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Sample records for 5-ht1a c-1019g polymorphism

  1. Functional 5-HT1a receptor polymorphism selectively modulates error-specific subprocesses of performance monitoring.

    PubMed

    Beste, Christian; Domschke, Katharina; Kolev, Vasil; Yordanova, Juliana; Baffa, Anna; Falkenstein, Michael; Konrad, Carsten

    2010-04-01

    Our study investigates the dependence of response monitoring and error detection on genetic influences modulating the serotonergic system. This was done using the event-related potentials (ERPs) after error (Ne/ERN) and correct trials (Nc/CRN). To induce a sufficient amount of errors, a standard flanker task was used. The subjects (N = 94) were genotyped for the functional 5-HT1A C(-1019)G polymorphism. The results show that the 5-HT1A C(-1019)G polymorphism specifically modulates error detection. Neurophysiological modulations on error detection were paralleled by a similar modulation of response slowing after an error, reflecting the behavioral adaptation. The 5-HT1A -1019 CC genotype group showed a larger Ne and stronger posterror slowing than the CG and GG genotype groups. More general processes of performance monitoring, as reflected in the Nc/CRN, were not affected. The finding that error-specific processes, but not general response monitoring processes, are modulated by the 5-HT1A C(-1019)G polymorphism is underlined by a wavelet analysis. In summary, the results suggest a specific effect of the 5-HT1A C(-1019)G polymorphism on error monitoring, as reflected in the Ne, and suggest a neurobiological dissociation between processes of error monitoring and general response monitoring at the level of the serotonin 1A receptor system.

  2. Transcriptional regulation of the 5-HT1A receptor: implications for mental illness.

    PubMed

    Albert, Paul R

    2012-09-05

    The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5-HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression.

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

    PubMed

    Meneses, Alfredo; Perez-Garcia, Georgina

    2007-01-01

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

  4. The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys

    PubMed Central

    Burnett, Elizabeth J.; Grant, Kathleen A.; Davenport, April T.; Hemby, Scott E.; Friedman, David P.

    2014-01-01

    BACKGROUND Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood. METHODS Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT1A receptor antagonist, [3H]MPPF, and the agonist, [3H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT1A receptors respectively. The expression of the genes encoding the 5-HT1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. RESULTS An increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up-regulation of total and G-protein coupled 5-HT1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT1A receptor mRNA expression. Chronic ethanol self-administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. CONCLUSIONS Chronic, ethanol self-administration up-regulates hippocampal 5-HT1A receptor density in a region-specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted. PMID:24467872

  5. The 5-HT1A receptor in Major Depressive Disorder

    PubMed Central

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

    2016-01-01

    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

  6. 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.

  7. Transcriptional dys-regulation in anxiety and major depression: 5-HT1A gene promoter architecture as a therapeutic opportunity.

    PubMed

    Albert, Paul R; Fiori, Laura M

    2014-01-01

    The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5- HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as post-synaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto- and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto- and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto- and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression.

  8. Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects.

    PubMed

    Bortolozzi, A; Castañé, A; Semakova, J; Santana, N; Alvarado, G; Cortés, R; Ferrés-Coy, A; Fernández, G; Carmona, M C; Toth, M; Perales, J C; Montefeltro, A; Artigas, F

    2012-06-01

    Depression is a major health problem worldwide. Most prescribed anti-depressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT(1A)-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT(1A) receptor (5-HT(1A)R) gene polymorphisms leading to high 5-HT(1A)-autoreceptor expression increase depression susceptibility and decrease treatment response. In this study, we report on a new treatment strategy based on the administration of small-interfering RNA (siRNA) to acutely suppress 5-HT(1A)-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT(1A) receptor mRNA with the SSRI sertraline in order to concentrate it in serotonin axons, rich in serotonin transporter (SERT) sites. The intracerebroventricular (i.c.v.) infusion of C-1A-siRNA to mice resulted in its selective accumulation in serotonin neurons. This evoked marked anti-depressant-like effects in the forced swim and tail suspension tests, but did not affect anxiety-like behaviors in the elevated plus-maze. In parallel, C-1A-siRNA administration markedly decreased 5-HT(1A)-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT(1A)R effect in mice) without affecting post-synaptic 5-HT(1A)R expression in hippocampus and prefrontal cortex. Moreover, i.c.v. C-1A-siRNA infusion augmented the increase in extracellular serotonin evoked by fluoxetine in prefrontal cortex to the level seen in 5-HT(1A)R knockout mice. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders as monotherapy or in combination with SSRI.

  9. Effect of the postsynaptic 5-HT1A receptor antagonist MM-77 on stressed mice treated with 5-HT1A receptor agents.

    PubMed

    Alfredo, Briones-Aranda; Ofir, Picazo

    2005-01-31

    The pharmacological effect of the 5-HT1A receptor ligands, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), indorenate, and buspirone, alone or in combination with the antagonist MM-77, was studied in mice subjected to forced swimming. It was confirmed that this stressful factor produces an anxiolytic-like effect, which is reversed by the mentioned 5-HT1A receptor agonists. Only the 8-OH-DPAT-induced decrease of such an effect could be blocked by the postsynaptic antagonist of the 5-HT1A receptor 1-(2-methoxyphenyl)-4-[(4-succinimido)butyl]-piperazine (MM-77). Stressing by forced swimming seems to induce plastic changes in 5-HT1A receptors, which in turn modify the behavioural actions of 5-HT1A receptor agents.

  10. 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.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-11-01

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

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

    PubMed Central

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

    2015-01-01

    The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA’s but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression. PMID:24946016

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

    PubMed

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

    2015-10-30

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

  15. 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

  16. Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors.

    PubMed

    Müller, Christian P; Carey, Robert J; Huston, Joseph P; De Souza Silva, Maria A

    2007-02-01

    Serotonin(1A)-receptors (5-HT(1A)-Rs) are important components of the 5-HT system in the brain. As somatodendritic autoreceptors they control the activity of 5-HT neurons, and, as postsynaptic receptors, the activity in terminal areas. Cocaine (COC), amphetamine (AMPH), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine ("Ecstasy", MDMA) are psychostimulant drugs that can lead to addiction-related behavior in humans and in animals. At the neurochemical level, these psychostimulant drugs interact with monoamine transporters and increase extracellular 5-HT, dopamine and noradrenalin activity in the brain. The increase in 5-HT, which, in addition to dopamine, is a core mechanism of action for drug addiction, hyperactivates 5-HT(1A)-Rs. Here, we first review the role of the various 5-HT(1A)-R populations in spontaneous behavior to provide a background to elucidate the contribution of the 5-HT(1A)-Rs to the organization of psychostimulant-induced addiction behavior. The progress achieved in this field shows the fundamental contribution of brain 5-HT(1A)-Rs to virtually all behaviors associated with psychostimulant addiction. Importantly, the contribution of pre- and postsynaptic 5-HT(1A)-Rs can be dissociated and frequently act in opposite directions. We conclude that 5-HT(1A)-autoreceptors mainly facilitate psychostimulant addiction-related behaviors by a limitation of the 5-HT response in terminal areas. Postsynaptic 5-HT(1A)-Rs, in contrast, predominantly inhibit the expression of various addiction-related behaviors directly. In addition, they may also influence the local 5-HT response by feedback mechanisms. The reviewed findings do not only show a crucial role of 5-HT(1A)-Rs in the control of brain 5-HT activity and spontaneous behavior, but also their complex role in the regulation of the psychostimulant-induced 5-HT response and subsequent addiction-related behaviors.

  17. Application of Quantitative Structure–Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands

    PubMed Central

    2015-01-01

    The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure–activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. PMID:24410373

  18. 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

  19. Molecular imaging of the 5-HT(1A) receptor in relation to human cognition.

    PubMed

    Borg, Jacqueline

    2008-12-16

    Animal studies and pharmacological studies in man have suggested that the serotonin 5-HT(1A) receptor may serve as a biomarker for cognitive functioning and a target for treatment of cognitive impairment. Consistent findings in man have nonetheless hitherto remained sparse. Positron emission tomography (PET) imaging of the 5-HT(1A) receptor in patients with Alzheimer's disease, schizophrenia and depression implicate an alteration in 5-HT(1A) receptor binding compared to control subjects, but it is yet unknown whether these alterations are related to the cognitive impairment associated with these disorders. Pharmacological challenge studies using 5-HT(1A) agonism and antagonism to manipulate the serotonin system support involvement of the 5-HT(1A) receptor in human cognition, mainly in verbal memory functioning. However, the effect varies across studies and it remains unclear if the 5-HT(1A) receptor serves as a validated target for treatment of cognitive deficits. This lack of confirmation of experimental preclinical data, calls for increased efforts in translational research. Molecular imaging techniques such as PET, holds the potential to facilitate translational neuroscience by confirming observations from animal models in man, and aid development of validated animal models of use for advancement of pharmacological treatment. Furthermore, in combination with molecular genetics, molecular imaging may suggest novel strategies for prevention and intervention, based on an understanding of the molecular mechanisms involved in disease pathogenesis of major neuropsychiatric disorder and associated cognitive impairment.

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

    PubMed

    Dabrowska, Joanna; Nowak, Przemysław; Brus, Ryszard

    2007-01-15

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

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

    PubMed

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

    1990-01-01

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

  2. 5-HT1A and 5-HT7 receptors contribute to lurasidone-induced dopamine efflux.

    PubMed

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

    2012-05-09

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

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

    DOEpatents

    Mukherjee, Jogeshwar [Irvine, CA; Saigal, Neil [Fresno, CA; Saigal, legal representative, Harsh

    2012-09-25

    Contemplated substituted arylpiperazinyl compounds, and most preferably .sup.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 .sup.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.

  4. 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.

  5. 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.

  6. Analysis of the 5-HT1A receptor involvement in passive avoidance in the rat

    PubMed Central

    Misane, Ilga; Johansson, Christina; Ove Ögren, Sven

    1998-01-01

    The effects of the 5-HT2A/2C agonist DOB, the selective 5-HT1A agonist NDO 008 (3-dipropylamino-5-hydroxychroman), and the two enantiomers of the selective 5-HT1A agonist 8-OH-DPAT (R(+)-8-OH-DPAT and S(−)-8-OH-DPAT) were studied in a step-through passive avoidance (PA) test in the male rat.The 5-HT1A agonists injected prior to training (conditioning) produced a dose-dependent impairment of PA retention when examined 24 h later. R(+)-8-OH-DPAT was four times more effective than S(−)-8-OH-DPAT to cause an impairment of PA retention. Both NDO 008 and the two enantiomers of 8-OH-DPAT induced the serotonin syndrome at the dose range that produced inhibition of the PA response, thus, indicating activation of postsynaptic 5-HT1A receptors.Neither NDO 008 nor R(+)-8-OH-DPAT induced head-twitches, a behavioural response attributed to stimulation of postsynaptic 5-HT2A receptors. In contrast, DOB induced head-twitches at the 0.01 mg kg−1 dose while a 200 times higher dose was required to produce a significant impairment of PA retention.The impairment of PA retention induced by both NDO 008 and R(+)-8-OH-DPAT was fully blocked by the active S(+)- enantiomer of the selective 5-HT1A antagonist WAY 100135 and the mixed 5-HT1A/β-adrenoceptor antagonist L(−)-alprenolol. In contrast, the mixed 5-HT2A/2C antagonists ketanserin and pirenperone were found to be ineffective. Moreover, the β2-adrenoceptor antagonist ICI 118551, the β1-antagonist metoprolol as well as the mixed β-adrenoceptor blocker D(+)-alprenolol all failed to modify the deficit of PA retention by NDO 008 and R(+)-8-OH-DPAT. None of the 5-HT1A or 5-HT2A/2C receptor antagonists tested or the β-blockers altered PA retention by themselves.A 3 day pretreatment procedure (200+100+100 mg kg−1) with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) did not alter PA retention and did not prevent the inhibitory action of the 5-HT1A agonists, indicating that their effects on PA do not

  7. Platelet 5-HT(1A) receptor correlates with major depressive disorder in drug-free patients.

    PubMed

    Zhang, Zhang-Jin; Wang, Di; Man, Sui Cheung; Ng, Roger; McAlonan, Grainne M; Wong, Hei Kiu; Wong, Wendy; Lee, Jade; Tan, Qing-Rong

    2014-08-04

    The platelet serotonergic system has potential biomarker utility for major depressive disorder (MDD). In the present study, platelet expression of 5-HT1A receptors and serotonin transporter (SERT) proteins, and serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were quantified in 53 patients with MDD and 22 unaffected controls. All were drug-free, non-smokers and had no other psychiatric and cardiovascular comorbidity. The severity of depression symptoms was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Self-rating Depression Scale (SDS). Patients with MDD had significantly higher expression of platelet 5-HT1A receptors but significantly lower contents of platelet 5-HT, platelet-poor plasma (PPP) 5-HT and PPP 5-HIAA compared to healthy controls, and this was correlated with the severity of depression. SERT expression did not differ between the two groups. Correlation analysis confirmed a strong, inverse relationship between the 5-HT1A receptor expression and the 5-HT and 5-HIAA levels. Thus overexpression of platelet 5-HT1A receptors and reduced 5-HT tone may function as a peripheral marker of depression.

  8. Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists.

    PubMed

    Miczek, K A; Hussain, S; Faccidomo, S

    1998-09-01

    One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with

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

    PubMed

    Perez-Garcia, Georgina; Meneses, Alfredo

    2009-08-24

    In an attempt to clarify conflicting results about serotonin (5-hydroxytryptamine, 5-HT) 5-HT(1A) and 5-HT(7) receptors in memory formation, their mRNA expression was determined by RT-PCR in key brain areas for explicit and implicit memory. The time-course (0-120 h) of autoshaped responses was progressive and mRNA 5-HT(1A) or 5-HT(7) receptors expression monotonically augmented or declined in prefrontal cortex, hippocampus and raphe nuclei, respectively. At 24-48 h acutely 8-OH-DPAT (0.062 mg/kg) administration enhanced memory and attenuated mRNA 5-HT(1A)<5-HT(7) receptors expression respect to saline group. WAY100635 (0.3 mg/kg) or SB-269970 (10.0 mg/kg) did not affect the former, partially blocked or reversed the latter, respectively. Furthermore, lower WAY100635 (0.001-0.1 mg/kg) or SB-269970 (1.0-5.0 mg/kg) doses plus 8-OHDPAT not affected memory; however both combinations suppressed or up-regulated mRNA expression 5-HT(1A) or 5-HT(7) receptors. In contrast, AS19 (5.0 mg/kg) facilitated memory consolidation, decreased or increased hippocampal 5-HT(7) and 5-HT(1A) receptors expression. Together these data revealed that, when both 5-HT(1A) and 5-HT(7) receptors were stimulated by 8-OHDPAT under memory consolidation, subtle changes emerged, not evident at behavioral level though detectable at genes expression. Notably, high levels of efficient memory were maintained even when serotonergic tone, via either 5-HT(1A) or 5-HT(7) receptor, was down- or up-regulated. Nevertheless, WAY100635 plus SB-269970 impaired memory consolidation and suppressed their expression. Considering that serotonergic changes are prominent in AD patients with an earlier onset of disease the present approach might be useful in the identification of functional changes associated to memory formation, memory deficits and reversing or even preventing these deficits.

