. We have previously shown that peripheral inflammation upregulates μ-opioid receptor (MOR) in rat trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we hypothesized that testosterone regulates MOR expression via transcriptional activities of AR in TG. We first examined whether AR is co-expressed with MOR in TG neurons. Our immunohistochemical experiment revealed that AR staining is detected in neurons of all sizes in TG and that a subset of AR is expressed in MOR as well as in TRPV1-positive neurons. We identified the promoter region of the rat MOR gene contains putative AR binding sites. Using chromatin immunoprecipitation assay, we demonstrated that AR directly binds to these sites in TG extracts. We confirmed with luciferase reporter assay that AR activated the MOR promoter in response to androgens in a human neuroblastoma cell line (5H-5YSY). These data demonstrated that AR functions as a transcriptional regulator of the MOR gene activity. Finally, we showed that flutamide, a specific AR antagonist, prevents complete Freund's adjuvant (CFA)-induced upregulation of MOR mRNA in TG, and that flutamide dose-dependently blocks the efficacy of DAMGO, a specific MOR agonist, on CFA-induced mechanical hypersensitivity. Our results expand the knowledge regarding the role of androgens and their receptor in pain and analgesia and have important clinical implications, particularly for inflammatory pain patients with low or compromised plasma testosterone levels. PMID:27320211

  20. Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells

    PubMed Central

    Ganesan, Latha P.; Mates, Jessica M.; Cheplowitz, Alana M.; Avila, Christina L.; Zimmerer, Jason M.; Yao, Zhili; Maiseyeu, Andrei; Rajaram, Murugesan V. S.; Robinson, John M.; Anderson, Clark L.

    2016-01-01

    Cholesterol from peripheral tissue, carried by HDL, is metabolized in the liver after uptake by the HDL receptor, SR-B1. Hepatocytes have long been considered the only liver cells expressing SR-B1; however, in this study we describe two disparate immunofluorescence (IF) experiments that suggest otherwise. Using high-resolution confocal microscopy employing ultrathin (120 nm) sections of mouse liver, improving z-axis resolution, we identified the liver sinusoidal endothelial cells (LSEC), marked by FcγRIIb, as the cell within the liver expressing abundant SR-B1. In contrast, the hepatocyte, identified with β-catenin, expressed considerably weaker levels, although optical resolution of SR-B1 was inadequate. Thus, we moved to a different IF strategy, first separating dissociated liver cells by gradient centrifugation into two portions, hepatocytes (parenchymal cells) and LSEC (non-parenchymal cells). Characterizing both portions for the cellular expression of SR-B1 by flow cytometry, we found that LSEC expressed considerable amounts of SR-B1 while in hepatocytes SR-B1 expression was barely perceptible. Assessing mRNA of SR-B1 by real time PCR we found messenger expression in LSEC to be about 5 times higher than in hepatocytes. PMID:26865459

  1. Transferrin receptor expression by stimulated cells in mixed lymphocyte culture.

    PubMed Central

    Salmon, M; Bacon, P A; Symmons, D P; Walton, K W

    1985-01-01

    Transferrin receptor (TRFr) expression by cells in mixed lymphocyte culture increases steadily for the first 5 days, but then reaches a plateau. By the sixth day in culture, about 20% of viable cells express TRFr in two-way mixed lymphocyte reactions. This subpopulation of TRFr-positive cells represents the proliferating population; it is heterogeneous, containing T-cell blasts and smaller cells which are a mixture of T and non-T cells. A small group of non-T cells have phenotypic similarity to natural killer (NK) cells. T cells appear to divide earlier in the course of the response than non-T cells. The biphasic nature of this response and the slower non-T reactivity may be due to a secondary stimulation of non-T cells by factors released from activated T cells (such as interleukin-2). PMID:2982734

  2. Murine Hematopoietic Stem cells and Progenitors Express Adrenergic Receptors

    PubMed Central

    Muthu, Kuzhali; Iyer, Sivaraman; He, L-K.; Szilagyi, Andrea; Gamelli, Richard L; Shankar, Ravi; Jones, Stephen B

    2007-01-01

    Association between the nervous and immune system is well documented. Immune cells originate within the bone marrow that is innervated. Thermal injury induces adrenergic stimulation, augments monocytopoiesis and alters the β-adrenergic receptor (AR) profile of bone marrow monocyte committed progenitors. This provides an impetus to study AR expression in hematopoietic progenitors along myeloid lineage. Using FACS analysis and confocal microscopy, we report the expression of α1-, α2- and β2- AR in enriched populations of ER-MP20+ and ER-MP12+ myeloid progenitors, CD117+ and CD34+ multi-potential progenitors and more importantly pluripotent stem cells suggesting a plausible role for catecholamine in hematopoietic development. PMID:17428548

  3. Epithelial P2X purinergic receptor channel expression and function

    PubMed Central

    Taylor, Amanda L.; Schwiebert, Lisa M.; Smith, Jeffrey J.; King, Chris; Jones, Julie R.; Sorscher, Eric J.; Schwiebert, Erik M.

    1999-01-01

    P2X purinergic receptor (P2XR) channels bind ATP and mediate Ca2+ influx — 2 signals that stimulate secretory Cl– transport across epithelia. We tested the hypotheses that P2XR channels are expressed by epithelia and that P2XRs transduce extracellular ATP signals into stimulation of Cl– transport across epithelia. Electrophysiological data and mRNA analysis of human and mouse pulmonary epithelia and other epithelial cells indicate that multiple P2XRs are broadly expressed in these tissues and that they are active on both apical and basolateral surfaces. Because P2X-selective agonists bind multiple P2XR subtypes, and because P2X agonists stimulate Cl– transport across nasal mucosa of cystic fibrosis (CF) patients as well as across non-CF nasal mucosa, P2XRs may provide novel targets for extracellular nucleotide therapy of CF. PMID:10510328

  4. Ionotropic glutamate receptor expression in human white matter.

    PubMed

    Christensen, Pia Crone; Samadi-Bahrami, Zahra; Pavlov, Vlady; Stys, Peter K; Moore, G R Wayne

    2016-09-01

    Glutamate is the key excitatory neurotransmitter of the central nervous system (CNS). Its role in human grey matter transmission is well understood, but this is less clear in white matter (WM). Ionotropic glutamate receptors (iGluR) are found on both neuronal cell bodies and glia as well as on myelinated axons in rodents, and rodent WM tissue is capable of glutamate release. Thus, rodent WM expresses many of the components of the traditional grey matter neuron-to-neuron synapse, but to date this has not been shown for human WM. We demonstrate the presence of iGluRs in human WM by immunofluorescence employing high-resolution spectral confocal imaging. We found that the obligatory N-methyl-d-aspartic acid (NMDA) receptor subunit GluN1 and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA4 co-localized with myelin, oligodendroglial cell bodies and processes. Additionally, GluA4 colocalized with axons, often in distinct clusters. These findings may explain why human WM is vulnerable to excitotoxic events following acute insults such as stroke and traumatic brain injury and in more chronic inflammatory conditions such as multiple sclerosis (MS). Further exploration of human WM glutamate signalling could pave the way for developing future therapies modulating the glutamate-mediated damage in these and other CNS disorders. PMID:27443784

  5. Galanin subtype 1 and subtype 2 receptors mediate opposite anxiety-like effects in the rat dorsal raphe nucleus.

    PubMed

    Morais, J S; Souza, M M; Campanha, T M N; Muller, C J T; Bittencourt, A S; Bortoli, V C; Schenberg, L C; Beijamini, V

    2016-11-01

    About 40% of the dorsal raphe nucleus (DRN) neurons co-express serotonin (5-HT) and galanin. Serotonergic pathways from the DRN to the amygdala facilitate learned anxiety, while those from the DRN to the dorsal periaqueductal grey matter (DPAG) impair innate anxiety. Previously, we showed that galanin infusion in the DRN of rats induces anxiolytic effect by impairing inhibitory avoidance without changing escape behaviour in the elevated T-maze (ETM). Here, we evaluated: (1) which galanin receptors would be involved in the anxiolytic effect of galanin in the DRN of rats tested in the ETM; (2) the effects of galanin intra-DRN on panic-like behaviours evoked by electrical stimulation of the DPAG. The activation of DRN GAL1 receptors by M617 (1.0 and 3.0nmol) facilitated inhibitory avoidance, whereas the activation of GAL2 receptors by AR-M1896 (3.0nmol) impaired the inhibitory avoidance in the ETM, suggesting an anxiogenic and an anxiolytic-like effect respectively. Both agonists did not change escape behaviour in the ETM or locomotor activity in the open field. The anxiolytic effect of AR-M1896 was attenuated by the prior administration of WAY100635 (0.18nmol), a 5-HT1A antagonist. Galanin (0.3nmol) administered in the DRN increased discreetly flight behaviours induced by electrical stimulation of the DPAG, suggesting a panicolytic effect. Together, our results showed that galanin mediates opposite anxiety responses in the DRN by activation of GAL1 and GAL2 receptors. The anxiolytic effect induced by activation of Gal2 receptors may depend on serotonergic tone. Finally, the role of galanin in panic related behaviours remains uncertain. PMID:27498247

  6. 5-Hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation

    PubMed Central

    Johnston, April; McBain, Chris J; Fisahn, André

    2014-01-01

    Rhythmic cortical neuronal oscillations in the gamma frequency band (30–80 Hz, gamma oscillations) have been associated with cognitive processes such as sensory perception and integration, attention, learning, and memory. Gamma oscillations are disrupted in disorders for which cognitive deficits are hallmark symptoms such as schizophrenia and Alzheimer's disease. In vitro, various neurotransmitters have been found to modulate gamma oscillations. Serotonin (5-HT) has long been known to be important for both behavioural and cognitive functions such as learning and memory. Multiple 5-HT receptor subtypes are expressed in the CA3 region of the hippocampus and high doses of 5-HT reduce the power of induced gamma oscillations. Hypothesizing that 5-HT may have cell- and receptor subtype-specific modulatory effects, we investigated the receptor subtypes, cell types and cellular mechanisms engaged by 5-HT in the modulation of gamma oscillations in mice and rats. We found that 5-HT decreases the power of kainate-induced hippocampal gamma oscillations in both species via the 5-HT1A receptor subtype. Whole-cell patch clamp recordings demonstrated that this decrease was caused by a hyperpolarization of CA3 pyramidal cells and a reduction of their firing frequency, but not by alteration of inhibitory neurotransmission. Finally, our results show that the effect on pyramidal cells is mediated via the G protein-coupled receptor inwardly rectifying potassium channel Kir3. Our findings suggest this novel cellular mechanism as a potential target for therapies that are aimed at alleviating cognitive decline by helping the brain to maintain or re-establish normal gamma oscillation levels in neuropsychiatric and neurodegenerative disorders. PMID:25107925

  7. Toll-like receptor 2 ligands regulate monocyte Fcγ receptor expression and function.

    PubMed

    Shah, Prexy; Fatehchand, Kavin; Patel, Hemal; Fang, Huiqing; Justiniano, Steven E; Mo, Xiaokui; Jarjoura, David; Tridandapani, Susheela; Butchar, Jonathan P

    2013-04-26

    Fcγ receptor (FcγR) clustering on monocytes/macrophages results in phagocytosis and inflammatory cytokine production, which serve to eliminate antibody-opsonized targets and activate neighboring immune cells. Toll-like receptor 2 (TLR2), which recognizes a range of both bacterial and fungal components, elicits strong proinflammatory responses in these cells when stimulated by ligands, either natural or synthetic. Thus, we explored the possibility that TLR2 agonists could strengthen FcγR activity within the context of antibody therapy. Human peripheral blood monocytes treated with the TLR2 agonist Pam2CSK4 showed significantly enhanced FcγR-mediated cytokine production as well as phagocytic ability. An examination of the molecular mechanism behind this enhancement revealed increased expression of both FcγRIIa and the common γ subunit following Pam2CSK4 treatment. Interestingly however, expression of the inhibitory receptor FcγRIIb was also modestly increased. Further investigation revealed that Pam2CSK4 also dramatically decreased the expression of SHIP, the major mediator of FcγRIIb inhibitory activity. Using a murine Her2/neu solid tumor model of antibody therapy, we found that Pam2CSK4 significantly enhanced the ability of anti-Her2 antibody to reduce the rate of tumor growth. To verify that the FcγR enhancement was not unique to the diacylated Pam2CSK4, we also tested Pam3CSK4, a related triacylated TLR2 agonist. Results showed significant enhancement in FcγR function and expression. Taken together, these findings indicate that TLR2 activation can positively modulate FcγR and suggest that TLR2 agonists should be considered for testing as adjuvants for antitumor antibody therapy. PMID:23504312