  10. Methylenedioxymethamphetamine induces spontaneous tail-flicks in the rat via 5-HT1A receptors.

    PubMed

    Millan, M J; Colpaert, F C

    1991-02-07

    In rats lightly restrained in horizontal cylinders, (+/-)-3,4-methylenedioxymethamphetamine (MDMA) dose dependently (0.16-10.0 mg/kg, s.c.) elicited spontaneous tail-flicks; that is, tail-flicks in the absence of extraneous stimulation. In contrast, amphetamine over a similar dose-range was inactive. Selective inhibitors of 5-hydroxytryptamine (5-HT) uptake and carrier-mediated 5-HT release, paroxetine and citalopram, did not induce spontaneous tail-flicks themselves and blocked those induced by MDMA. In distinction, maprotiline and bupropion, selective inhibitors of noradrenaline and dopamine uptake, respectively, failed to modify the action of MDMA. Spontaneous tail-flicks elicited by MDMA were unaffected by the selective 5-HT3 receptor antagonists, ICS 205,930 and GR 38032F. They were attenuated by the mixed 5-HT1/5-HT2 receptor antagonist, methiotepin, the mixed 5-HT1A/5-HT1B receptor antagonist, (-)-alprenolol and the mixed 5-HT1A/5-HT2 receptor antagonist, spiperone, but not by the selective 5-HT1C/5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ketanserin. The novel 5-HT1A receptor antagonists, BMY 7378 and NAN-190, each abolished MDMA-evoked spontaneous tail-flicks. Selective D1, D2, alpha 1, alpha 2, beta 1 and beta 2 antagonists had little influence upon induction of spontaneous tail-flicks by MDMA. These data indicate that MDMA evokes spontaneous tail-flicks in the rat via a release of 5-HT which acts at 5-HT1A receptors. Thus, 5-HT1A receptors appear to be involved in the acute functional actions of MDMA.

  11. Role of maternal 5-HT(1A) receptor in programming offspring emotional and physical development.

    PubMed

    van Velzen, A; Toth, M

    2010-11-01

    Serotonin(1A) receptor (5-HT(1A)R) deficiency has been associated with anxiety and depression and mice with genetic receptor inactivation exhibit heightened anxiety. We have reported that 5-HT(1A)R is not only a genetic but also a maternal 'environmental' factor in the development of anxiety in Swiss-Webster mice. Here, we tested whether the emergence of maternal genotype-dependent adult anxiety is preceded by early behavioral abnormalities or whether it is manifested following a normal emotional development. Pups born to null or heterozygote mothers had significantly reduced ultrasonic vocalization (USV) 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 physical development of the offspring. Except a short perinatal deficit during the dark period, heterozygote females displayed normal maternal behavior, which, with the early appearance of USV deficit, suggests a role for 5-HT(1A)R 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-HT(1A)R in regulating emotional and physical development of their offspring. Because reduced receptor binding has been reported in depression, including postpartum depression, reduced 5-HT(1A)R function in mothers may influence the emotional development of their offspring.

  12. [5-HT1A/5-HT7 receptor interplay: Chronic activation of 5-HT7 receptors decreases the functional activity of 5-HT1A receptor and its сontent in the mouse brain].

    PubMed

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

    2017-01-01

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

  13. 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

  14. The partial 5-HT1A receptor agonist buspirone enhances neurogenesis in the opossum (Monodelphis domestica).

    PubMed

    Grabiec, Marta; Turlejski, Kris; Djavadian, Rouzanna L

    2009-06-01

    We demonstrate for the first time that neurogenesis in the adult Monodelphis opossum has a typical mammalian pattern and occurs only in the dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles. In these two brain regions neurogenesis is present throughout the lifespan, although its rate is reduced by half in the old age. Treatment with buspirone, a partial 5-HT1A receptor agonist which is used in human clinic as an anxiolytic agent, boosts proliferation in the SVZ and DG in both adult and aged opossums. The neuronal phenotype dominates among newly generated cells in both non-treated and buspirone-treated opossums. We suggest that if functional importance of adult neurogenesis is in improving olfactory discrimination and generation of hippocampus-dependent memory, both spatial and emotional, then administration of drugs increasing the rate of neurogenesis via activation of 5-HT1A receptors may be a valuable aid in combating problems of the advanced age.

  15. 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.

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

    PubMed

    de Paulis, Tomas

    2007-01-01

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

  17. 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

  18. 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.

  19. Arylpiperazines with N-acylated amino acids as 5-HT1A receptor ligands.

    PubMed

    Zajdel, Paweł; Subra, Gilles; Bojarski, Andrzej J; Duszyńska, Beata; Pawłowski, Maciej; Martinez, Jean

    2006-07-01

    A library consisting of 60 arylpiperazines modified with N-acylated amino acids was prepared on BAL linker SynPhasetrade mark Lanterns and evaluated in vitro for 5-HT(1A) receptor affinity. Biological screening, followed by a simple Fujita-Ban analysis, enabled the description of structure-activity relationships and allowed the selection of some potent, high-affinity ligands for in vivo pharmacological investigations.

  20. 5-HT1A receptors modulate the consolidation of learning in normal and cognitively impaired rats.

    PubMed

    Meneses, A; Hong, E

    1999-03-01

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

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

    PubMed

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

    2014-07-01

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

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

    PubMed

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

    1989-01-01

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

  3. 5-HT(1A)-like receptor activation inhibits abstinence-induced methamphetamine withdrawal in planarians.

    PubMed

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

    2010-10-29

    No pharmacological therapy is approved to treat methamphetamine physical dependence, but it has been hypothesized that serotonin (5-HT)-enhancing drugs might limit the severity of withdrawal symptoms. To test this hypothesis, we used a planarian model of physical dependence that quantifies withdrawal as a reduction in planarian movement. Planarians exposed to methamphetamine (10 μM) for 60 min, and then placed (tested) into drug-free water for 5 min, displayed less movement (i.e., withdrawal) than either methamphetamine-naïve planarians tested in water or methamphetamine-exposed planarians tested in methamphetamine. A concentration-related inhibition of withdrawal was observed when methamphetamine-exposed planarians were placed into a solution containing either methamphetamine and 5-HT (0.1-100 μM) or methamphetamine and the 5-HT(1A) receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) (10, 20 μM). Planarians with prior methamphetamine exposure displayed enhanced withdrawal when tested in a solution of the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635) (1 μM). Methamphetamine-induced withdrawal was not affected by the 5-HT(2B/2C) receptor agonist meta-chlorophenylpiperazine (m-CPZ) (0.1-20 μM). These results provide pharmacological evidence that serotonin-enhancing drugs inhibit expression of methamphetamine physical dependence in an invertebrate model of withdrawal, possibly through a 5-HT(1A)-like receptor-dependent mechanism.

  4. Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers.

    PubMed

    Di Stefano, M; Papathanasopoulos, A; Blondeau, K; Vos, R; Boecxstaens, V; Farré, R; Rommel, N; Tack, J

    2012-07-01

    There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.

  5. 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

  6. 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

  7. Modification of the anxiolytic effects of 5-HT1A agonists by shock intensity.

    PubMed

    Meneses, A; Hong, E

    1993-11-01

    Contradictory evidence exists concerning the anxiolytic effects of 5-HT1A agonists in the conflict test. In the present work, a modification of the Vogel conflict model was used to assess different doses of diazepam (0.1-5.6 mg/kg), ipsapirone (1.0-17.8 mg/kg), buspirone (1.7-17.8 mg/kg), and indorenate (0.56-17.8 mg/kg) in rats receiving two different electric shock intensities (0.16 and 0.32 mA). The results show that the three 5-HT1A agonists had a smaller anticonflict effect than diazepam. The anticonflict effect with each compound was of a greater magnitude at 0.16 mA intensity than at 0.32 mA. This study shows that, using different electric shock intensities, compounds produce a differential effect: the anticonflict effects were more pronounced with the lower electric shock intensity than with the higher intensity. The present results suggest that the use of different shock intensities can play distinct roles over the drug's effect in the conflict test.

  8. 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.

  9. 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

  10. Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models.

    PubMed

    Overstreet, David H; Commissaris, Randall C; De La Garza, Richard; File, Sandra E; Knapp, Darin J; Seiden, Lewis S

    2003-06-01

    Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive disorders because partial 5-HT1A receptor agonists such as buspirone are therapeutic. The present review considers evidence from genetic animal models that support a role for 5-HT1A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT1A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT1A agonist. Although the HDS rats do exhibit elevations in 5-HT1A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT1A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT1A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT1A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.

  11. New insight into the therapeutic role of 5-HT1A receptors in central nervous system disorders.

    PubMed

    Ohno, Yukihiro

    2010-06-01

    The serotonergic system plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among 5-HT receptor subtypes, 5-HT(1A) receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. 5-HT(1A) receptors function as both presynaptic (autoreceptor) and postsynaptic receptors in specific brain regions such as the limbic areas, septum and raphe nuclei. 5-HT(1A) receptors negatively regulate cAMP-dependent signal transduction and inhibit neuronal activity by opening G-protein-gated inwardly rectifying potassium channels. The therapeutic action of 5-HT(1A) agonists and their mechanism in alleviating anxiety and depressive disorders have been well documented. In addition, recent studies have revealed new insights into the therapeutic role of 5-HT(1A) receptors in treating various CNS disorders, including not only depressive disorders (e.g., delayed onset of action and refractory symptoms), but also schizophrenia (e.g., cognitive impairment and antipsychotic-induced extrapyramidal side effects) and Parkinson's disease (e.g., extrapyramidal motor symptoms and L-DOPA-induced dyskinesia). These lines of evidences encourage us to design new generation 5-HT(1A) ligands such as 5-HT(1A) agonists with greater potency, higher selectivity and improved pharmacokinetic properties, and 5-HT(1A) ligands which combine multiple pharmacological actions (e.g., inhibition of serotonin transporter, dopamine D(2) receptors and other 5-HT receptor subtypes). Such new 5-HT(1A) ligands may overcome clinical efficacy limitations and/or improve adverse reactions in current CNS therapies.

  12. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist

    PubMed Central

    Newman-Tancredi, A; Martel, J-C; Assié, M-B; Buritova, J; Lauressergues, E; Cosi, C; Heusler, P; Slot, L Bruins; Colpaert, FC; Vacher, B; Cussac, D

    2009-01-01

    Background and purpose: Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. Key results: F15599 was highly selective for 5-HT1A receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A receptors. In cell lines expressing h5-HT1A receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition. PMID:19154445

  13. 5-HT1A receptor pharmacophores to screen for off-target activity of α1-adrenoceptor antagonists

    NASA Astrophysics Data System (ADS)

    Ngo, Tony; Nicholas, Timothy J.; Chen, Junli; Finch, Angela M.; Griffith, Renate

    2013-04-01

    The α1-adrenoceptors (α1-ARs), in particular the α1A-AR subtype, are current therapeutic targets of choice for the treatment of urogenital conditions, such as benign prostatic hyperplasia (BPH). Due to the similarity between the transmembrane domains of the α1-AR subtypes, and the serotonin receptor subtype 1A (5-HT1A-R), currently used α1-AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT1A-R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT1A-R agonists and antagonists. Through the structural diversity of the training sets used in their development, these pharmacophores define the properties of a compound needed to bind to 5-HT1A receptors. Using these and previously published pharmacophores in virtual screening and profiling, we have identified unique chemical compounds (hits) that fit the requirements to bind to our target, the α1A-AR, selectively over the off-target, the 5-HT1A-R. Selected hits have been obtained and their affinities for α1A-AR, α1B-AR and 5-HT1A-R determined in radioligand binding assays, using membrane preparations which contain human receptors expressed individually. Three of the tested hits demonstrate statistically significant selectivity for α1A-AR over 5-HT1A-R. All seven tested hits bind to α1A-AR, with two compounds displaying K i values below 1 μM, and a further two K i values of around 10 μM. The insights and knowledge gained through the development of the new 5-HT1A-R pharmacophores will greatly aid in the design and synthesis of derivatives of our lead compound, and allow the generation of more efficacious and selective ligands.

  14. MDMA stimulus generalization to the 5-HT(1A) serotonin agonist 8-hydroxy-2- (di-n-propylamino)tetralin.

    PubMed

    Glennon, R A; Young, R

    2000-07-01

    The abused substance N-methyl-1-(3, 4-methylenedioxyphenyl)-2-aminopropane, or MDMA, serves as a training drug in animals. Because the 5-HT(1A) receptor antagonist NAN-190 has been shown to partially antagonize the MDMA stimulus, and because NAN-190 binds at several different types of receptors, in the present study we examined other agents (e.g., adrenergic, dopaminergic, sigma) in tests of stimulus generalization and stimulus antagonism to determine their influence on the MDMA stimulus. Each of these agents (i.e., clenbuterol, S(-)propranolol, R(+)SCH-23390, amantadine, NANM) was without effect on MDMA-appropriate responding. The finding that NAN-190 behaves as a 5-HT(1A) partial agonist in some studies prompted examination of the 5-HT(1A) receptor agonist 8-OH DPAT and its optical isomers. MDMA-stimulus generalization occurred to racemic 8-OH DPAT (ED(50) = 0.3 mg/kg), R(+)8-OH DPAT (ED(50) = 0.2 mg/kg), and to the 5-HT(1A) receptor partial agonist S(-)8-OH DPAT (ED(50) = 0.4 mg/kg). The results suggest that the MDMA stimulus might possess a 5-HT(1A) component of action. Furthermore, because 8-OH DPAT is known to enhance the stimulus effects of hallucinogens as discriminative stimuli, and because MDMA reportedly enhances the effects of hallucinogenic agents in humans ("flipping," "candy flipping"), this latter MDMA-induced phenomenon might involve a 5-HT(1A) mechanism.

  15. 5-HT 1A/1B receptor-mediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice.

    PubMed

    Monaca, Christelle; Boutrel, Benjamin; Hen, René; Hamon, Michel; Adrien, Joëlle

    2003-05-01

    Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT(1A) and 5-HT(1B) types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT(1A) or 5-HT(1B) receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT(1A) or 5-HT(1B) receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT(1B)-/- mice, but not in 5-HT(1A)-/- mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT(1A) antagonist WAY 100635, but only partially with the 5-HT(1B) antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT(1A) receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT(1A) antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs.

  16. 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.