  8. Linking estrogen receptor β expression with inflammatory bowel disease activity

    PubMed Central

    Pierdominici, Marina; Maselli, Angela; Varano, Barbara; Barbati, Cristiana; Cesaro, Paola; Spada, Cristiano; Zullo, Angelo; Lorenzetti, Roberto; Rosati, Marco; Rainaldi, Gabriella; Limiti, Maria Rosaria; Guidi, Luisa

    2015-01-01

    Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)β expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERβ expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERβ expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERβ downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of endoscopic disease activity. PMID:26497217

  9. Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα1a or NEα2b receptors in the thoraco-lumbar spinal cord

    PubMed Central

    Johnson, Dawn M. G.; Riesgo, Mirta I.; Pinzon, Alberto

    2011-01-01

    Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα1A and NEα2B receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10–40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα1A receptors. In contrast, NEα2B receptor immunoreactivity was observed in 70–90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα2B = 5-HT2A ≥ 5-HT7 = 5-HT1A > NEα1A. These results suggest that noradrenergic modulation of locomotion involves NEα1A/NEα2B receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted. PMID:21307324

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

    PubMed

    Borg, J; Cervenka, S; Kuja-Halkola, R; Matheson, G J; Jönsson, E G; Lichtenstein, P; Henningsson, S; Ichimiya, T; Larsson, H; Stenkrona, P; Halldin, C; Farde, L

    2016-08-01

    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 the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic 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 receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease. PMID:26821979

  11. Expression of functional leptin receptors in rodent Leydig cells.

    PubMed

    Caprio, M; Isidori, A M; Carta, A R; Moretti, C; Dufau, M L; Fabbri, A

    1999-11-01

    Several studies indicate that the size of body fat stores and the circulating levels of the adipocyte-derived hormone leptin are able to influence the activity of the hypothalamic-pituitary-gonadal axis. The leptin-hypothalamic-pituitary-gonadal interactions have been mainly studied at the level of the central nervous system. In this study, we investigated the possibility that leptin may have direct effects on the rodent Leydig cell function. To probe this hypothesis, we first analyzed the expression of leptin receptors (OB-R) in rodent Leydig cells in culture. RT-PCR studies showed that rat Leydig cells express both the long (OB-Rb) and short isoform (OB-Ra) of leptin receptor, whereas MLTC-1 cells (a murine Leydig tumor cell line) express only the long isoform. Short-term (30-90 min) incubation of rat Leydig cells with increasing concentrations ofleptin (2-500 ng/ml) led to a significant and dose-dependent inhibition of human (h)CG-stimulated testosterone (T) production (approximately 60% reduction, IC50 = 20 ng/ml) but no change in basal androgen release. Also, leptin (150 ng/ml) amplified hCG-induced intracellular cAMP formation (1- to 2-fold) without modifying basal cAMP levels. Subsequent experiments showed that leptin inhibited 8Br-cAMP-stimulated T production, indicating that leptin's effect is exerted beyond cAMP. The inhibitory effect of leptin on hCG-induced T secretion was accompanied by a significant reduction of androstenedione and a concomitant rise of the precursor metabolites pregnenolone, progesterone, and 17-OH-progesterone, conceivable with a leptin-induced lesion of 17,20 lyase activity. Separate experiments performed with the MLTC-1 cells (not expressing cytochrome P450-17alpha) showed that leptin, though amplifying hCG-stimulated cAMP production, did not modify hCG-stimulated pregnenolone and progesterone release. These results further indicate that leptin action on steroidogenesis occurs downstream of progesterone synthesis. Northern Blot

  12. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types.

    PubMed Central

    McMahan, C J; Slack, J L; Mosley, B; Cosman, D; Lupton, S D; Brunton, L L; Grubin, C E; Wignall, J M; Jenkins, N A; Brannan, C I

    1991-01-01

    cDNA clones corresponding to an Mr approximately 80,000 receptor (type I receptor) for interleukin-1 (IL-1) have been isolated previously by mammalian expression. Here, we report the use of an improved expression cloning method to isolate human and murine cDNA clones encoding a second type (Mr approximately 60,000) of IL-1 receptor (type II receptor). The mature type II IL-1 receptor consists of (i) a ligand binding portion comprised of three immunoglobulin-like domains; (ii) a single transmembrane region; and (iii) a short cytoplasmic domain of 29 amino acids. This last contrasts with the approximately 215 amino acid cytoplasmic domain of the type I receptor, and suggests that the two IL-1 receptors may interact with different signal transduction pathways. The type II receptor is expressed in a number of different tissues, including both B and T lymphocytes, and can be induced in several cell types by treatment with phorbol ester. Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location. Like the type I receptor, the human type II IL-1 receptor can bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1ra). Vaccinia virus contains an open reading frame bearing strong resemblance to the type II IL-1 receptor. Images PMID:1833184

  13. Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.

    PubMed

    Winters, Bradley D; Krüger, Juliane M; Huang, Xiaojie; Gallaher, Zachary R; Ishikawa, Masago; Czaja, Krzysztof; Krueger, James M; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan

    2012-10-01

    Endocannabinoid signaling critically regulates emotional and motivational states via activation of cannabinoid receptor 1 (CB1) in the brain. The nucleus accumbens (NAc) functions to gate emotional and motivational responses. Although expression of CB1 in the NAc is low, manipulation of CB1 signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders, and these effects cannot be exclusively attributed to CB1 located at afferents to the NAc. Rather, CB1-expressing neurons in the NAc, although sparse, appear to be critical for emotional and motivational responses. However, the cellular properties of these neurons remain largely unknown. Here, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein td-Tomato (tdT). Using these mice, we demonstrated that tdT-positive neurons within the NAc were exclusively fast-spiking interneurons (FSIs). These FSIs were electrically coupled with each other, and thus may help synchronize populations/ensembles of NAc neurons. CB1-expressing FSIs also form GABAergic synapses on adjacent medium spiny neurons (MSNs), providing feed-forward inhibition of NAc output. Furthermore, the membrane excitability of tdT-positive FSIs in the NAc was up-regulated after withdrawal from cocaine exposure, an effect that might increase FSI-to-MSN inhibition. Taken together with our previous findings that the membrane excitability of NAc MSNs is decreased during cocaine withdrawal, the present findings suggest that the basal functional output of the NAc is inhibited during cocaine withdrawal by multiple mechanisms. As such, CB1-expressing FSIs are targeted by cocaine exposure to influence the overall functional output of the NAc. PMID:23012412

  14. Melanocortin 4 Receptor and Dopamine D2 Receptor Expression in Brain Areas Involved in Food Intake

    PubMed Central

    Yoon, Ye Ran

    2015-01-01

    Background The melanocortin 4 receptor (MC4R) is involved in the regulation of homeostatic energy balance by the hypothalamus. Recent reports showed that MC4R can also control the motivation for food in association with a brain reward system, such as dopamine. We investigated the expression levels of MC4R and the dopamine D2 receptor (D2R), which is known to be related to food rewards, in both the hypothalamus and brain regions involved in food rewards. Methods We examined the expression levels of D2R and MC4R by dual immunofluorescence histochemistry in hypothalamic regions and in the bed nucleus of the stria terminalis (BNST), the central amygdala, and the ventral tegmental area of transgenic mice expressing enhanced green fluorescent protein under the control of the D2R gene. Results In the hypothalamic area, significant coexpression of MC4R and D2R was observed in the arcuate nucleus. We observed a significant coexpression of D2R and MC4R in the BNST, which has been suggested to be an important site for food reward. Conclusion We suggest that MC4R and D2R function in the hypothalamus for control of energy homeostasis and that within the brain regions related with rewards, such as the BNST, the melanocortin system works synergistically with dopamine for the integration of food motivation in the control of feeding behaviors. PMID:26790386

  15. Expression of the human muscarinic receptor gene m2 in Dictyostelium discoideum

    SciTech Connect

    Voith, G.; Dingermann, T.

    1995-11-01

    We have expressed a functional human muscarinic M2 receptor, under the control of the homologous discoidin I{gamma} promoter, in the cellular slime mold Dictyostelium discoideum. The use of a contact site A leader peptide ensured insertion of the newly synthesized receptor protein into the plasma membrane. Due to the characteristics of the discoidin I{gamma} promoter, the M2 receptor is expressed during late growth and early development. The heterologously expressed M2 receptors show binding characteristics similar to authentic receptors. Membranes as well as whole cells can be used in ligand binding assays. 36 refs., 4 figs.

  16. Expression of the human muscarinic receptor gene m2 in Dictyostelium discoideum.

    PubMed

    Voith, G; Dingermann, T

    1995-11-01

    We have expressed a functional human muscarinic M2 receptor, under the control of the homologous discoidin I gamma promoter, in the cellular slime mold Dictyostelium discoideum. The use of a contact site A leader peptide ensured insertion of the newly synthesized receptor protein into the plasma membrane. Due to the characteristics of the discoidin I gamma promoter, the M2 receptor is expressed during late growth and early development. The heterologously expressed M2 receptors show binding characteristics similar to authentic receptors. Membranes as well as whole cells can be used in ligand binding assays. PMID:9636297

  17. Endothelin ETA receptor expression in human cerebrovascular smooth muscle cells.

    PubMed Central

    Yu, J. C.; Pickard, J. D.; Davenport, A. P.

    1995-01-01

    151242 competed for the binding of [125I]-ET-1 monophasically and analysis of the competition curves indicated that a one-site fit was preferred over a two-site model, implying that the cultures express mainly ETA receptors. 6. Although messenger RNA encoding both ETA and ETB receptors was detected, autoradiographical analysis, as well as binding studies indicate that human cultured brain smooth muscle cells express only ETA receptor protein. Antagonism of this sub-type may be necessary to block the actions of ET-1 in the human cerebral resistance vessels in the vasospasm observed subsequent to subarachnoid haemorrhage. Images Figure 1 Figure 2 PMID:8581282

  18. Glucocorticoids down-regulate beta 1-adrenergic-receptor expression by suppressing transcription of the receptor gene.

    PubMed Central

    Kiely, J; Hadcock, J R; Bahouth, S W; Malbon, C C

    1994-01-01

    The expression of beta 2-adrenergic receptors is up-regulated by glucocorticoids. In contrast, beta 1-adrenergic receptors display glucocorticoid-induced down-regulation. In rat C6 glioma cells, which express both of these subtypes of beta-adrenergic receptors, the synthetic glucocorticoid dexamethasone stimulates no change in the total beta-adrenergic receptor content, but rather shifts the beta 1:beta 2 ratio from 80:20 to 50:50. Radioligand binding and immunoblotting demonstrate a sharp decline in beta 1-adrenergic receptor expression. Metabolic labelling of cells with [35S]-methionine in tandem with immunoprecipitation by beta 1-adrenergic-receptor-specific antibodies reveals a sharp decline in the synthesis of the receptor within 48 h for cells challenged with glucocorticoid. Steady-state levels of beta 1-adrenergic-receptor mRNA declined from 0.47 to 0.26 amol/microgram of total cellular RNA within 2 h of dexamethasone challenge, as measured by DNA-excess solution hybridization. The stability of receptor mRNA was not influenced by glucocorticoid; the half-lives of the beta 1- and beta 2-subtype mRNAs were 1.7 and 1.5 h respectively. Nuclear run-on assays revealed the basis for the down-regulation of receptor expression, i.e. a sharp decline in the relative rate of transcription for the beta 1-adrenergic-receptor gene in nuclei from dexamethasone-treated as compared with vehicle-treated cells. These data demonstrate transcriptional suppression as a molecular explanation for glucocorticoid-induced down-regulation of beta 1-adrenergic receptors. Images Figure 1 Figure 2 Figure 6 PMID:8092990

  19. Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist.

    PubMed

    Yamaura, Katsunori; Oda, Manabu; Suwa, Eriko; Suzuki, Masahiko; Sato, Hiromi; Ueno, Koichi

    2009-10-01

    Many medicines exist which can cause pruritus (itching) as "serious adverse events." Many severe pruritic conditions respond poorly to histamine H1 receptor antagonists; there is no generally accepted antipruritic treatment. Recently described histamine H4 receptors are expressed in haematopoietic cells and have been linked to the pathology of allergy and asthma. We previously reported their expression in human dermal fibroblasts; in this study we have investigated H4 receptor expression in human epidermal tissue and found it to be greater in keratinocytes in the epidermal upper layer than in the lower layer. We have also investigated the effect of histamine H4 receptor antagonists on histamine H1 receptor antagonist-resistant pruritus using a mouse model. Scratching behavior was induced by histamine (300 nmol) or substance P (100 nmol) injected intradermally into the rostral part of the back of each mouse. Fexofenadine, a histamine H1 receptor antagonist, reduced scratching induced by histamine but not by substance P, whereas JNJ7777120, a histamine H4 receptor antagonist, significantly reduced both histamine- and substance P-induced scratching. These results suggest that H4 receptor antagonists may be useful for treatment of H1 receptor antagonist-resistant pruritus. PMID:19652466