  17. 5-HT1A Agonist Properties Contribute to a Robust Response to Vilazodone in the Novelty Suppressed Feeding Paradigm

    PubMed Central

    Garcia-Garcia, Alvaro L.; Navarro-Sobrino, Míriam; Pilosof, Gila; Banerjee, Pradeep; Dranovsky, Alex

    2016-01-01

    Background: Differences in 5-HT1A receptor function have been implicated in vulnerability to depression and in response to treatment. Adding 5-HT1A partial agonists to selective serotonin reuptake inhibitors has been touted as a strategy to increase their efficacy. Here we use the novelty suppressed feeding paradigm to compare the effects of vilazodone, a high-potency selective serotonin reuptake inhibitor, with high affinity for 5-HT1A receptors to the reference selective serotonin reuptake inhibitor fluoxetine across several mouse strains that differ in their response to selective serotonin reuptake inhibitors. Methods: To confirm 5-HT1A agonist activity, body temperature was measured after acute administration of vilazodone or fluoxetine, as administration of 5-HT1A agonists induces hypothermia. We next used 3 strains of mice to examine the effects of the drugs on latency in the novelty suppressed feeding, a paradigm generally sensitive to chronic but not acute effects of antidepressants. Results: Vilazodone induces robust hypothermia and blocks stress-induced hyperthermia in a 5-HT1A-dependent manner, consistent with agonist effects at 5-HT1A autoreceptors. In 129SvEv mice, vilazodone (10mg/kg/d) reduces the latency to eat in the novelty suppressed feeding test within 8 days, while no effect of fluoxetine (20mg/kg/d) was detected at that time. In contrast, both vilazodone and fluoxetine are effective at decreasing latency to eat in the novelty suppressed feeding paradigm in a strain with low autoreceptor levels. In mice with higher autoreceptor levels, no significant difference was detected between fluoxetine and vehicle (P=.8) or vilazodone and vehicle (P=.06). Conclusion: In mice, vilazodone may offer advantages in time of onset and efficacy over a reference selective serotonin reuptake inhibitor in the novelty suppressed feeding test. PMID:27352617

  18. Pre- or postsynaptic activity of 5-HT1A compounds in mice depends on the anxiety paradigm.

    PubMed

    López-Rubalcava, C

    1996-08-01

    The purpose of the present study was to compare the contribution of pre and postsynaptic 5-HT1A receptors to the anxiolytic effects of serotonergic1A compounds in two animal models of anxiety. To this aim, the 5-HT1A ligands buspirone, ipsapirone, indorenate, and 8-OH-DPAT were tested in the burying behavior test and the avoidance exploratory behavior paradigm in control, pCPA-treated, and 5,7-DHT-lesioned mice, p-CPA and 5,7-DHT treatments did not modify the burying behavior per se, while 5-HT1A agonists produced a significant reduction in this behavior in both p-CPA- and 5,7,-DHT-lesioned animals. In the exploratory behavior paradigm, p-CPA per se but not 5,7-DHT increased the black/white transitions, interpreted as an antianxiety action. The ICV injection of 5,7-DHT blocked such effect of the 5-HT1A compounds in the avoidance exploratory behavior test. Data suggest that the effect of 5-HT1A compounds in the burying behavior test is mediated via the stimulation of postsynaptic receptors, while in the avoidance exploratory behavior paradigm these compounds act through the stimulation of the presynaptic site. Discussion is based on the differences between the animal models of anxiety.

  19. The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor.

    PubMed

    Markowitz, J S; DeVane, C L; Ramamoorthy, S; Zhu, Hao-Jie

    2009-02-01

    The present study was undertaken to determine whether d-threo-(R,R)-methylphenidate (MPH) was exerting binding activity as an agonist or antagonist of 5-HT1A and 5-HT2B receptors. [35S]guanosine5'[gamma-thio]triphosphate ([35S]GTPgammaS) binding assay and field-stimulated Guinea pig ileum assay were used to determine 5-HT(1A) receptor agonism and antagonism activity of d-threo-(R,R)-MPH. The results suggested d-threo-(R,R)-MPH induced 5-HT(1A) receptor agonist activity at 100 microM. The Guinea pig ileum functional assay showed that d-threo-(R,R)-MPH produced agonist-like reduction of neurogenic twitch with an EC50 5.65 +/- 0.36 microM. At 30 microM concentrations, d-threo-(R,R)-MPH produced 171 +/- 4.24% of the relaxation relative to that caused by 0.12 microM 8-OH-DPAT. However, d-threo-(R,R)-MPH exhibited no significant pharmacological activity in rat stomach fundus 5-HT(2B) receptor functional assay. Thus, d-threo-(R,R)-MPH appears to act as a selective 5-HT(1A) receptor agonist in vitro. It is speculated that the activation of 5-HT(1A) receptor might play a partial role in d-threo-(R,R)-MPH mediated dopamine (DA) release in the brain.

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

    PubMed Central

    Rojas, Paulina S.; Fiedler, Jenny L.

    2016-01-01

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

  1. 5-HT(1A) and NMDA receptors interact in the rat medial septum and modulate hippocampal-dependent spatial learning.

    PubMed

    Elvander-Tottie, Elin; Eriksson, Therese M; Sandin, Johan; Ogren, Sven Ove

    2009-12-01

    Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT(1A) receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT(1A) receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT(1A) receptor agonist (R)-8-OH-DPAT (1 or 4 microg/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 microg/rat). While intraseptal administration of (R)-8-OH-DPAT (4 microg) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 microg) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT(1A) receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT(1A) and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT(1A) receptor activation on memory, which may be clinically relevant.

  2. Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus.

    PubMed

    Verdurand, Mathieu; Bérod, Anne; Le Bars, Didier; Zimmer, Luc

    2011-01-01

    A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-β (Aβ) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Aβ injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aβ injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.

  3. Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder: support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants.

    PubMed

    Stahl, Stephen M.; Kaiser, Lee; Roeschen, Julie; Keppel Hesselink, Jan M.; Orazem, John

    1998-07-01

    Desensitisation of serotonin 1A (5-HT-1A) receptors is a leading hypothesis for the mechanism of action of antidepressants which block serotonin reuptake. This hypothesis predicts that direct-acting 5-HT-1A agonists should also exhibit anti-depressant properties. Here we report the results of the first large-scale controlled study of the efficacy and tolerability of a 5-HT-1A agonist in outpatients with major depressive disorder (MDD). Three hundred and seventy-three subjects meeting DSM-III-R criteria for MDD participated in this randomised, double-blind comparison of the 5-HT-1A partial agonist ipsapirone (5 mg, 7.5 mg and 10 mg t.i.d.) to placebo t.i.d. Improvement in depressive symptoms relative to placebo, as measured by the Hamilton Depression Rating Scale, occurred in the ipsapirone (7.5 mg t.i.d.) group with a magnitude of effect (D=-2.53 points) that was statistically significant (p=0.010). Adverse events occurred in 76% of the placebo patients and 92% of the ipsapirone patients. A dose-related increase in the incidence of adverse events led to discontinuation of treatment with the 10 mg t.i.d. Results of this study demonstrate that ipsapirone, at a dose of 7.5 mg t.i.d., is an effective antidepressant agent in the treatment of MDD, supporting the hypothesised role of 5-HT-1A receptors in the mechanism of action of serotonin reuptake inhibitors. However, as a potential therapeutic agent for depression, ipsapirone shows only a modest magnitude of drug-placebo differences as well as a side-effect profile less favorable than many of the newer antidepressants.

  4. 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.

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

    PubMed

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

    2003-01-03

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

  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. 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

    2016-05-03

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

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

    PubMed

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

    2014-08-01

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

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

    PubMed

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

    2010-01-01

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

  10. F 11440, a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential.

    PubMed

    Koek, W; Patoiseau, J F; Assié, M B; Cosi, C; Kleven, M S; Dupont-Passelaigue, E; Carilla-Durand, E; Palmier, C; Valentin, J P; John, G; Pauwels, P J; Tarayre, J P; Colpaert, F C

    1998-10-01

    F 11440 (4-methyl-2-[4-(4-(pyrimidin-2-yl)-piperazino)-butyl]-2H, 4H-1,2,4-triazin-3,5-dione) was the outcome of a research effort guided by the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines the magnitude of their antidepressant and anxiolytic-like effects. The affinity of F 11440 for 5-HT1A binding sites (pKi, 8.33) was higher than that of buspirone (pKi, 7.50), and somewhat lower than that of flesinoxan (pKi, 8.91). In vivo, F 11440 was 4- to 20-fold more potent than flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal extracellular serotonin (5-HT) levels and to increase plasma corticosterone levels, respectively). F 11440 did not have detectable antidopaminergic activity (unlike buspirone, which inhibited all of the directly observable behavioral effects of methylphenidate in rats), showed no evidence of antihistaminergic activity (unlike flesinoxan, which protected against the effects of a histamine aerosol in guinea pigs), and had a 70-fold separation between its 5-HT1A agonist and alpha-1 adrenergic antagonist properties (measured as the ability to inhibit the methoxamineinduced increase in blood pressure in rats), unlike flesinoxan, which showed a <3-fold separation. In HeLa cells expressing human 5-HT1A receptors, F 11440 decreased the forskolin-induced increase in AMP, and, based on its maximal effect, was found to have an intrinsic activity of 1.0 relative to that of 5-HT, which was significantly higher than that of buspirone (0.49), ipsapirone (0.46) and flesinoxan (0.93). Consistent with the aforementioned hypothesis, F 11440 produced anxiolytic- and antidepressant-like effects in animal models (i.e., increased punished responding in a pigeon conflict procedure and decreased immobility in a rat forced swimming test, respectively) that were more

  11. 5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission.

    PubMed

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

    2012-04-01

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

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

    PubMed

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

    2007-07-01

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

  13. 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.

  14. Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

    PubMed Central

    Backus, L. I.; Sharp, T.; Grahame-Smith, D. G.

    1990-01-01

    1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function. PMID:2145051

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

    PubMed

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

    2013-08-01

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

  16. 5-HT1A receptor-responsive pedunculopontine tegmental neurons suppress REM sleep and respiratory motor activity.

    PubMed

    Grace, Kevin P; Liu, Hattie; Horner, Richard L

    2012-02-01

    Serotonin type 1A (5-HT(1A)) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct then inactivation of such neurons ought to suppress REM sleep. We test this hypothesis using bilateral microperfusion of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 μm) into the PPTn; this tool has been shown to selectively silence REM sleep-active PPTn neurons while the activity of wake/REM sleep-active PPTn neurons is unaffected. Contrary to the prevailing model, bilateral microperfusion of 8-OH-DPAT into the PPTn (n = 23 rats) significantly increased REM sleep both as a percentage of the total recording time and sleep time, compared with both within-animal vehicle controls and between-animal time-controls. This increased REM sleep resulted from an increased frequency of REM sleep bouts but not their duration, indicating an effect on mechanisms of REM sleep initiation but not maintenance. Furthermore, an increased proportion of the REM sleep bouts stemmed from periods of low REM sleep drive quantified electrographically. Targeted suppression of 5-HT(1A) receptor-responsive PPTn neurons also increased respiratory rate and respiratory-related genioglossus activity, and increased the frequency and amplitude of the sporadic genioglossus activations occurring during REM sleep. These data indicate that 5-HT(1A) receptor-responsive PPTn neurons normally function to restrain REM sleep by elevating the drive threshold for REM sleep induction, and restrain the expression of respiratory rate and motor activities.

  17. Molecular dynamics of 5-HT1A and 5-HT2A serotonin receptors with methylated buspirone analogues

    NASA Astrophysics Data System (ADS)

    Bronowska, Agnieszka; Chilmonczyk, Zdzisław; Leś, Andrzej; Edvardsen, Øyvind; Østensen, Roy; Sylte, Ingebrigt

    2001-11-01

    In the present study experimentally determined ligand selectivity of three methylated buspirone analogues (denoted as MM2, MM5 and P55) towards 5-HT1A and 5-HT2A serotonin receptors was theoretically investigated on a molecular level. The relationships between the ligand structure and 5-HT1A and 5-HT2A receptor affinities were studied and the results were found to be in agreement with the available site-directed mutagenesis and binding affinity data. Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT1A/5-HT2A, each time in a different orientation. Present results were compared with our previous theoretical results, obtained for buspirone and its non-methylated analogues. It was found that due to the presence of the methyl group in the piperazine ring the ligand position alters and the structure of the ligand-receptor complex is modified. Further, the positions of derivatives with pyrimidinyl aromatic moiety and quinolinyl moiety are significantly different at the 5-HT2A receptor. Thus, methylation of such derivatives alters the 3D structures of ligand-receptor complexes in different ways. The ligand-induced changes of the receptor structures were also analysed. The obtained results suggest, that helical domains of both receptors have different dynamical behaviour. Moreover, both location and topography of putative binding sites for buspirone analogues are different at 5-HT1A and 5-HT2A receptors.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

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

    2015-01-01

    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 100635. 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 1 mg/kg significantly activate these receptors. PMID:26366943

  1. Role of 5-HT1A receptors in the forced swimming wheel test in reserpine-treated mice.

    PubMed

    Kasahara, K; Nagatani, T; Takao, K; Hashimoto, S

    1993-01-01

    The antidepressant-like effect of 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT), a selective 5-HT1A receptor agonist, was studied in the forced swimming wheel test in reserpine-treated mice. 8-OH-DPAT and the antidepressant imipramine, dose-dependently increased the number of turns of a water wheel made by mice. This effect of imipramine (30 mg/kg, i.p.) was enhanced by reserpine treatment 24 hr before the test. The effect of 8-OH-DPAT (0.3 mg/kg, i.p.) was also enhanced in reserpine-treated mice. This enhanced effect of 8-OH-DPAT was blocked by pretreatment with the 5-HT1A receptor antagonists, (-)-propranolol (3 mg/kg, i.p.) and NAN-190 (1 mg/kg, i.p.), but was not blocked by a beta-blocker, (-)-atenolol (3 mg/kg, i.p.). 8-OH-DPAT did not affect locomotor activity in the reserpinized mice and did not affect the reduction of monoamine content induced by reserpine. These results suggest that the effect of 8-OH-DPAT in increasing the number of turns of the wheel made by mice was exerted through a 5-HT1A receptor and that this effect did not reflect only changes in the locomotor activity of the mice.

  2. 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.

  3. The role of activation of the 5-HT1A receptor and adenylate cyclase in the antidepressant-like effect of YL-0919, a dual 5-HT1A agonist and selective serotonin reuptake inhibitor.

    PubMed

    Qin, Juan-Juan; Chen, Hong-Xia; Zhao, Nan; Yuan, Li; Zhang, You-Zhi; Yang, Ri-Fang; Zhang, Li-Ming; Li, Yun-Feng

    2014-10-17

    This study aimed to explore the possible mechanisms underlying the antidepressant-like effect of YL-0919, a novel antidepressant candidate with dual activity as a 5-HT1A receptor agonist and a selective serotonin reuptake inhibitor. The animal models commonly used to evaluate potential antidepressants, i.e., tail suspension (TST) in mice and forced swimming test (FST) in mice were used to evaluate the antidepressant effect of YL-0919. The activity of adenylate cyclase (AC) on the synaptic membrane was determined by the homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay. The results indicated that YL-0919 (1.25-2.5mg/kg, i.g.) significantly decreased the immobility time in both the tail suspension test and the forced swim test in a dose-dependent manner, demonstrating the antidepressant-like effect of YL-0919. Furthermore, this effect was completely antagonized by the co-administration of WAY-100635 (0.3mg/kg, s.c.), a 5-HT1A selective antagonist. YL-0919 (10(-9)-10(-5)mol/L) was also shown to activate AC in vitro in a dose-dependent manner in synaptic membranes extracted from the rat prefrontal cortex, and this effect (10(-7)-10(-5)mol/L) was antagonized by WAY-100635 (10(-7)mol/L). Finally, the antidepressant-like effect of YL-0919 (2.5mg/kg, i.g.) was also blocked by the co-administration of H-89 (3 μg/site, i.c.v.), a protein kinase A (PKA) selective inhibitor. These results indicate that the activation of 5-HT1A receptors and the subsequent activation of the AC-cAMP-PKA signaling pathway in the frontal cortex play a critical role in the antidepressant-like effect of YL-0919.