  20. Myoglobin expression in prostate cancer is correlated to androgen receptor expression and markers of tumor hypoxia.

    PubMed

    Meller, Sebastian; Bicker, Anne; Montani, Matteo; Ikenberg, Kristian; Rostamzadeh, Babak; Sailer, Verena; Wild, Peter; Dietrich, Dimo; Uhl, Barbara; Sulser, Tullio; Moch, Holger; Gorr, Thomas A; Stephan, Carsten; Jung, Klaus; Hankeln, Thomas; Kristiansen, Glen

    2014-10-01

    Recent studies identified unexpected expression and transcriptional complexity of the hemoprotein myoglobin (MB) in human breast cancer but its role in prostate cancer is still unclear. Expression of MB was immunohistochemically analyzed in three independent cohorts of radical prostatectomy specimens (n = 409, n = 625, and n = 237). MB expression data were correlated with clinicopathological parameters and molecular parameters of androgen and hypoxia signaling. Expression levels of novel tumor-associated MB transcript variants and the VEGF gene as a hypoxia marker were analyzed using qRT-PCR. Fifty-three percent of the prostate cancer cases were MB positive and significantly correlated with androgen receptor (AR) expression (p < 0.001). The positive correlation with CAIX (p < 0.001) and FASN (p = 0.008) as well as the paralleled increased expression of the tumor-associated MB transcript variants and VEGF suggest that hypoxia participates in MB expression regulation. Analogous to breast cancer, MB expression in prostate cancer is associated with steroid hormone signaling and markers of hypoxia. Further studies must elucidate the novel functional roles of MB in human carcinomas, which probably extend beyond its classic intramuscular function in oxygen storage. PMID:25172328

  1. Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications

    PubMed Central

    PONIEWIERSKA-BARAN, AGATA; SUSZYNSKA, MALWINA; SUN, WENYUE; ABDELBASET-ISMAIL, AHMED; SCHNEIDER, GABRIELA; BARR, FREDERIC G.; RATAJCZAK, MARIUSZ Z.

    2015-01-01

    The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. PMID:26412593

  2. Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications.

    PubMed

    Poniewierska-Baran, Agata; Suszynska, Malwina; Sun, Wenyue; Abdelbaset-Ismail, Ahmed; Schneider, Gabriela; Barr, Frederic G; Ratajczak, Mariusz Z

    2015-11-01

    The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. PMID:26412593

  3. Characterization of the Olfactory Receptors Expressed in Human Spermatozoa

    PubMed Central

    Flegel, Caroline; Vogel, Felix; Hofreuter, Adrian; Schreiner, Benjamin S. P.; Osthold, Sandra; Veitinger, Sophie; Becker, Christian; Brockmeyer, Norbert H.; Muschol, Michael; Wennemuth, Gunther; Altmüller, Janine; Hatt, Hanns; Gisselmann, Günter

    2016-01-01

    The detection of external cues is fundamental for human spermatozoa to locate the oocyte in the female reproductive tract. This task requires a specific chemoreceptor repertoire that is expressed on the surface of human spermatozoa, which is not fully identified to date. Olfactory receptors (ORs) are candidate molecules and have been attributed to be involved in sperm chemotaxis and chemokinesis, indicating an important role in mammalian spermatozoa. An increasing importance has been suggested for spermatozoal RNA, which led us to investigate the expression of all 387 OR genes. This study provides the first comprehensive analysis of OR transcripts in human spermatozoa of several individuals by RNA-Seq. We detected 91 different transcripts in the spermatozoa samples that could be aligned to annotated OR genes. Using stranded mRNA-Seq, we detected a class of these putative OR transcripts in an antisense orientation, indicating a different function, rather than coding for a functional OR protein. Nevertheless, we were able to detect OR proteins in various compartments of human spermatozoa, indicating distinct functions in human sperm. A panel of various OR ligands induced Ca2+ signals in human spermatozoa, which could be inhibited by mibefradil. This study indicates that a variety of ORs are expressed at the mRNA and protein level in human spermatozoa. PMID:26779489

  4. Defining Breast Cancer Intrinsic Subtypes by Quantitative Receptor Expression

    PubMed Central

    Cheang, Maggie C.U.; Martin, Miguel; Nielsen, Torsten O.; Prat, Aleix; Voduc, David; Rodriguez-Lescure, Alvaro; Ruiz, Amparo; Chia, Stephen; Shepherd, Lois; Ruiz-Borrego, Manuel; Calvo, Lourdes; Alba, Emilio; Carrasco, Eva; Caballero, Rosalia; Tu, Dongsheng; Pritchard, Kathleen I.; Levine, Mark N.; Bramwell, Vivien H.; Parker, Joel; Bernard, Philip S.; Ellis, Matthew J.; Perou, Charles M.; Di Leo, Angelo

    2015-01-01

    Purpose. To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. Methods. We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), with intrinsic subtyping by research-based PAM50 RT-qPCR assay. Results. Among 283 HER2-negative tumors with <1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%), were present. Among the 1,298 HER2-negative tumors, borderline HR (1%–9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2-enriched, and only 7 (18%) basal-like. Including them in the definition of triple-negative breast cancer significantly diminished enrichment for basal-like cancer (p < .05). Among 106 HER2-positive tumors with <1% HR expression by IHC, the HER2-enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (>10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT-qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. Conclusion. Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HR IHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology. PMID:25908555

  5. Functional expression of bradykinin B1 and B2 receptors in neonatal rat trigeminal ganglion neurons

    PubMed Central

    Kawaguchi, Aya; Sato, Masaki; Kimura, Maki; Yamazaki, Takaki; Yamamoto, Hitoshi; Tazaki, Masakazu; Ichinohe, Tatsuya; Shibukawa, Yoshiyuki

    2015-01-01

    Bradykinin (BK) and its receptors (B1 and B2 receptors) play important roles in inflammatory nociception. However, the patterns of expression and physiological/pathological functions of B1 and B2 receptors in trigeminal ganglion (TG) neurons remain to be fully elucidated. We investigated the functional expression of BK receptors in rat TG neurons. We observed intense immunoreactivity of B2 receptors in TG neurons, while B1 receptors showed weak immunoreactivity. Expression of the B2 receptor colocalized with immunoreactivities against the pan-neuronal marker, neurofilament H, substance P, isolectin B4, and tropomyosin receptor kinase A antibodies. Both in the presence and absence of extracellular Ca2+ ([Ca2+]o), BK application increased the concentration of intracellular free Ca2+ ([Ca2+]i). The amplitudes of BK-induced [Ca2+]i increase in the absence of [Ca2+]o were significantly smaller than those in the presence of Ca2+. In the absence of [Ca2+]o, BK-induced [Ca2+]i increases were sensitive to B2 receptor antagonists, but not to a B1 receptor antagonist. However, B1 receptor agonist, Lys-[Des-Arg9]BK, transiently increased [Ca2+]i in primary cultured TG neurons, and these increases were sensitive to a B1 receptor antagonist in the presence of [Ca2+]o. These results indicated that B2 receptors were constitutively expressed and their activation induced the mobilization of [Ca2+]i from intracellular stores with partial Ca2+ influx by BK. Although constitutive B1 receptor expression could not be clearly observed immunohistochemically in the TG cryosection, cultured TG neurons functionally expressed B1 receptors, suggesting that both B1 and B2 receptors involve pathological and physiological nociceptive functions. PMID:26124706

  6. Expression of melatonin receptors in arteries involved in thermoregulation

    SciTech Connect

    Viswanathan, M.; Laitinen, J.T.; Saavedra, J.M. )

    1990-08-01

    Melatonin binding sites were localized and characterized in the vasculature of the rat by using the melatonin analogue 2-(125I)iodomelatonin (125I-melatonin) and quantitative in vitro autoradiography. The expression of these sites was restricted to the caudal artery and to the arteries that form the circle of Willis at the base of the brain. The arterial 125I-melatonin binding was stable, saturable, and reversible. Saturation studies revealed that the binding represented a single class of high-affinity binding sites with a dissociation constant (Kd) of 3.4 x 10(-11) M in the anterior cerebral artery and 1.05 x 10(-10) M in the caudal artery. The binding capacities (Bmax) in these arteries were 19 and 15 fmol/mg of protein, respectively. The relative order of potency of indoles for inhibition of 125I-melatonin binding at these sites was typical of a melatonin receptor: 2-iodomelatonin greater than melatonin greater than N-acetylserotonin much much greater than 5-hydroxytryptamine. Norepinephrine-induced contraction of the caudal artery in vitro was significantly prolonged and potentiated by melatonin in a concentration-dependent manner, suggesting that these arterial binding sites are functional melatonin receptors. Neither primary steps in smooth muscle contraction (inositol phospholipid hydrolysis) nor relaxation (adenylate cyclase activation) were affected by melatonin. Melatonin, through its action on the tone of these arteries, may cause circulatory adjustments in these arteries, which are believed to be involved in thermoregulation.

  7. Increased expression of the nicotinic acetylcholine receptor in stimulated muscle.

    PubMed

    O'Reilly, Clare; Pette, Dirk; Ohlendieck, Kay

    2003-01-10

    Chronic low-frequency stimulation has been used as a model for investigating responses of skeletal muscle fibres to enhanced neuromuscular activity under conditions of maximum activation. Fast-to-slow isoform shifting of markers of the sarcoplasmic reticulum and the contractile apparatus demonstrated successful fibre transitions prior to studying the effect of chronic electro-stimulation on the expression of the nicotinic acetylcholine receptor. Comparative immunoblotting revealed that the alpha- and delta-subunits of the receptor were increased in 10-78 day stimulated specimens, while an associated component of the surface utrophin-glycoprotein complex, beta-dystroglycan, was not drastically changed in stimulated fast skeletal muscle. Previous studies have shown that electro-stimulation induces degeneration of fast glycolytic fibres, trans-differentiation leading to fast-to-slow fibre transitions and activation of muscle precursor cells. In analogy, our results indicate a molecular modification of the central functional unit of the post-synaptic muscle surface within existing neuromuscular junctions and/or during remodelling of nerve-muscle contacts. PMID:12504123

  8. The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

    PubMed Central

    Jung, Yoon Seok; Lee, Ji-Min; Kim, Don-Kyu; Lee, Yong-Soo; Kim, Ki-Sun; Kim, Yong-Hoon; Kim, Jina; Lee, Myung-Shik; Lee, In-Kyu; Kim, Seong Heon; Cho, Sung Jin; Jeong, Won-Il; Lee, Chul-Ho; Harris, Robert A.; Choi, Hueng-Sik

    2016-01-01

    Background Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown. Results Activation of the hepatic CB1 receptor by arachidonyl-2’-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) γ increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRγ decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRγ, but not ERRα and ERRβ, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRγ-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRγ to the FGF21 gene promoter. Finally, GSK5182, an ERRγ inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion. Conclusion Based on our data, we conclude that ERRγ plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion. PMID:27455076

  9. Expression of bile acid receptor TGR5 in gastric adenocarcinoma.

    PubMed

    Cao, Weibiao; Tian, Wei; Hong, Jie; Li, Dan; Tavares, Rosemarie; Noble, Lelia; Moss, Steven F; Resnick, Murray B

    2013-02-15

    Bile reflux is a risk factor in the development of intestinal metaplasia in the stomach and is believed to function as an initiator of gastric carcinogenesis. However, whether the G protein-coupled bile acid receptor TGR5 is expressed in this tumor is not known. In this study, we determined the expression of TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation. Strong TGR5 staining was present in 12% of cases of intestinal metaplasia but in no cases of normal gastric epithelium (P < 0.01). Moderate to strong TGR5 membranous and cytoplasmic staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas (P < 0.001). Kaplan-Meier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival (P < 0.05). Treatment with taurodeoxycholic acid (TDCA, a bile acid) significantly increased thymidine incorporation in the AGS gastric adenocarcinoma cell line, suggesting that bile acids may increase cell proliferation. This increase was significantly decreased by knockdown of TGR5 with TGR5 small-interfering RNA (siRNA). In addition, overexpression of TGR5 significantly enhanced TDCA-induced increases in thymidine incorporation. TGR5 is coupled with G(q)α and Gα(i-3) proteins. TDCA-induced increase in thymidine incorporation was significantly decreased by knockdown of G(q)α and Gα(i-3) with their siRNAs. We conclude that TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. Bile acids increase cell proliferation via activation of TGR5 receptors and G(q)α and Gα(i-3) proteins. PMID:23238937

  10. Expression density of receptors to IL-1β in atopic dermatitis.

    PubMed

    Alshevskaya, Alina A; Lopatnikova, Julia A; Krugleeva, Olga L; Nepomnyschih, Vera M; Lukinov, Vitaliy L; Karaulov, Aleksander V; Sennikov, Sergey V