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

    PubMed

    Marvin, Eric; Scrogin, Karie; Dudás, Bertalan

    2010-07-01

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

  5. Serotonin 1A receptor (5-HT1A) of the sea lamprey: cDNA cloning and expression in the central nervous system.

    PubMed

    Cornide-Petronio, María Eugenia; Anadón, Ramón; Barreiro-Iglesias, Antón; Rodicio, María Celina

    2013-09-01

    Serotonergic cells are among the earliest neurons to be born in the developing central nervous system and serotonin is known to regulate the development of the nervous system. One of the major targets of the activity of serotonergic cells is the serotonin 1A receptor (5-HT1A), an ancestral archetypical serotonin receptor. In this study, we cloned and characterized the 3D structure of the sea lamprey 5-HT1A, and studied the expression of its transcript in the central nervous system by means of in situ hybridization. In phylogenetic analyses, the sea lamprey 5-HT1A sequence clustered together with 5-HT1A sequences of vertebrates and emerged as an outgroup to all gnathostome sequences. In situ hybridization analysis during prolarval, larval and adult stages showed a widespread expression of the lamprey 5-ht1a transcript. In P1 prolarvae 5-ht1a mRNA expression was observed in diencephalic nuclei, the rhombencephalon and rostral spinal cord. At P2 prolarval stage the 5-ht1a expression extended to other brain areas including telencephalic regions. 5-ht1a expression in larvae was observed throughout almost all the main brain regions with the strongest expression in the olfactory bulbs, lateral pallium, striatum, preoptic region, habenula, prethalamus, thalamus, pretectum, hypothalamus, rhombencephalic reticular area, dorsal column nucleus and rostral spinal cord. In adults, the 5-ht1a transcript was also observed in cells of the subcommissural organ. Comparison of the expression of 5-ht1a between the sea lamprey and other vertebrates reveals a conserved pattern in most of the brain regions, likely reflecting the ancestral vertebrate condition.

  6. Oppositional Effects of Serotonin Receptors 5-HT1a, 2, and 2c in the Regulation of Adult Hippocampal Neurogenesis

    PubMed Central

    Klempin, Friederike; Babu, Harish; Tonelli, Davide De Pietri; Alarcon, Edson; Fabel, Klaus; Kempermann, Gerd

    2009-01-01

    Serotonin (5-HT) appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lacked acute effects on adult neurogenesis in many studies, which suggested a surprisingly long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self-renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late-stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT receptors. PMID

  7. Intracellular Loop 2 Peptides of the Human 5HT1a Receptor are Differential Activators of Gi

    PubMed Central

    Hall, Brian; Squires, Carley; Parker, Keith K.

    2012-01-01

    Peptide mimics of intracellular loop 2 (ic2) of the human 5HT1a receptor have been studied with respect to their ability to inhibit agonist binding via interference with receptor-G-protein coupling. These peptides give shallow concentration-effect relationships. Additionally, these peptides have been studied with respect to their ability to trigger the signal transduction system of this Gi-coupled receptor. Two signaling parameters have been quantified: concentration of intracellular cAMP and changes in incorporation into the G protein of a stable analog of GTP. In both cases, peptide mimics near midloop of ic2 actually show agonist activity with efficacy falling off toward both loop termini near TM 3 and TM 4. Previous results have suggested that the loop region near the TM3/ic2 interface is primarily responsible for receptor-G-protein coupling, while the current result emphasizes the mid-ic2 loop region's ability to activate the G protein following initial coupling. A limited number of peptides from the receptor's TM5/ic3 loop vicinity were also studied regarding agonist inhibition and G-protein activation. These peptides provide additional evidence that the human 5HT1a receptor, TM5/ic3 loop region, is involved in both coupling and activation actions. Overall, these results provide further information about potential pharmacological intervention and drug development with respect to the human 5HT1a receptor/G-protein system. Finally, the structural evidence generated here provides testable models pending crystallization and X-ray analysis of the receptor. PMID:22649462

  8. Cloned human 5-HT1A receptor pharmacology determined using agonist binding and measurement of cAMP accumulation.

    PubMed

    Sharif, Najam A; Drace, Colene D; Williams, Gary W; Crider, Julie Y

    2004-10-01

    Twenty agonists and nine antagonists were evaluated for their ability to compete for [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) binding to the cloned human serotonin-1A (ch-5-HT1A) receptor expressed in Chinese hamster ovary cells and for their ability to alter adenylyl cyclase activity in the same cells. The most potent full agonists of high affinity included N,N-dipropyl-5-carboxamidotryptamine (pEC50=9.6 +/- 0.1), MDL 73005EF (pEC50=9.3 +/- 0.2), 5-methyl-urapidil (pEC50=9.2 +/- 0.1), 5-carboxamidotryptamine (pEC50=9.1 +/- 0.2), R(+)-8-OH-DPAT (pEC50=8.6 +/- 0.1) and BMY-7378 (pEC50=8.6 +/- 0.1). WB-4101 (pEC50=8.3 +/- 0.2; IA=79%), clozapine (pEC50=8.1 +/- 0.3; IA=29%), (buspirone (pEC50=7.6 +/- 0.2; IA=79%), quipazine (pEC50 <5; IA=45%) and R-DOI (pEC50 < 5; IA=31%) were weaker agonists with partial agonist properties. The most potent antagonists were WAY-100,635 (pKi=10.2 +/- 0.1), methiothepin (pKi=8.8 +/- 0.2), spiperone (pKi=8.7 +/- 0.2) and NAN-190 (pKi=8.5 +/- 0.2). The receptor affinities and functional potencies were well correlated (r=0.88; P <0.0001). Our binding data correlated well with the pharmacology of endogenous 5-HT1A receptors in the rabbit iris-ciliary body (r=0.91; P <0.001) and rat hippocampus (r=0.93, P <0.0001). Our functional cAMP data correlated well with other cAMP accumulation data (r=0.8, P <0.01 vs calf hippocampus) but less so with [35S]-GTPgammaS binding to the ch-5-HT(1A) receptor as a functional activity read-out (r=0.58, P <0.05). The present study provides a detailed pharmacological characterization of the ch-5-HT1A receptor using binding and functional assays.

  9. 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.

  10. Activation of the serotonergic 5-HT1A receptor in the paraventricular nucleus of the hypothalamus inhibits water intake and increases urinary excretion in water-deprived rats.

    PubMed

    de Souza Villa, Patrícia; Menani, José Vanderlei; de Arruda Camargo, Gabriela Maria Pavan; de Arruda Camargo, Luiz Antônio; Saad, Wilson Abrão

    2008-10-09

    The paraventricular nucleus (PVN) may be considered as a dynamic mosaic of chemically-specified subgroups of neurons. 5-HT(1A) is one of the prime receptors identified and there is expressed throughout all magnocellular regions of the PVN. Several reports have demonstrated that a subpopulation of the magnocellular neurons expressing 5-HT(1A) receptors are oxytocin (OT) neurons and activation of 5-HT(1A) receptors in the PVN increases the plasma OT. Increasing evidence shows that OT inhibits water intake and increases urinary excretion in rats. The aim of this study was to investigate the role of serotonergic 5-HT(1A) receptors in the lateral-medial posterior magnocellular region of the PVN in the water intake and diuresis induced by 24 h of water deprivation. Cannulae were implanted in the PVN of rats. 5-HT injections in the PVN reduced water intake and increased urinary excretion. 8-OH-DPAT (a 5-HT(1A) agonist) injections blocked the water intake and increased urinary output in all the periods of the observation. pMPPF (a 5-HT(1A) antagonist) injected bilaterally before the 8-OH-DPAT blocked its inhibitory effect on water intake and its diuretic effect. We suggest that antidipsogenic and diuretic responses seem to be mediated via 5-HT(1A) receptors of the lateral-medial posterior magnocellular region of the PVN in water-deprived rats.

  11. High intensity social conflict in the Swiss albino mouse induces analgesia modulated by 5-HT1A receptors.

    PubMed

    Canto de Souza, A; Nunes de Souza, R L; Péla, I R; Graeff, F G

    1997-03-01

    Social conflict between mice produces analgesia in the attacked mouse. Both the magnitude and type (opioid or nonopioid) of this analgesia have been related to attack intensity and strain of mouse. In the present study low intensity social conflict (7 bites) did not produce analgesia, whereas high intensity - 30 and 60 bites - interactions produced, respectively, short-lasting (5 min) and very short-lasting (1 min) analgesia in Swiss albino mice, when compared with nonaggressive interaction (0 bite). The 30 bites aggressive interaction induced analgesia (AIIA) was not affected by IP injection of either naloxone (5.0 and 7.5 mg/kg) or diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg). However, this attack-induced analgesia was reduced after IP administration of the 5-HT1A agonists, gepirone (0.3 and 3.0 mg/kg) and BAY R 1531 (0.01 mg/kg). These results indicate that the analgesia induced by 30 bites social conflict in Swiss albino mice does not involve opioid and GABA-benzodiazepine (GABA-BZD) mechanisms. In addition, they suggest that high-intensity social conflict activates serotonergic pain modulatory systems that act through 5-HT1A receptors.

  12. Levo-Tetrahydroberberrubine Produces Anxiolytic-Like Effects in Mice through the 5-HT1A Receptor

    PubMed Central

    Mi, Guiyun; Liu, Shuai; Zhang, Jian; Liang, Huichun; Gao, Yunyun; Li, Nuomin; Yu, Boyang; Yang, Hongju; Yang, Zheng

    2017-01-01

    Tetrahydroprotoberberines (THPBs) are isoquinoline alkaloids isolated from the Chinese herb Corydalis yanhusuo. In the present study, we performed competitive binding assays to examine the binding of l-THBr to neurotransmitter receptors known to be involved in sedation, hypnosis and anxiety. Our results show that l-THBr does not interact with GABAergic receptors but has binding affinities for dopamine and serotonin receptors. In addition, cAMP and [35S]GTPγS assays were used to determine the agonist or antagonist properties of l-THBr at dopamine (D1, D2) or serotonin (5-HT) receptors. Our results show that l-THBr displays D1 and D2 antagonist and 5-HT1A agonist properties. Moreover, l-THBr-treated rodents exhibit anxiolytic-like effects in the light/dark box and elevated plus-maze tests, and the anxiolytic effect of l-THBr can be reduced by WAY-100635, a selective 5-HT1A receptor antagonist. Our results suggest that l-THBr may produce potent anxiolytic-like effects mainly through serotonin receptors. PMID:28085967

  13. 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

  14. 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

  15. Initial in vivo PET imaging of 5-HT1A receptors with 3-[(18)F]mefway.

    PubMed

    Wooten, Dustin W; Hillmer, Ansel T; Murali, Dhanabalan; Barnhart, Todd E; Thio, Joanne P; Bajwa, Alisha K; Bonab, Ali A; Normandin, Marc D; Schneider, Mary L; Mukherjee, Jogeshwar; Christian, Bradley T

    2014-01-01

    4-trans-[(18)F]Mefway is a PET radiotracer with high affinity for 5-HT1A receptors. Our preliminary work indicated the positional isomer, 3-[(18)F]mefway, would be suitable for PET imaging of 5-HT1A receptors. We now compare the in vivo behaviour of 3-mefway with 4-mefway to evaluate 3-[(18)F]mefway as a potential 5-HT1A PET radiotracer. Two male rhesus macaques were given bolus injections of both 3- and 4-trans-[(18)F]mefway in separate experiments. 90 minute dynamic PET scans were acquired. TACs were extracted in the mesial temporal lobe (MTL) and caudal anterior cingulate gyrus (cACg). The cerebellum (CB) was used as a reference region. In vivo behavior of the radiotracers in the CB was compared based upon the ratio of normalized PET uptake for 3- and 4-trans-[(18)F]mefway. Specific binding was compared by examining MTL/CB and cACg/CB ratios. The subject-averaged ratio of 3-[(18)F]mefway to 4-trans-[(18)F]mefway in the cerebellum was 0.96 for 60-90 minutes. MTL/CB reached plateaus of ~2.7 and ~6 by 40 minutes and 90 minutes for 3- and 4-trans-[(18)F]mefway, respectively. cACg/CB reached plateaus of ~2.5 and ~6 by 40 minutes and 70 minutes for 3- and 4-trans-[(18)F]mefway, respectively. The short pseudoequilibration times and sufficient uptake of 3-[(18)F]mefway may be useful in studies requiring short scan times. Furthermore, the similar nondisplaceable clearance in the CB to 4-trans-[(18)F]mefway suggests the lower BPND of 3-[(18)F]mefway is due to a lower affinity. The lower affinity of 3-[(18)F]mefway may make it useful for measuring changes in endogenous 5-HT levels, however, this remains to be ascertained.

  16. Suppression of inflammatory events associated to intestinal ischemia-reperfusion by 5-HT1A blockade in mice.

    PubMed

    Bertoni, Simona; Arcaro, Valentina; Vivo, Valentina; Rapalli, Alberto; Tognolini, Massimiliano; Cantoni, Anna Maria; Saccani, Francesca; Flammini, Lisa; Domenichini, Giuseppe; Ballabeni, Vigilio; Barocelli, Elisabetta

    2014-03-01

    Intestinal ischemia and reperfusion (I/R) is a potentially life-threatening disease, ensuing from various clinical conditions. Experimentally, either protective or detrimental roles have been attributed to 5-HT in the functional and morphological injury caused by mesenteric I/R. Recently, we proved the involvement of 5-HT2A receptors in the intestinal dysmotility and leukocyte recruitment induced by 45min occlusion of the superior mesenteric artery (SMA) followed by 24h reperfusion in mice. Starting from these premises, the aim of our present work was to investigate the role played by endogenous 5-HT in the same experimental model where 45min SMA clamping was followed by 5h reflow. To this end, we first observed that ischemic preconditioning before I/R injury (IPC+I/R) reverted the increase in 5-HT tissue content and in inflammatory parameters induced by I/R in mice. Second, the effects produced by intravenous administration of 5-HT1A ligands (partial agonist buspirone 10mgkg(-1), antagonist WAY100135 0.5-5mgkg(-1)), 5-HT2A antagonist sarpogrelate (10mgkg(-1)), 5-HT3 antagonist alosetron (0.1mgkg(-1)), 5-HT4 antagonist GR125487 (5mgkg(-1)) and 5-HT re-uptake inhibitor fluoxetine (10mgkg(-1)) on I/R-induced inflammatory response were investigated in I/R mice and compared to those obtained in sham-operated animals (S). Our results confirmed the significant role played by 5-HT2A receptors not only in the late but also in the early I/R-induced microcirculatory dysfunction and showed that blockade of 5-HT1A receptors protected against the intestinal leukocyte recruitment, plasma extravasation and reactive oxygen species formation triggered by SMA occlusion and reflow. The ability of α7 nicotinic receptor (α7nAchR) antagonist methyllycaconitine (5mgkg(-1)) to counteract the beneficial action provided by buspirone on I/R-induced neutrophil infiltration suggests that the anti-inflammatory effect produced by 5-HT1A receptor antagonism could be partly ascribed to the

  17. Shifting topographic activation and 5-HT1A receptor-mediated inhibition of dorsal raphe serotonin neurons produced by nicotine exposure and withdrawal.

    PubMed

    Sperling, Robin; Commons, Kathryn G

    2011-05-01

    Nicotine activates serotonin [5-hydroxytryptamine (5-HT)] neurons innervating the forebrain, and this is thought to reduce anxiety. Nicotine withdrawal has also been associated with an activation of 5-HT neurotransmission, although withdrawal increases anxiety. In each case, 5-HT1A receptors have been implicated in the response. To determine whether there are different subgroups of 5-HT cells activated during nicotine administration and withdrawal, we mapped the appearance of Fos, a marker of neuronal activation, in 5-HT cells of the dorsal raphe nucleus (DR) and median raphe nucleus (MR). To understand the role of 5-HT1A receptor feedback inhibitory pathways in 5-HT cell activity during these conditions, we administered a selective 5-HT1A receptor antagonist and measured novel disinhibited Fos expression within 5-HT cells. Using these approaches, we found evidence that acute nicotine exposure activates 5-HT neurons rostrally and in the lateral wings of the DR, whereas there is 5-HT1A receptor-dependent inhibition of cells located ventrally at both the rostral level and mid-level. Previous chronic nicotine exposure did not modify the pattern of activation produced by acute nicotine exposure, but increased 5-HT1A receptor-dependent inhibition of 5-HT cells in the caudal DR. This pattern was nearly reversed during nicotine withdrawal, when there was evidence for caudal activation and mid-level and rostral 5-HT1A receptor-dependent inhibition. These results suggest that the distinct behavioral states produced by nicotine exposure and withdrawal correlate with reciprocal rostral-caudal patterns of activation and 5-HT1A receptor-mediated inhibition of DR 5-HT neurons. The complementary patterns of activation and inhibition suggest that 5-HT1A receptors may help to shape distinct topographic patterns of activation within the DR.