    2016-07-01

    Interleukin 1 (IL-1 β) and the system for regulation of its biological effects play an important role in the development and behavior of inflammatory processes in atopic dermatitis. Notably, cells that are actively involved in the pathological process have altered expression of cytokine receptors. However, standard evaluation of cells by flow cytometry measures only the percentage of cells expressing the appropriate marker, which is not enough for a full assessment of these changes. The aim of this study was to investigate changes in the expression of IL-1β cytokine receptors in patients with atopic dermatitis by both percentage of cells with receptors in various subsets and the absolute number of membrane-bound receptors themselves. It was found that an increase or decrease in the percentage of cells expressing the receptors in subsets of immune cells in patients with atopic dermatitis was not associated with a change in the number of receptors on the cell surface. Moreover, the changes in the percentage of cells and the number of receptors may occur in different directions, as shown for IL-1R2 expression on B cells and IL-1R1 expression for monocytes. Changes in the parameters of IL-1β receptor expressions are associated with disease severity index SCORAD in atopic dermatitis. These findings underline the importance of studying the density of cytokine receptor expression in the pathology. PMID:27267269

  11. Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice.

    PubMed

    Savignac, Helene M; Couch, Yvonne; Stratford, Michael; Bannerman, David M; Tzortzis, George; Anthony, Daniel C; Burnet, Philip W J

    2016-02-01

    The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host's inflammatory response, alter brain chemistry, and modulate anxiety behaviour in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behaviour have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno®, BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4h after LPS injection, and after 24h, anxiety in the light-dark box was assessed. Cytokine expression, and key components of the serotonergic (5-Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS-fed mice were less anxious in the light-dark box compared to controls 24h after the LPS injection. Elevated cortical IL-1β concentrations in control mice 28 h after LPS were not observed in BGOS-fed animals. This significant BGOS×LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behaviour, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS has an anxiolytic effect, which may be related to the modulation of cortical IL-1β and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features. PMID:26476141

  12. GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5-HT5B receptors involved?

    PubMed

    Sánchez-Maldonado, Carolina; López-Sánchez, Pedro; Anguiano-Robledo, Liliana; Leopoldo, Marcello; Lacivita, Enza; Terrón, José A

    2015-04-01

    The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors. PMID:25502305

  13. Interaction between 5-HT1B receptors and nitric oxide in zebrafish responses to novelty.

    PubMed

    Maximino, Caio; Lima, Monica Gomes; Batista, Evander de Jesus Oliveira; Oliveira, Karen Renata Herculano Matos; Herculano, Anderson Manoel

    2015-02-19

    Nitric oxide (NO) and serotonin (5-HT) interact at the molecular and systems levels to control behavioral variables, including agression, fear, and reactions to novelty. In zebrafish, the 5-HT1B receptor has been implicated in anxiety and reactions to novelty, while the 5-HT1A receptor is associated with anxiety-like behavior; this role of the 5-HT1A receptor is mediated by NO. This work investigated whether NO also participates in the mediation of novelty responses by the 5-HT1B receptor. The 5-HT1B receptor inverse agonist SB 224,289 decreased bottom-dwelling and erratic swimming in zebrafish; the effects on bottom-dwelling, but not on erratic swimming, were blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME. These effects underline a novel mechanism by which 5-HT controls zebrafish reactivity to novel environments, with implications for the study of neotic reactions, exploratory behavior, and anxiety-like states. PMID:25545556

  14. Expression of the transferrin receptor gene during the process of mononuclear phagocyte maturation

    SciTech Connect

    Hirata, T.; Bitterman, P.B.; Mornex, J.; Crystal, R.G.

    1986-02-15

    The expression of transferrin receptors by blood monocytes, human alveolar macrophages, and in vitro matured macrophages was evaluated by immunofluorescence, radioligand binding, and Northern analysis, using the monoclonal anti-human transferrin receptor antibody OKT9, (/sup 125/I)-labeled human transferrin and a (/sup 32/P)-labeled human transferrin receptor cDNA probe, respectively. By immunofluorescence, the majority of alveolar macrophages expressed transferrin receptors (86 +/- 3%). The radioligand binding assay demonstrated the affinity constant (K/sub a/) of the alveolar macrophage transferrin receptor was 4.4 +/- 0.7 x 10/sup 8/ M/sup -1/, and the number of receptors per cell was 4.4 +/- 1.2 x 10/sup 4/. In marked contrast, transferrin receptors were not present on the surface or in the cytoplasm of blood monocytes, the precursors of the alveolar macrophages. However, when monocytes were cultured in vitro and allowed to mature, > 80% expressed transferrin receptors by day 6, and the receptors could be detected by day 3. Consistent with these observations, a transferrin receptor mRNA with a molecular size of 4.9 kb was demonstrated in alveolar macrophages and in vitro matured macrophages but not in blood monocytes. Thus, although blood monocytes do not express the transferrin receptor gene, it is expressed by mature macrophages, an event that probably occurs relatively early in the process of monocyte differentiation to macrophages.

  15. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking.

    PubMed

    Monti, Jaime M; Jantos, Héctor

    2008-01-01

    Based on electrophysiological, neurochemical and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) and dopamine (DA) function to promote waking (W) and to inhibit slow wave sleep (SWS) and/or rapid-eye-movement sleep (REMS). Serotonergic neurons of the dorsal raphe nucleus (DRN) fire at a steady rate during W, decrease their firing during SWS and virtually cease activity during REMS. On the other hand, DA cells in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. Available evidence tends to indicate that during W and REMS an increase of burst firing activity of DA neurons occurs together with an enhanced release of DA in the VTA, the nucleus accumbens and several forebrain structures. Recently, DA neurons were characterised in the ventral periaqueductal grey matter (VPAG) that express Fos protein during W. Lesioning of these cells resulted in an increase of SWS and REMS, which led to the proposal that VPAG DA neurons may play a role in the promotion of W. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94,253), 5-HT(2A/2C) (DOI, DOM) and 5-HT(3) (m-chlorophenylbiguanide) receptors increases W and reduces SWS and REMS. On the other hand, microdialysis perfusion or direct infusion of 8-OH-DPAT or flesinoxan into the DRN, where somatodendritic 5-HT(1A) receptors are located, significantly increases REMS. Systemic administration of the selective DA D(1) receptor agonist SKF 38393 induces behavioural arousal together with an increase of W and a reduction of sleep. On the other hand, injection of a DA D(2) receptor agonist (apomorphine, bromocriptine, quinpirole) gives rise to biphasic effects, such that low doses reduce W and augment SWS and REMS

  16. Receptor Expression in Rat Skeletal Muscle Cell Cultures

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.

    1996-01-01

    One on the most persistent problems with long-term space flight is atrophy of skeletal muscles. Skeletal muscle is unique as a tissue in the body in that its ability to undergo atrophy or hypertrophy is controlled exclusively by cues from the extracellular environment. The mechanism of communication between muscle cells and their environment is through a group of membrane-bound and soluble receptors, each of which carries out unique, but often interrelated, functions. The primary receptors include acetyl choline receptors, beta-adrenergic receptors, glucocorticoid receptors, insulin receptors, growth hormone (i.e., somatotropin) receptors, insulin-like growth factor receptors, and steroid receptors. This project has been initiated to develop an integrated approach toward muscle atrophy and hypertrophy that takes into account information on the populations of the entire group of receptors (and their respective hormone concentrations), and it is hypothesized that this information can form the basis for a predictive computer model for muscle atrophy and hypertrophy. The conceptual basis for this project is illustrated in the figure below. The individual receptors are shown as membrane-bound, with the exception of the glucocorticoid receptor which is a soluble intracellular receptor. Each of these receptors has an extracellular signalling component (e.g., innervation, glucocorticoids, epinephrine, etc.), and following the interaction of the extracellular component with the receptor itself, an intracellular signal is generated. Each of these intracellular signals is unique in its own way; however, they are often interrelated.

  17. Differential expression of estrogen receptor α and progesterone receptor in the normal and cryptorchid testis of a dog.

    PubMed

    Jung, Hyo Young; Yoo, Dae Young; Jo, Young Kwang; Kim, Geon A; Chung, Jin Young; Choi, Jung Hoon; Jang, Goo; Hwang, In Koo

    2016-06-01

    Descending of the testes is an important process for spermatogenesis and cryptorchidism is one of the most relevant genital defects in dogs. In a previous study, we observed abnormal morphology and proliferation of Sertoli cells in a cryptorchid testis. In the present study, we investigated the expression of estrogen and progesterone receptors in the normal and cryptorchid testis of a dog. Elective orchidectomy was performed on the dog's abdominal right testis (undescended, cryptorchid) and scrotal left testis (descended, normal). In the normal testis, estrogen receptor α immunoreactivity was detected in Leydig cells alone, while estrogen receptor α immunoreactivity in the cryptorchid testis was significantly prominent in the Sertoli cells as well. In addition, progesterone receptor immunoreactivity in the control testis was detected in the spermatids, but was not detected in the cryptorchid testis. This result suggests that unilateral cryptorchidism causes increases of estrogen receptor α expression in Sertoli cells. PMID:27382382

  18. Differential expression of estrogen receptor α and progesterone receptor in the normal and cryptorchid testis of a dog

    PubMed Central

    Jung, Hyo Young; Yoo, Dae Young; Jo, Young Kwang; Kim, Geon A; Chung, Jin Young; Choi, Jung Hoon

    2016-01-01

    Descending of the testes is an important process for spermatogenesis and cryptorchidism is one of the most relevant genital defects in dogs. In a previous study, we observed abnormal morphology and proliferation of Sertoli cells in a cryptorchid testis. In the present study, we investigated the expression of estrogen and progesterone receptors in the normal and cryptorchid testis of a dog. Elective orchidectomy was performed on the dog's abdominal right testis (undescended, cryptorchid) and scrotal left testis (descended, normal). In the normal testis, estrogen receptor α immunoreactivity was detected in Leydig cells alone, while estrogen receptor α immunoreactivity in the cryptorchid testis was significantly prominent in the Sertoli cells as well. In addition, progesterone receptor immunoreactivity in the control testis was detected in the spermatids, but was not detected in the cryptorchid testis. This result suggests that unilateral cryptorchidism causes increases of estrogen receptor α expression in Sertoli cells. PMID:27382382

  19. Selective Toll-Like Receptor Expression in Human Fetal Lung

    PubMed Central

    Petrikin, Joshua E; Gaedigk, Roger; Leeder, J Steven; Truog, William E

    2010-01-01

    Toll-like receptors (TLRs) are critical components of the innate immune system, acting as pattern recognition molecules and triggering an inflammatory response. TLR associated gene products are of interest in modulating inflammatory related pulmonary diseases of the neonate. The ontogeny of TLR related genes in human fetal lung has not been previously described and could elucidate additional functions and identify strategies for attenuating the effects of fetal inflammation. We examined the expression of 84 TLR related genes on 23 human fetal lung samples from three groups with estimated ages of 60 (57-59d), 90 (89-91d), and 130 (117-154d) days. Using a false detection rate algorithm, we identified 32 genes displaying developmental regulation with TLR2 having the greatest up-regulation of TLR genes (9.2 fold increase) and TLR4 unchanged. We confirmed the TLR2 up-regulation by examining an additional 133 fetal lung tissue samples with a fluorogenic polymerase chain reaction assay (TaqMan®) and found an exponential best-fit curve over the time studied. The best-fit curve predicts a 6.1 fold increase from 60d to 130d. We conclude that TLR2 is developmentally expressed from the early pseudoglandular stage of lung development to the canalicular stage. PMID:20581745

  20. Expression of estrogen and progesterone receptors in astrocytomas: a literature review.

    PubMed

    Tavares, Cléciton Braga; Gomes-Braga, Francisca das Chagas Sheyla Almeida; Costa-Silva, Danylo Rafhael; Escórcio-Dourado, Carla Solange; Borges, Umbelina Soares; Conde-Junior, Airton Mendes; Barros-Oliveira, Maria da Conceição; Sousa, Emerson Brandão; Barros, Lorena da Rocha; Martins, Luana Mota; Facina, Gil; da-Silva, Benedito Borges

    2016-08-01

    Gliomas are the most common type of primary central nervous system neoplasm. Astrocytomas are the most prevalent type of glioma and these tumors may be influenced by sex steroid hormones. A literature review for the presence of estrogen and progesterone receptors in astrocytomas was conducted in the PubMed database using the following MeSH terms: "estrogen receptor beta" OR "estrogen receptor alpha" OR "estrogen receptor antagonists" OR "progesterone receptors" OR "astrocytoma" OR "glioma" OR "glioblastoma". Among the 111 articles identified, 13 studies met our inclusion criteria. The majority of reports showed the presence of estrogen and progesterone receptors in astrocytomas. Overall, higher tumor grades were associated with decreased estrogen receptor expression and increased progesterone receptor expression. PMID:27626480