  18. 5-HT1A and 5-HT1B receptors differentially modulate rate and timing of auditory responses in the mouse inferior colliculus

    PubMed Central

    Ramsey, Lissandra Castellan Baldan; Sinha, Shiva R.; Hurley, Laura M.

    2010-01-01

    Serotonin is a physiological signal that translates both internal and external information about behavioral context into changes in sensory processing through a diverse array of receptors. The details of this process, particularly how receptors interact to shape sensory encoding, are poorly understood. In the inferior colliculus, a midbrain auditory nucleus, serotonin (5-HT) 1A receptors have suppressive and 5-HT1B receptors have facilitatory effects on evoked responses of neurons. We explored how these two receptor classes interact by testing three hypotheses: that they 1) affect separate neuron populations, 2) affect different response properties, or 3) have different endogenous patterns of activation. The first two hypotheses were tested by iontophoretic application of 5-HT1A and 5-HT1B receptor agonists individually and together to neurons in vivo. 5-HT1A and 5-HT1B agonists affected overlapping populations of neurons. During co-application, 5-HT1A and 5-HT1B agonists influenced spike rate and frequency bandwidth additively, with each moderating the effect of the other. In contrast, although both agonists individually influenced latencies and interspike intervals, the 5-HT1A agonist dominated these measurements during co-application. The third hypothesis was tested by applying antagonists of the 5-HT1A and 5-HT1B receptors. Blocking 5-HT1B receptors was complementary to activation of the receptor, but blocking 5-HT1A receptors was not, suggesting the endogenous activation of additional receptor types. These results suggest that cooperative interactions between 5-HT1A and 5-HT1B receptors shape auditory encoding in the IC, and that the effects of neuromodulators within sensory systems may depend nonlinearly on the specific profile of receptors that are activated. PMID:20646059

  19. 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.

  20. 5-HT1A receptor activation counteracted the effect of acute immobilization of noradrenergic neurons in the rat locus coeruleus.

    PubMed

    Rioja, José; Santín, Luis J; López-Barroso, Diana; Doña, Alicia; Ulzurrun, Eugenia; Aguirre, José A

    2007-01-22

    The aim of our study was to evaluate the effect of acute stress and the 5-HT(1A) receptor involvement in both, the hippocampus noradrenaline (NA) tissue levels and the c-Fos immunoreactivity (c-Fos-IR) in the catecholaminergic neurons of the locus coeruleus (LC). Double immunocytochemical staining of tyrosine hydroxilase (TH) and c-Fos protein combined with stereological techniques were used to study the specific cell activation in the LC neurons in five experimental groups (control group, immobilization (1h) group, 8-OH-DPAT group (8-OH-DPAT 0.3mg/kg, s.c.), DPAT+IMMO group (8-OH-DPAT 0.3mg/kg, s.c., 30' prior acute immobilization) and WAY+DPAT+IMMO group (WAY-100635 0.3mg/kg, s.c. and 8-OH-DPAT 0.3mg/kg, s.c., 45'and 30', respectively, before immobilization). The results showed that hippocampal NA tissue levels and c-Fos-IR in the TH positive neurons of the LC were significantly increased immediately and after 90', respectively, after the immobilization period. Pre-treatment with 8-OH-DPAT counteracted the effects induced by immobilization, but pre-treatment with WAY-100635 did not block the effects induced by 8-OH-DPAT. These results suggest that noradrenaline system is associated in a significant way with immobilization stress. The role of 5-HT(1A) receptor activation in this stress response is also discussed.

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

    PubMed

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

    2013-10-01

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

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

    PubMed

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

    2015-01-02

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

  3. The relation of developmental changes in brain serotonin transporter (5HTT) and 5HT1A receptor binding to emotional behavior in female rhesus monkeys: effects of social status and 5HTT genotype.

    PubMed

    Embree, M; Michopoulos, V; Votaw, J R; Voll, R J; Mun, J; Stehouwer, J S; Goodman, M M; Wilson, M E; Sánchez, M M

    2013-01-03

    The goal of the present study was to examine how social subordination stress and 5HTT polymorphisms affect the development of brain serotonin (5HT) systems during the pubertal transition in female rhesus monkeys. We also examined associations with developmental changes in emotional reactivity in response to a standardized behavioral test, the Human Intruder (HI). Our findings provide the first longitudinal evidence of developmental increases in 5HT1A receptor and 5HTT binding in the brain of female primates from pre- to peripuberty. The increase in 5HT1A BP(ND) in these socially housed female rhesus monkeys is a robust finding, occurring across all groups, regardless of social status or 5HTT genotype, and occurring in the left and right hemispheres of all prefrontal regions studied, as well as the amygdala, hippocampus, hypothalamus, and raphe nuclei. 5HTT BP(ND) also showed an increase with age in raphe, anterior cingulate cortex, and dorsolateral prefrontal cortex. These changes in brain 5HT systems take place as females establish more adult-like patterns of social behavior, as well as during the HI paradigm. Indeed, the main developmental changes in behavior during the HI (increase in freezing and decrease in submission/appeasement) were related to neurodevelopmental increases in 5HT1A receptors and 5HTT, because the associations between these behaviors and 5HT endpoints emerge at peripuberty. We detected an effect of social status on 5HT1A BP(ND) in the hypothalamus and on 5HTT BP(ND) in the orbitofrontal cortex, with subordinates showing higher BP(ND) than dominants in both cases during the pubertal transition. No main effects of 5HTT genotype were observed for 5HT1A or 5HTT BP(ND). Our findings indicate that adolescence in female rhesus monkeys is a period of central 5HT reorganization, partly influenced by exposure to the social stress of subordination, that likely functions to integrate adrenal and gonadal systems and shape the behavioral response to

  4. Divergent effects of the ‘biased’ 5-HT1A receptor agonists F15599 and F13714 in a novel object pattern separation task

    PubMed Central

    van Goethem, N P; Schreiber, R; Newman-Tancredi, A; Varney, M; Prickaerts, J

    2015-01-01

    Background and Purpose Pattern separation, that is, the formation of distinct representations from similar inputs, is an important hippocampal process implicated in cognitive domains like episodic memory. A deficit in pattern separation could lead to memory impairments in several psychiatric and neurological disorders. Hence, mechanisms by which pattern separation can be increased are of potential therapeutic interest. Experimental approach 5-HT1A receptors are involved in spatial memory. Herein we tested the ‘biased’ 5-HT1A receptor agonists F15599, which preferentially activates post-synaptic heteroreceptors, and F13714, which preferentially activates raphe-located autoreceptors, in rats in a novel spatial task assessing pattern separation, the object pattern separation (OPS) task. Key Results The acetylcholinesterase inhibitor donepezil, which served as a positive control, significantly improved spatial pattern separation at a dose of 1 mg·kg−1, p.o. F15599 increased pattern separation at 0.04 mg·kg−1, i.p., while F13714 decreased pattern separation at 0.0025 mg·kg−1, i.p. The selective 5-HT1A receptor antagonist WAY-100635 (0.63 mg·kg−1, s.c.) counteracted the effects of both agonists. These data suggest that acute preferential activation of post-synaptic 5-HT1A heteroreceptors improves spatial pattern separation, whereas acute preferential activation of raphe-located 5-HT1A autoreceptors impairs performance. Conclusions and Implications We successfully established and validated a novel, simple and robust OPS task and observed a diverging profile of response with ‘biased’ 5-HT1A receptor agonists based on their targeting of receptors in distinct brain regions. Our data suggest that the post-synaptic 5-HT1A receptor consists of a potential novel molecular target to improve pattern separation performance. PMID:25572672

  5. 5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19.

    PubMed

    Wang, Qin; Terauchi, Akiko; Yee, Christopher H; Umemori, Hisashi; Traynor, John R

    2014-09-01

    The 5-HT1A receptor is a G protein coupled receptor (GPCR) that activates G proteins of the Gαi/o family. 5-HT1A receptors expressed in the raphe, hippocampus and prefrontal cortex are implicated in the control of mood and are targets for anti-depressant drugs. Regulators of G protein signaling (RGS) proteins are members of a large family that play important roles in signal transduction downstream of G protein coupled receptors (GPCRs). The main role of RGS proteins is to act as GTPase accelerating proteins (GAPs) to dampen or negatively regulate GPCR-mediated signaling. We have shown that a mouse expressing Gαi2 that is insensitive to all RGS protein GAP activity has an anti-depressant-like phenotype due to increased signaling of postsynaptic 5-HT1A receptors, thus implicating the 5-HT1A receptor-Gαi2 complex as an important target. Here we confirm that RGS proteins act as GAPs to regulate signaling to adenylate cyclase and the mitogen-activated protein kinase (MAPK) pathway downstream of the 5-HT1A receptor, using RGS-insensitive Gαi2 protein expressed in C6 cells. We go on to use short hairpin RNA (shRNA) to show that RGS19 is responsible for the GAP activity in C6 cells and also that RGS19 acts as a GAP for 5-HT1A receptor signaling in human neuroblastoma SH-SY5Y cells and primary hippocampal neurons. In addition, in both cell types the synergy between 5-HT1A receptor and the fibroblast growth factor receptor 1 in stimulating the MAPK pathway is enhanced following shRNA reduction of RGS19 expression. Thus RGS19 may be a viable new target for anti-depressant medications.

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

    PubMed

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

    2009-03-01

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

  7. 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

  8. 5HT1A receptor agonist differentially increases cyclic AMP concentration in intact and lesioned goldfish retina. In vitro inhibition of outgrowth by forskolin.

    PubMed

    Urbina, M; Schmeer, C; Lima, L

    1996-11-01

    5HT1A receptors occur in the retina of various species and the administration of 5HT1A agonists results in the inhibition of outgrowth from postcrush goldfish retinal explants. The levels of cyclic AMP (cAMP) play a role in the modulation of the outgrowth of the nevous system. Moreover, the stimulation of central 5HT1A receptors with the agonist 8-hydroxy-2-(di-n-propylamino)tetralin has been reported to produce an increase or decrease in the activity of adenylate cyclase. In the present investigation we studied the effect of adenylate cyclase stimulation by forskolin, as well as the modulatory effects of 5HT1A receptor agonists and antagonists on the production of cAMP in the goldfish retina, and on the outgrowth of this tissue in vitro. 8-Hydroxy-2-(di-n-propylamino)tetralin produced a significant and dose-dependent increase in cAMP concentration. This effect was not additive to the stimulation produced by forskolin. By contrast, as previously described, the 5HT1A agonist decreased cAMP concentration in the hippocampus of the rat. Both effects were significantly impaired by the 5HT1A antagonist WAY-100,135. A significant effect of the antagonist alone was observed only in the goldfish retina. The increase in cAMP levels was greater in the intact than in the postcrush retina. In addition, forskolin decreased the outgrowth of postcrush retinal explants in a dose-dependent manner, suggesting the importance of critical levels of cAMP in this process. Taken together, 5HT1A receptors seem to be positively coupled to adenylate cyclase in the goldfish retina, where cAMP plays a role as a modulator of outgrowth and regeneration. The inhibitory effect of 5HT1A receptor agonists on retinal outgrowth might be mediated through the production of cAMP. The activation of other subtypes of 5HT receptors positively coupled to adenylate cyclase by the 5HT1A agonist, such as 5HT7, cannot be discarded.

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

    PubMed

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

    2012-11-01

    Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.

  10. 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.

  11. Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.

    PubMed

    Yoshinaga, Hidefumi; Masumoto, Shuji; Koyama, Koji; Kinomura, Naoya; Matsumoto, Yuji; Kato, Taro; Baba, Satoko; Matsumoto, Kenji; Horisawa, Tomoko; Oki, Hitomi; Yabuuchi, Kazuki; Kodo, Toru

    2017-01-01

    We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.

  12. Discovery of Natural Product-Derived 5-HT1A Receptor Binders by Cheminfomatics Modeling of Known Binders, High Throughput Screening and Experimental Validation.

    PubMed

    Luo, Man; Reid, Terry-Elinor; Wang, Xiang Simon

    2015-01-01

    The human 5-hydroxytryptamine receptor subtype 1A (5-HT1A) is highly expressed in the raphe nuclei region and limbic structures; for that reason 5-HT1A has served as a promising target for treating human mood disorders and neurodegenerative diseases. We have developed binary quantitative structure-activity relationship (QSAR) models for 5- HT1A binding using data retrieved from the WOMBAT database and the k-Nearest Neighbor (kNN) machine learning method. A rigorous QSAR modeling and screening workflow had been followed, with extensive internal and external validation processes. The models' classification accuracies to discriminate 5-HT1A binders from the non-binders are as high as 96% for the external validation. These models were employed further to mine two major natural products screening libraries, i.e. TimTec Natural Product Library (NPL) and Natural Derivatives Library (NDL). In the end five screening hits were tested by radioligand binding assays with a success rate of 40%, and two Library compounds were confirmed to be binders at the μM concentration against the human 5-HT1A receptor. The combined application of rigorous QSAR modeling and model-based virtual screening presents a powerful means for profiling natural products compounds with important biomedical activities.

  13. 5-HT(1A) receptor and 5-HTT binding during the menstrual cycle in healthy women examined with [(11)C] WAY100635 and [(11)C] MADAM PET.

    PubMed

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

    2009-04-30

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

  14. [Differences between the effects of indorenate and other 5-HT1A agonists on the rabbit aorta].

    PubMed

    Castillo, C; Rosas-Lezama, M A; Castillo, E F; Larios, F J; Hong, E

    1995-01-01

    The aim of this study was to determine if like buspirone, ipsapirone and 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT), the alpha 1-adrenoceptors are involved in the responses elicited by indorenate in rabbit aorta. Exception made of ipsapirone, all the 5-HT1A agonists above mentioned contracted aortic rings. The contraction elicited by buspirone and 8-OH-DPAT was blocked with prazosin (alpha 1-adrenergic antagonist), whereas the effect of indorenate was unaffected with this blocker but it was inhibited with ritanserin (5-HT2 antagonist). On the other hand, buspirone, ipsapirone and 8-OH-DPAT but not indorenate relaxed arteries precontracted with methoxamine (alpha 1-adrenergic agonist) and none of the agonists relaxed preparations precontracted with acetylcholine or KCl. The results indicate that buspirone and 8-OH-DPAT are partial alpha 1-adrenoceptor agonists since they elicited contractions which are blocked with prazosin and relaxed only rings precontracted with methoxamine. Ipsapirone behaved as an alpha 1-adrenoceptor antagonist since it showed the relaxant but not the contractile effect. Finally, we found no evidence that indorenate has afinity for alpha 1-adrenoceptors. Contraction elicited by this agonist seems to be mediated by 5-HT2 receptors, inasmuch it was blocked with ritanserin.

  15. Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): a search for new dual-acting agents as potential antidepressants.

    PubMed

    Zhu, Xue Y; Etukala, Jagan R; Eyunni, Suresh V K; Setola, Vincent; Roth, Bryan L; Ablordeppey, Seth Y

    2012-07-01

    The synthesis and evaluation of several benzothiazole-based compounds are described in an attempt to identify novel dual-acting 5HT(1A) receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT(1A) receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT(1A) receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT(2C) receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side effects.

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

    PubMed

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

    2014-12-01

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

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

    PubMed

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

    2012-05-01

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

  18. 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.

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

    PubMed

    Araragi, Naozumi; Mlinar, Boris; Baccini, Gilda; Gutknecht, Lise; Lesch, Klaus-Peter; Corradetti, Renato

    2013-01-01

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

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

    PubMed

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

    2015-07-15

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

  1. 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

    2015-05-05

    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.

  2. Lack of GSK3β activation and modulation of synaptic plasticity by dopamine in 5-HT1A-receptor KO mice.

    PubMed

    Meunier, C N J; Cancela, J-M; Fossier, P

    2017-02-01

    Psychiatric disorders are associated with excitation-inhibition (E-I) balance impairment in the prefrontal cortex. However, how the E-I balance is regulated is poorly known. The E-I balance of neuronal networks is linked to the action of numerous neuromodulators such as dopamine and 5-HT. We investigated the role of D2-receptors in tuning the E-I balance in a mouse model of anxiety, the 5-HT1A-receptor KO mice. We focused on synaptic plasticity of excitation and inhibition on layer 5 pyramidal neurons. We show that D2-receptor activation decreases the excitation and favors HFS-induced LTD of excitatory synapses via the activation of GSK3β. This effect is absent in 5-HT1A-receptor KO mice. Our data show that the fine control of excitatory transmission by GSK3β requires recruitment of D2-receptors and depends on the presence of 5-HT1A-receptors. In psychiatric disorders in which the number of 5-HT1A-receptors decreased, therapies should reconsider how serotonin and dopamine receptors interact and control neuronal network activity.

  3. 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.

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

    PubMed

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

    2009-08-18

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

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

    PubMed

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

    2007-07-16

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

  6. 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

  7. 5-HT(1A)-receptor over-expressing mice: genotype and sex dependent responses to antidepressants in the forced swim-test.

    PubMed

    Günther, Lydia; Rothe, Julia; Rex, André; Voigt, Jörg-Peter; Millan, Mark J; Fink, Heidrun; Bert, Bettina

    2011-09-01

    Deficiencies in serotonergic neurotransmission are involved in the pathophysiology of depression. Due to its modulatory effect on serotonin (5-HT) release, the 5-HT(1A)-receptor is thought to play a decisive role in the therapy of this mood disorder. However, it is not fully understood how antidepressant effects are mediated by pre- and postsynaptic receptor sites. In this study we examined the impact of postsynaptic 5-HT(1A)-receptor over-expression in corticolimbic areas of male and female mice on the performance in the forced swim-test (FST). Furthermore, we investigated their response to the serotonin selective reuptake inhibitor (SSRI) citalopram in comparison to the selective noradrenaline reuptake inhibitor reboxetine, as well as the partial 5-HT(1A)-receptor agonists, buspirone and S 15535. Additionally, these drugs were evaluated in the open field-test in order to observe effects on motor activity. The density of 5-HT(1A)-receptors in discrete corticolimbic regions was determined in detail by quantitative autoradiography with [(3)H]8-OH-DPAT to investigate genotype as well as sex dependent differences in the expression pattern. [(3)H]8-OH-DPAT binding differed depending on sex with female mice of both genotypes displaying higher receptor binding in distinct brain areas. In the FST untreated male but not female over-expressing (OE) mice showed an antidepressant-like behaviour compared to wild-type (WT) mice. Citalopram yielded an antidepressant effect without influencing locomotor activity in OE mice but not in WT mice. Reboxetine had no antidepressant-like effect in OE mice, but sex-dependently in WT mice. The two partial agonists, buspirone and S 15535 produced no antidepressant-like activity in both genotypes and sexes, but aberrant motor effects. The antidepressant-like phenotype of male transgenic mice accounts for an involvement of postsynaptic 5-HT(1A)-receptors in the FST behaviour. In addition, the selective over-expression of postsynaptic 5-HT(1A

  8. Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

    PubMed Central

    Zhang, Li-ming; Xue, Rui; Xu, Xiao-dan; Zhao, Nan; Qiu, Zhi-kun; Wang, Xian-wang; Zhang, You-zhi; Yang, Ri-fang; Li, Yun-feng

    2013-01-01

    It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder. PMID:24367588

  9. Novel class of arylpiperazines containing N-acylated amino acids: their synthesis, 5-HT1A, 5-HT2A receptor affinity, and in vivo pharmacological evaluation.

    PubMed

    Zajdel, Paweł; Subra, Gilles; Bojarski, Andrzej J; Duszyńska, Beata; Tatarczyńska, Ewa; Nikiforuk, Agnieszka; Chojnacka-Wójcik, Ewa; Pawłowski, Maciej; Martinez, Jean

    2007-04-15

    Novel arylpiperazines with N-acylated amino acids, selected on the basis of a preliminary screening of two libraries previously synthesized on SynPhase Lanterns, were prepared in solution and their affinity for 5-HT(1A), 5-HT(2A), and D(2) receptors was evaluated. The compounds bearing (3-acylamino)pyrrolidine-2,5-dione (19-26) and N-acylprolinamide (29-34) moieties showed high affinity for 5-HT(1A) (K(i)=3-47 nM), high-to-low for 5-HT(2A) (K(i)=4.2-990 nM), and low for D(2) receptors (K(i)=0.77-21.19 microM). All the new o-methoxy derivatives of (3-acylamino)pyrrolidine-2,5-diones tested in vivo revealed agonistic activity at postsynaptic 5-HT(1A) receptors, while m-chloro derivatives were classified as antagonists of these sites; similar relations were observed for o-methoxy (29) and m-chlorophenylpiperazine derivatives of N-acylprolinamides. The reported results show that the amino acid-derived terminal fragment modified the in vivo functional profile. Finally, the selected compounds 19 and 20, a 5-HT(1A) partial agonist and a full agonist, respectively, and 26, a mixed 5-HT(1A)/5-HT(2A) antagonist, were evaluated in preclinical animal models of depression and anxiety. The project allowed selecting the lead compound 20 which exhibited an anxiolytic-like effect in the four-plate test in mice and revealed distinct antidepressant-like effects in the forced swimming and tail suspension tests in mice.

  10. 5-HT1A receptor activation counteracts c-Fos immunoreactivity induced in serotonin neurons of the raphe nuclei after immobilization stress in the male rat.

    PubMed

    Rioja, José; Santín, Luis J; Doña, Alicia; de Pablos, Laura; Minano, Francisco J; Gonzalez-Baron, Salvador; Aguirre, Jose A

    2006-04-24

    The serotoninergic system and the 5-HT1A receptors have been involved in the brain response to acute stress. The aim of our study was evaluate the role of the 5-HT1A receptors in serotoninergic cells of rostral and caudal raphe nuclei under acute immobilization in rats. Double immunocytochemical staining of 5-hydroxy-tryptamine and c-Fos protein and stereology techniques were used to study the specific cell activation in the raphe nuclei neurons in five groups (control group, immobilization group (immobilization lasting 1 h), DPAT group (8-OH-DPAT 0.3 mg/kg, s.c.), DPAT+IMMO group (8-OH-DPAT 0.3 mg/kg, s.c., 30' prior acute immobilization) and WAY+DPAT+IMMO group (WAY-100635 0.3 mg/kg, s.c. and 8-OH-DPAT 0.3 mg/kg, s.c., 45' and 30', respectively, before immobilization). Our results showed an increase in the number of c-Fos immunoreactive nuclei in serotoninergic cells in both dorsal and median raphe nuclei in the immobilized group. The 8-OH-DPAT pretreatment counteracted the excitatory effects of the acute immobilization in these brain regions. In addition, WAY-100635 administration reduced the effect of 8-OH-DPAT injection, suggesting a selective 5-HT1A receptor role. Raphe pallidus and raphe obscurus did not show any differences among experimental groups. We suggest that somatodendritic 5-HT1A receptors in rostral raphe nuclei may play a crucial role in both mediating the consequences of uncontrollable stress and the possible beneficial effects of treatment with 5-HT1A receptor agonists.

  11. Serotonin transporter, 5-HT1A receptor, and behavior in DBA/2J mice in comparison with four inbred mouse strains.

    PubMed

    Popova, Nina K; Naumenko, Vladimir S; Tibeikina, Marina A; Kulikov, Alexander V

    2009-12-01

    Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5-HT transporter (5-HTT) mRNA level, 5-HT(1A) receptor mRNA level, and 5-HT(1A) receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5-HTT mRNA level in the midbrain and a reduced density of 5-HT(1A) receptors in the frontal cortex without significant changes in 5-HT(1A) receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light-dark box and elevated plus-maze tests, were found. The results suggested the involvement of decreased 5-HTT gene expression and 5-HT(1A) receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive-like behaviors.

  12. Antidepressant-like activity of YL-0919: a novel combined selective serotonin reuptake inhibitor and 5-HT1A receptor agonist.

    PubMed

    Chen, Hong-xia; Jin, Zeng-liang; Zhang, Li-ming; Xue, Rui; Xu, Xiao-dan; Zhao, Nan; Qiu, Zhi-kun; Wang, Xian-wang; Zhang, You-zhi; Yang, Ri-fang; Li, Yun-feng

    2013-01-01

    It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder.

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

    PubMed

    Smith, G Troy; Combs, Nicole

    2008-06-01

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

  14. 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

  15. Synthesis and Docking of Novel 3-Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5-HT1A R/SERT.

    PubMed

    Pessoa-Mahana, Hernán; Silva-Matus, Paul; Pessoa-Mahana, C David; Chung, Hery; Iturriaga-Vásquez, Patricio; Quiroz, Gabriel; Möller-Acuña, Patricia; Zapata-Torres, Gerald; Saitz-Barría, Claudio; Araya-Maturana, Ramiro; Reyes-Parada, Miguel

    2017-01-01

    A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT1A R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT1A R (Ki  = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (Ki  = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities.

  16. 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

  17. 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

  18. A comparative study of the effects of some 5-HT1A receptor agonists on the blood pressure of pithed rats.

    PubMed

    Castillo, C; Bobadilla, R A; Ibarra, M; Castillo, E F; Hong, E

    1995-01-01

    The intention of this study was to supply additional information about direct effects of the 5-HT1A receptor agonist indorenate on the arterial blood pressure. The effects of indorenate were compared with those of buspirone and ipsapirone (all selective 5-HT1A agonists) on the blood pressure of pithed rats. These compounds increased the blood pressure in a dose-dependent fashion. The effects of either ipsapirone or buspirone were clearly inhibited with 100 micrograms/kg of prazosin (selective alpha 1-adrenoceptor antagonist), whereas 1 mg/kg of this blocker elicited only a mild inhibition of the pressor effect of indorenate. Pindolol (100 micrograms/kg; a beta-adrenoceptor and 5-HT1 receptor blocker) was unable to modify the effects of all the 5-HT1A agonists tested. In addition, the 5-HT2 receptor and weak alpha 1-adrenoceptor blocker ketanserin (10-100 micrograms/kg) antagonized the pressor effect of indorenate. Nevertheless, only a mild inhibition was observed in the case of both ipsapirone and buspirone. On the other hand, the latter drugs diminished the blood pressure of pithed rats intravenously infused with norepinephrine, but indorenate was inactive. However, in rats infused with quipazine, all the 5-HT1A agonists failed to reduce blood pressure. These results indicate that buspirone and ipsapirone behaved as partial alpha 1-adrenoceptor agonists. Furthermore, the results show that indorenate-elicited pressor effects are probably due to stimulation of 5-HT2 receptors. Thus, unlike ipsapirone and buspirone, indorenate did not show conclusively activity related with alpha 1-adrenoceptors.

  19. The guinea-pig ileum preparation as a model for 5-HT1A receptors: anomalous effects with RS-30199-193.

    PubMed Central

    Small, C.; Brown, C. M.; Redfern, W. S.; Spedding, M.

    1991-01-01

    1. Agents that have high and selective affinity for the 5-HT1A site such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and N,N-dipropyl-5-carboxamidotryptamine (DP5CT) inhibited the responses to field stimulation in guinea-pig ileum preparations; the inhibitory effects were antagonized by methiothepin and spiperone, consistent with effects at the 5-HT1A site. 2. The inhibitory effects of DP5CT were pronounced in Tyrode solution containing low Ca2+ (0.9 mM), but were much less apparent in Tyrode solution containing 1.8 or 5.4 mM Ca2+. 3. Responses to DP5CT were abolished by pretreatment with phorbol dibutyrate (3 microM), whereas the responses to UK14304 were only slightly inhibited. 4. Buspirone and ipsapirone (1 microM) inhibited the responses to field stimulation, and the effects were resistant to idazoxan, but inhibited by 8-OH-DPAT or spiperone. 5. RS-30199-193 (5-chloro-2-methyl-1,2,3,4,8,9,10,10a-octahydronaphth-[1,8-cd]- aze pine hydrochloride) an azepine with high affinity for the 5-HT1A site in rat cerebral cortex in binding experiments, augmented contractions, but did not antagonize the responses to DP5CT or to 8-OH-DPAT. 6. The hybrid compound of RS-30199-193 with buspirone, RS-64459-193 (5-chloro-2-[4-(8-azaspiro[4,5]decane-7,9-dione)-but-1-yl]- 1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]-3-azepine hydrochloride) maintained high affinity for the 5-HT1A binding site in rat brain and both inhibited the response to field stimulation and antagonized the responses to 8-OH-DPAT and DP5CT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1839137

  20. 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

  1. 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

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

    PubMed

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

    2016-03-15

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

  3. 5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors.

    PubMed

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

    2012-11-01

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

  4. 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

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

    2015-06-01

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

  5. 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.

  6. Serotonin modifies the spontaneous spiking activity of gracile nucleus neurons in rats: role of 5-HT1A and 5-HT2 receptors.

    PubMed

    Grasso, C; Li Volsi, G; Barresi, M

    2016-06-01

    We tested the effects of microiontophoretic application of serotonin (5-HT) on the firing rate of neurons located in the gracile nucleus (GN) of rats. Application of 5-HT1A and 5-HT2 agonists and antagonists respectively mimicked/ modulated and blocked the effects produced by the amine, respectively. Among the tested neurons, 88.2% modified their background firing activity in the presence of 5-HT. Responsive neurons decreased their mean firing activity (MFA) in 56.7% of cases and increased it in the remaining 43.3%. To ascertain the specificity of the effects induced by 5-HT, we utilized 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and alpha-methyl-5-hydroxytryptamine (α-MET-5-HT), agonists for 5-HT1A and 5-HT2 receptors, respectively. The microiontophoresis of 8-OH-DPAT modified the background firing rate of all GN neurons (100% of tested neurons) mimicking the decrease of MFA evoked by 5-HT. The application of a-MET-5-HT modified the MFA in 76.9% of tested neurons, decreasing it in 61.5% of cases and increasing in the remaining 23.1%. The decrease of MFA induced by 8-OH-DPAT was antagonized by application of the 5-HT1A receptor antagonist N-[2-[-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635), while application of 5-HT2 receptor antagonist ketanserine tartrate (KET) antagonized only the increase of MFA induced by a-MET-5-HT. These results indicate that 5-HT is able to modulate the background firing activity of GN neurons by 5-HT1A and 5-HT2 receptors.

  7. Effect of selective agonist of serotonin 5-HT1A receptors on defensive behavior in mice with different predisposition to catalepsy.

    PubMed

    Bazovkina, D V; Terenina, E E; Kulikov, A V

    2010-12-01

    We studied the effect of activation of serotonin 5-HT1A receptors with selective agonist 8-OH-DPAT (0.1, 0.5, and 1.0 mg/kg) on intraspecies aggression and freezing reaction (catalepsy) in male mice of catalepsy-resistant AKR/J and two catalepsy-prone strains CBA/Lac and congenic AKR.CBA-D13Mit76. The latter strain differs from AKR strain only by terminal chromosome 13 fragment transferred from CBA strain and containing a locus determining predisposition to catalepsy and a gene encoding 5-HT1A receptor. 8-OH-DPAT in a low dose (0.1 mg/kg) affecting primarily presynaptic receptors suppressed aggressive behavior in CBA mice, but had no effect on the time of cataleptic freezing. At the same time, this dose of the drug produced no significant effect on aggression in AKR and AKR.CBA-D13Mit76 mice, but significantly attenuated freezing in AKR.CBA-D13Mit76 mice. High doses of 8-OH-DPAT (0.5 and 1 mg/kg) which affected mainly postsynaptic receptors inhibited catalepsy in CBA and AKR.CBA-D13Mit76 mice and in a dose of 1 mg/kg it suppressed aggression in all tested mouse strains. We concluded that the genome of the recipient strain (AKR) modulated the involvement of 5-HT(1A) receptors into the regulation of aggression and catalepsy in mice.

  8. Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats

    PubMed Central

    Shin, Mal-Soon; Park, Sang-Seo; Lee, Jae-Min; Kim, Tae-Woon; Kim, Young-Pyo

    2017-01-01

    The olfactory bulbectomy (OBX) is a well-known method inducing animal model of depression. Depression is associated with dysfunction of serotonin (5-hydroxytryptamine, 5-HT) system. In the present study, antidepressive effect of treadmill exercise was investigated using olfactory bulbectomized rats. After bilateral bulbectomy, the rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 28 days. Increased immobility time and decreased fast time in the forced swim test were observed in the olfactory bulbectomized rats. Sucrose preference in the sucrose preference test was decreased and activity in the open field test was also increased in the olfactory bulbectomized rats. Treadmill exercise decreased immobility time and activity and increased fast time and sucrose preference in the olfactory bulbectomized rats. Expressions of 5-HT and tryptophan hydroxylase (TPH) in the dorsal raphe of rats were suppressed by OBX and treadmill exercise increased the expressions of 5-HT and TPH in the olfactory bulbectomized rats. Serotonin receptor type 1A (5-HT1A) expression in the dorsal raphe was reduced by OBX and treadmill exercise increased 5-HT1A expression in the olfactory bulbectomized rats. In the present study, treadmill exercise ameliorated OBX-induced depressive symptoms. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe. PMID:28349031

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

    PubMed

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

    2015-11-01

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

  10. P2X3 receptors induced inflammatory nociception modulated by TRPA1, 5-HT3 and 5-HT1A receptors.

    PubMed

    Krimon, Suzy; Araldi, Dionéia; do Prado, Filipe César; Tambeli, Cláudia Herrera; Oliveira-Fusaro, Maria Cláudia G; Parada, Carlos Amílcar

    2013-11-01

    It has been described that endogenous ATP via activation of P2X3 and P2X2/3 receptors contributes to inflammatory nociception in different models, including the formalin injected in subcutaneous tissue of the rat's hind paw. In this study, we have evaluated whether TRPA1, 5-HT3 and 5-HT1A receptors, whose activation is essential to formalin-induced inflammatory nociception, are involved in the nociception induced by activation of P2X3 receptors on subcutaneous tissue of the rat's hind paw. We have also evaluated whether the activation of P2X3 receptors increases the susceptibility of primary afferent neurons to formalin action modulated by activation of TRPA1, 5-HT3 or 5-HT1A receptors. Nociceptive response intensity was measured by observing the rat's behavior and considering the number of times the animal reflexively raised its hind paw (flinches) in 60min. Local subcutaneous administration of the selective TRPA1, 5-HT3 or 5-HT1A receptor antagonists HC 030031, tropisetron and WAY 100,135, respectively, prevented the nociceptive responses induced by the administration in the same site of the non-selective P2X3 receptor agonist αβmeATP. Administration of the selective P2X3 and P2X2/3 receptor antagonist A-317491 or pretreatment with oligonucleotides antisense against P2X3 receptor prevented the formalin-induced behavioral nociceptive responses during the first and second phases. Also, the co-administration of a subthreshold dose of αβmeATP with a subthreshold dose of formalin induced nociceptive behavior, which was prevented by local administration of tropisetron, HC 030031 or WAY 100, 135. These findings have demonstrated that the activation of P2X3 receptors induces inflammatory nociception modulated by TRPA1, 5-HT3 and 5-HT1A receptors. Also, they suggest that inflammatory nociception is modulated by the release of endogenous ATP and P2X3 receptor activation, which in turn, increases primary afferent nociceptor susceptibility to the action of inflammatory

  11. Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat.

    PubMed

    Bruins Slot, Liesbeth A; Kleven, Mark S; Newman-Tancredi, Adrian

    2005-12-01

    Considerable interest has arisen in identifying antipsychotic agents with improved efficacy against negative symptoms, such as social withdrawal. In rats, a social interaction deficit can be induced by the NMDA antagonist phencyclidine (PCP). Here, we examined the effects of antipsychotics, reported to exert dual 5-HT(1A)/D(2) actions, on PCP-induced social interaction deficits. Drugs were administered daily for 3 days in combination with either vehicle or PCP (2.5mg/kg, SC) and social interaction was measured on the last day of drug treatment. Pairs of unfamiliar rats receiving the same treatment were placed in a large open field for 10 min and the number of social behaviors were scored. The results indicate that: (1) PCP significantly reduced social interaction by over 50% compared with vehicle-treated controls; (2) haloperidol (0.0025-0.16 mg/kg, SC) and clozapine (0.04-10mg/kg, IP) did not reverse PCP-induced social interaction deficits; (3) the substituted benzamide remoxipride reversed PCP-induced deficits at 0.63 and 2.5mg/kg (4) the 5-HT(1A) agonist 8-OH-DPAT was inactive (at 0.01-0.63 mg/kg, SC); (5) among compounds reported to exert dual 5-HT(1A)/D(2) actions, SSR181507 (at 0.16 mg/kg, SC) and aripiprazole (at 0.04 and 0.16 mg/kg, IP), but not ziprasidone (0.04-2.5mg/kg, IP), SLV313 (0.0025-0.16 mg/kg, SC) or bifeprunox (0.01-0.63 mg/kg, IP), significantly reversed PCP-induced social interaction deficits; and (6) the 5-HT(1A) receptor antagonist WAY100635 blocked the effects of SSR181507 and aripiprazole. These findings indicate that the balance of activity at 5-HT(1A) and D(2) receptors profoundly influences the activity of antipsychotics in this model of social withdrawal, and their potential benefit on at least some of the negative symptoms of schizophrenia.

  12. 5-HT1A receptor antagonists reduce food intake and body weight by reducing total meals with no conditioned taste aversion.

    PubMed

    Dill, M Joelle; Shaw, Janice; Cramer, Jeff; Sindelar, Dana K

    2013-11-01

    Serotonin acts through receptors controlling several physiological functions, including energy homeostasis regulation and food intake. Recent experiments demonstrated that 5-HT1A receptor antagonists reduce food intake. We sought to examine the microstructure of feeding with 5-HT1A receptor antagonists using a food intake monitoring system. We also examined the relationship between food intake, inhibition of binding and pharmacokinetic (PK) profiles of the antagonists. Ex vivo binding revealed that, at doses used in this study to reduce food intake, inhibition of binding of a 5-HT1A agonist by ~40% was reached in diet-induced obese (DIO) mice with a trend for higher binding in DIO vs. lean animals. Additionally, PK analysis detected levels from 2 to 24h post-compound administration. Male DIO mice were administered 5-HT1A receptor antagonists LY439934 (10 or 30 mg/kg, p.o.), WAY100635 (3 or 10mg/kg, s.c.), SRA-333 (10 or 30 mg/kg, p.o.), or NAD-299 (3 or 10mg/kg, s.c.) for 3 days and meal patterns were measured. Analyses revealed that for each antagonist, 24-h food intake was reduced through a specific decrease in the total number of meals. Compared to controls, meal number was decreased 14-35% in the high dose. Average meal size was not changed by any of the compounds. The reduction in food intake reduced body weight 1-4% compared to Vehicle controls. Subsequently, a conditioned taste aversion (CTA) assay was used to determine whether the feeding decrease might be an indicator of aversion, nausea, or visceral illness caused by the antagonists. Using a two bottle preference test, it was found that none of the compounds produced a CTA. The decrease in food intake does not appear to be a response to nausea or malaise. These results indicate that 5-HT1A receptor antagonist suppresses feeding, specifically by decreasing the number of meals, and induce weight loss without an aversive side effect.

  13. The effect of the selective 5-HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain

    PubMed Central

    Casanovas, J M; Lésourd, M; Artigas, F

    1997-01-01

    We have examined the effects of the systemic administration of the selective 5-HT1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated differentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus). Alnespirone (0.1–3 mg kg−1, s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT1A antagonist WAY-100635 (0.5 mg kg−1, s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg−1, s.c.) in frontal cortex. 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg−1, s.c.) also reduced extracellular 5-HT in a regionally-selective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg−1, s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined. Doses of both compounds close to their respective ED50 values (0.3 mg kg−1 alnespirone, 0.025 mg kg−1 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT. These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by differences in the sensitivity of 5-HT1A autoreceptors controlling 5-HT release, given

  14. 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

  15. Synthesis and structure-activity relationships of a new model of arylpiperazines. 5. Study of the physicochemical influence of the pharmacophore on 5-HT(1a)/alpha(1)-adrenergic receptor affinity: synthesis of a new derivative with mixed 5-HT(1a)/d(2) antagonist properties.

    PubMed

    López-Rodríguez, M L; Morcillo, M J; Fernández, E; Porras, E; Orensanz, L; Beneytez, M E; Manzanares, J; Fuentes, J A

    2001-01-18

    In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT(1A) and alpha(1)-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin or a diketopiperazine (X = -(CH(2))(3)-, -(CH(2))(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT(1A) and alpha(1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationships (QSAR) and neural networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT(1A): K(i) = 27 nM; alpha(1): K(i) > 1000 nM). This derivative displays affinity for the dopamine D(2) receptor (K(i) = 22 nM) and is selective versus all other receptors examined (5-HT(2A), 5-HT(3), 5-HT(4) and Bz; K(i) > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT(1A) receptor sites and as an antagonist in the dopamine D(2) receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT(1A)/D(2) antagonist properties and this derivative could be useful as a pharmacological tool.

  16. Bidirectional amygdaloid control of neuropathic hypersensitivity mediated by descending serotonergic pathways acting on spinal 5-HT3 and 5-HT1A receptors.

    PubMed

    Sagalajev, B; Bourbia, N; Beloushko, E; Wei, H; Pertovaara, A

    2015-04-01

    Amygdala is involved in processing of primary emotions and particularly its central nucleus (CeA) also in pain control. Here we studied mechanisms mediating the descending control of mechanical hypersensitivity by the CeA in rats with a peripheral neuropathy in the left hind limb. For drug administrations, the animals had a guide cannula in the right CeA and an intrathecal catheter or another guide cannula in the medullary raphe. Hypersensitivity was tested with monofilaments. Glutamate administration in the CeA produced a bidirectional effect on hypersensitivity that varied from an increase at a low-dose (9μg) to a reduction at high doses (30-100μg). The increase but not the reduction of hypersensitivity was prevented by blocking the amygdaloid NMDA receptor with a dose of MK-801 that alone had no effects. The glutamate-induced increase in hypersensitivity was reversed by blocking the spinal 5-HT3 receptor with ondansetron, whereas the reduction in hypersensitivity was reversed by blocking the spinal 5-HT1A receptor with WAY-100635. Both the increase and decrease of hypersensitivity induced by amygdaloid glutamate treatment were reversed by medullary administration of a 5-HT1A agonist, 8-OH-DPAT, that presumably produced autoinhibition of serotonergic cell bodies in the medullary raphe. The results indicate that depending on the dose, glutamate in the CeA has a descending facilitatory or inhibitory effect on neuropathic pain hypersensitivity. Serotoninergic raphe neurons are involved in mediating both of these effects. Spinally, the 5-HT3 receptor contributes to the increase and the 5-HT1A receptor to the decrease of neuropathic hypersensitivity induced by amygdaloid glutamate.

  17. 5-HT1A receptor blockade targeting the basolateral amygdala improved stress-induced impairment of memory consolidation and retrieval in rats.

    PubMed

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

    2015-08-06

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

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

    PubMed

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

    2012-08-01

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

  19. Brown adipose tissue sympathetic nerve activity is potentiated by activation of 5-hydroxytryptamine (5-HT)1A/5-HT7 receptors in the rat spinal cord

    PubMed Central

    Madden, C. J.; Morrison, S. F.

    2008-01-01

    In urethane-chloralose anesthetized, neuromuscularly blocked, ventilated rats, microinjection of NMDA (12 pmol) into the right fourth thoracic segment (T4) spinal intermediolateral nucleus (IML) immediately increased ipsilateral brown adipose tissue (BAT) sympathetic nerve activity (SNA; peak +492% of control), expired CO2 (+0.1%) heart rate (+48 beats min−1) and arterial pressure (+8 mmHg). The increase in BAT SNA evoked by T4 IML microinjection of NMDA was potentiated when it was administered immediately following a T4 IML microinjection of 5-hydroxytryptamine (5-HT, 100 pmol) or the 5-HT1A/5-HT7 receptor agonist, 8-OH-DPAT (600 pmol), (area under the curve: 184%, and 259% of the NMDA-only response, respectively). In contrast, T4 IML microinjection of the 5-HT2 receptor agonist, DOI (28 pmol) did not potentiate the NMDA-evoked increase in BAT SNA (101% of NMDA-only response). Microinjection into the T4 IML of the selective 5-HT1A antagonist, WAY-100635 (500 pmol), plus the 5-HT7 antagonist, SB-269970 (500 pmol), prevented the 5-HT-induced potentiation of the NMDA-evoked increase in BAT SNA. When administered separately, WAY-100635 (800 pmol) and SB-269970 (800 pmol) attenuated the 8-OH-DPAT-induced potentiation of the NMDA-evoked increase in BAT SNA through effects on the amplitude and duration of the response, respectively. The selective 5-HT2 receptor antagonist, ketanserin (100 pmol), did not attenuate the potentiations of the NMDA-evoked increase in BAT SNA induced by either 5-HT or 8-OH-DPAT. These results demonstrate that activation of 5-HT1A/5-HT7 receptors can act synergistically with NMDA receptor activation within the IML to markedly increase BAT SNA. PMID:18082230

  20. 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

  1. Higher Pre-treatment 5-HT1A Receptor Binding Potential in Bipolar Disorder Depression is Associated with Treatment Remission: A Naturalistic Treatment Pilot PET Study

    PubMed Central

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

    2013-01-01

    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 (5HT1A) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5HT1A levels correlates with antidepressant medication outcome. 41 medication-free DSM-IV diagnosed, bipolar patients in a major depressive episode (MDE) had brain PET scans performed using [11C]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 BPF (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and non-remitters. 34 patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and non-remitters did not differ in age, sex or recent medication history with serotonergic medications. Remitters had higher [11C]WAY-100635 BPF across all brain regions compared with non-remitters (p=0.02). Higher pre-treatment brain 5HT1A 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

  2. Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors.

    PubMed

    Cervo, L; Bendotti, C; Tarizzo, G; Cagnotto, A; Skorupska, M; Mennini, T; Samanin, R

    1994-02-21

    SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10(-7)-10(-6) M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and alpha 1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10(-6) and 10(-5) M. The effect of 10(-6) M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10(-6) M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (+/-)-sulpiride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. 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.

  4. Women with Multiple Chemical Sensitivity Have Increased Harm Avoidance and Reduced 5-HT1A Receptor Binding Potential in the Anterior Cingulate and Amygdala

    PubMed Central

    Åhs, Fredrik; Savic, Ivanka

    2013-01-01

    Multiple chemical sensitivity (MCS) is a common condition, characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the underlying mechanisms are unknown. Contrary to the expectations it was recently found that persons with MCS activate the odor-processing brain regions less than controls, while their activation of the anterior cingulate cortex (ACC) is increased. The present follow-up study was designed to test the hypotheses that MCS subjects have increased harm avoidance and deviations in the serotonin system, which could render them intolerant to environmental odors. Twelve MCS and 11 control subjects, age 22–44, all working or studying females, were included in a PET study where 5-HT1A receptor binding potential (BP) was assessed after bolus injection of [11C]WAY100635. Psychological profiles were assessed by the Temperament and Character Inventory and the Swedish universities Scales of Personality. All MCS and 12 control subjects were also tested for emotional startle modulation in an acoustic startle test. MCS subjects exhibited significantly increased harm avoidance, and anxiety compared to controls. They also had a reduced 5-HT1A receptor BP in amygdala (p = 0.029), ACC (p = 0.005) (planned comparisons, significance level 0.05), and insular cortex (p = 0.003; significance level p<0.005 with Bonferroni correction), and showed an inverse correlation between degree of anxiety and the BP in the amygdala (planned comparison). No group by emotional category difference was found in the startle test. Increased harm avoidance and the observed changes in the 5-HT1A receptor BP in the regions processing harm avoidance provides a plausible pathophysiological ground for the symptoms described in MCS, and yields valuable information for our general understanding of idiopathic environmental intolerances. PMID:23349968

  5. Activation of 5-HT1A and 5-HT7 receptors in the parafascicular nucleus suppresses the affective reaction of rats to noxious stimulation.

    PubMed

    Harte, Steven E; Kender, Robert G; Borszcz, George S

    2005-02-01

    The antinociceptive effects of the serotonin (5-HT)1A/7 receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) administered into the medial thalamus were evaluated. Pain behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization after discharges, VADs) levels of the neuraxis were elicited by tailshock. Administration of 8-OH-DPAT (5, 10, and 20 microg/side) into nucleus parafascicularis (nPf) produced dose-dependent increases in VDS and VAD thresholds, but failed to elevate SMR threshold. The increase in VAD threshold was significantly greater than that of VDS threshold. Similar effects were observed with administration of 8-OH-DPAT (20 microg/side) into the rostral portion of the central lateral thalamic nucleus. The bilateral or unilateral administration of 8-OH-DPAT (20 microg) into other thalamic nuclei, or into sites dorsal to nPf, did not elevate vocalization thresholds. Increases in vocalization thresholds produced by nPf-administered 8-OH-DPAT were mediated by both 5-HT1A and 5-HT7 receptors. Intra-nPf administration of the 5-HT1A receptor antagonist WAY-100635 (0.05 or 0.5 microg/side), or the 5-HT7 receptor antagonist SB-269970 (1 or 2 microg/side), but not the dopamine D2 receptor antagonist raclopride (10 microg/side), reversed 8-OH-DPAT induced elevations in vocalization thresholds. These results provide the first reported evidence of behavioral antinociception following the administration of a 5-HT agonist into the medial thalamus.

  6. Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies.

    PubMed

    Satała, Grzegorz; Duszyńska, Beata; Stachowicz, Katarzyna; Rafalo, Anna; Pochwat, Bartlomiej; Luckhart, Christine; Albert, Paul R; Daigle, Mireille; Tanaka, Kenji F; Hen, René; Lenda, Tomasz; Nowak, Gabriel; Bojarski, Andrzej J; Szewczyk, Bernadeta

    2016-12-01

    Recent data has indicated that Zn can modulate serotonergic function through the 5-HT1A receptor (5-HT1AR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HT1ARs in more detail. The influence of Zn on agonist binding to 5-HT1ARs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [(3)H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT1A autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT1A autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HT1ARs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HT1ARs; however, Zn's effects at presynaptic receptors seem to be more potent.

  7. 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects.

    PubMed

    Stenkrona, Per; Halldin, Christer; Lundberg, Johan

    2013-10-01

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

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

    PubMed

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

    2011-10-24

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

  9. (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.

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

    PubMed

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

    2011-12-01

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

  11. Chronic imipramine enhances 5-HT(1A) and 5-HT(2) receptors-mediated inhibition of panic-like behavior in the rat dorsal periaqueductal gray.

    PubMed

    Jacob, Cláudia A; Cabral, Alfredo H C L; Almeida, Leandro P; Magierek, Valeska; Ramos, Patrício L; Zanoveli, Janaína M; Landeira-Fernandez, Jesus; Zangrossi, Hélio; Nogueira, Regina L

    2002-07-01

    Electrical stimulation of the dorsal periaqueductal gray (DPAG) has been used to induce panic-like behavior in rats. In the present study, we investigated the effect of chronic imipramine treatment on the sensitivity of different 5-HT receptor subtypes in inhibiting aversion induced by electrical stimulation of this brain area. For that, the effects of intra-DPAG administration of the endogenous agonist 5-HT (20 nmol), the 5-HT(1A) receptor agonist 8-OH-DPAT (8 nmol) and the 5-HT(2A/2C) receptor agonist DOI (16 nmol) were measured in female Wistar rats given either chronic injection of imipramine (15 mg/kg, 3 weeks, ip) or saline. The results showed that the three receptor agonists raised the threshold of aversive electrical stimulation in both groups of animals, but this antiaversive effect was significantly higher in rats treated with imipramine. Treatment with imipramine did not change the basal threshold of aversive electrical stimulation measured before intra-DPAG injection of the 5-HT agonists. The results suggest that sensitization of both 5-HT(1A) and 5-HT(2) receptors within the DPAG may be involved in the beneficial effect of imipramine in panic disorder (PD).

  12. The role of peripheral 5HT2A and 5HT1A receptors on the orofacial formalin test in rats with persistent temporomandibular joint inflammation.

    PubMed

    Okamoto, K; Imbe, H; Tashiro, A; Kimura, A; Donishi, T; Tamai, Y; Senba, E

    2005-01-01

    The role of peripheral serotonin (5HT) 2A and 5HT1A receptors on the orofacial nocifensive behavioral activities evoked by the injection of formalin into the masseter muscle was evaluated in the rats with persistent temporomandibular joint (TMJ) inflammation evoked by Complete Freund's Adjuvant (CFA). The orofacial nocifensive behavioral activities evoked by the injection of formalin into masseter muscle were significantly enhanced at 1 day (CFA day 1 group) or 7 days (CFA day 7 group) during TMJ inflammation. Pretreatment with local administration of 5HT2A receptor antagonist, ketanserin (0.01, 0.1 mg/rat) into the masseter muscle or systemic administration of ketanserin via i.p. injection (1 mg/kg) reduced the orofacial nocifensive behavioral activities of the late phase evoked by formalin injection into masseter muscle on the side of TMJ inflammation (CFA day 7 group). However, local (0.001-0.1 mg/rat) or systemic (1 mg/kg) administration of 5HT1A receptor antagonist, propranolol, into masseter muscle did not produce the antinociceptive effect in CFA day 7 group. Moreover, local administration of ketanserin (0.1 mg) or propranolol (0.1 mg) into masseter muscle did not inhibit nocifensive orofacial behavior in rats without TMJ inflammation. These data suggest that persistent TMJ inflammation causes the elevation of the orofacial nocifensive behavior, and peripheral 5HT2A receptors play an important role in mediating the deep craniofacial tissue nociception in rats with TMJ inflammation.

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

    PubMed

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

    2016-12-01

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

  14. 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.

  15. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity.

    PubMed

    Jensen, Niels H; Rodriguiz, Ramona M; Caron, Marc G; Wetsel, William C; Rothman, Richard B; Roth, Bryan L

    2008-09-01

    Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo[b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H(1) receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT(1A), 5-HT(1E), 5-HT(2A), 5-HT(2B), 5-HT(7) receptors, the alpha(1B)-adrenergic receptor, and the M(1), M(3), and M(5) muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT(1D), 5-HT(2C), 5-HT(3), 5-HT(5), 5-HT(6), alpha(1A), alpha(2A), alpha(2B), alpha(2C), H(2), M(2), M(4), and dopamine D(1), D(2), D(3), and D(4) receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K(i) of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT(1A) receptor. N-Desalkylquetiapine was an antagonist at 5-HT(2A), 5-HT(2B), 5-HT(2C), alpha(1A), alpha(1D), alpha(2A), alpha(2C), H(1), M(1), M(3), and M(5) receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT(1A) agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.

  16. 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

  17. Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.

    PubMed

    Brindisi, Margherita; Butini, Stefania; Franceschini, Silvia; Brogi, Simone; Trotta, Francesco; Ros, Sindu; Cagnotto, Alfredo; Salmona, Mario; Casagni, Alice; Andreassi, Marco; Saponara, Simona; Gorelli, Beatrice; Weikop, Pia; Mikkelsen, Jens D; Scheel-Kruger, Jorgen; Sandager-Nielsen, Karin; Novellino, Ettore; Campiani, Giuseppe; Gemma, Sandra

    2014-11-26

    Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.

  18. Sleep and EEG power spectrum effects of the 5-HT1A antagonist NAN-190 alone and in combination with citalopram.

    PubMed

    Neckelmann, D; Bjørkum, A A; Bjorvatn, B; Ursin, R

    1996-02-01

    The sleep and waking and EEG power spectrum effects of the putative 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.) were studied alone and in co-administration with the selective serotonin re-uptake inhibitor citalopram (5.0 mg/kg, i.p.) in the rat. Citalopram, as in a prior dose-response study, reduced REM sleep. In addition, a slight increase in NREM sleep was observed. Citalopram reduced NREM fronto-parietal (FP) EEG power density in the 5-20 Hz range. When administered alone, NAN-190 suppressed REM sleep in the first 2 h, and reduced SWS-2 in the first 4 after administration. NAN-190 also suppressed selectively NREM sleep slow-wave activity in both fronto-frontal (FF) and FP EEG power spectrum. When administered in combination with citalopram, an attenuation of the power density reduction in the 7-15 Hz range in the FF EEG of citalopram alone, was observed. However, the EEG power spectral density and REM sleep suppressive effects of NAN-190 were both augmented. The results are compatible with the notion that serotonin is involved in the modulation of the slow wave activity in the EEG during NREM sleep. The results are cordant with other data suggesting that postsynaptic 5-HT1A stimulation might increase slow wave activity in the NREM EEG, and that serotonergic stimulation of other receptor subtypes (possibly 5-HT2) may decrease slow wave activity in the NREM EEG.

  19. Effect of Sarizotan, a 5-HT1a and D2-Like Receptor Agonist, on Respiration in Three Mouse Models of Rett Syndrome

    PubMed Central

    Abdala, Ana P.; Lioy, Daniel T.; Garg, Saurabh K.; Knopp, Sharon J.; Paton, Julian F. R.

    2014-01-01

    Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2–like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa–induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG–binding protein 2-–deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT. PMID:24351104

  20. 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

  1. Hallucinogen-like effects of N,N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents

    PubMed Central

    Fantegrossi, William E.; Reissig, Chad J.; Katz, Elyse B.; Yarosh, Haley L.; Rice, Kenner C.; Winter, Jerrold C.

    2008-01-01

    N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin), or 3,4-methylenedioxymethamphetamine (MDMA). A separate group of rats was also trained to recognize DPT itself as a discriminative stimulus, and in all cases, the behavioral effects of DPT were challenged with the selective serotonin (5-HT)2A antagonist M100907, the 5-HT1A selective antagonist WAY-100635, or their combination. In the head twitch assay, DPT elicited dose-dependent effects, producing a biphasic dose-effect curve. WAY-100635 produced a parallel rightward shift in the dose-effect curve for head twitches, indicative of surmountable antagonism, but the antagonist effects of M100907 were functionally insurmountable. DPT produced partial to full substitution when tested in rats trained to discriminate LSD, psilocybin or MDMA, and served as a discriminative stimulus. In all cases, the antagonist effects of M100907 were more profound than were those of WAY-100635. DPT is thus active in two rodent models relevant to 5-HT2 agonist activity. The effectiveness with which M100907 antagonizes the behavioral actions of this compound strongly suggests that the 5-HT2A receptor is an important site of action for DPT, but the modulatory actions of WAY-100635 also imply a 5-HT1A-mediated component to the actions of this compound. PMID:17905422

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

    PubMed

    Perez-García, G; Meneses, A

    2008-12-16

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

  3. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity.

    PubMed

    Ishibashi, Tadashi; Horisawa, Tomoko; Tokuda, Kumiko; Ishiyama, Takeo; Ogasa, Masaaki; Tagashira, Rie; Matsumoto, Kenji; Nishikawa, Hiroyuki; Ueda, Yoko; Toma, Satoko; Oki, Hitomi; Tanno, Norihiko; Saji, Ikutaro; Ito, Akira; Ohno, Yukihiro; Nakamura, Mitsutaka

    2010-07-01

    Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.

  4. 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.

  5. Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome.

    PubMed

    Abdala, Ana P; Lioy, Daniel T; Garg, Saurabh K; Knopp, Sharon J; Paton, Julian F R; Bissonnette, John M

    2014-06-01

    Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2-like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa-induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG-binding protein 2--deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT.

  6. Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats.

    PubMed

    Avila-Rojas, Sabino Hazael; Velázquez-Lagunas, Isabel; Salinas-Abarca, Ana Belen; Barragán-Iglesias, Paulino; Pineda-Farias, Jorge Baruch; Granados-Soto, Vinicio

    2015-10-05

    Serotonin (5-HT) participates in pain modulation by interacting with different 5-HT receptors. The role of 5-HT5A receptor in neuropathic pain has not previously studied. The purpose of this study was to investigate: A) the role of 5-HT5A receptors in rats subjected to spinal nerve injury; B) the expression of 5-HT5A receptors in dorsal spinal cord and dorsal root ganglia (DRG). Neuropathic pain was induced by L5/L6 spinal nerve ligation. Tactile allodynia in neuropathic rats was assessed with von Frey filaments. Western blot methodology was used to determine 5-HT5A receptor protein expression. Intrathecal administration (on day 14th) of 5-HT (10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) reversed nerve injury-induced tactile allodynia. Intrathecal non-selective (methiothepin, 0.1-0.8 nmol) and selective (SB-699551, 1-10 nmol) 5-HT5A receptor antagonists reduced, by ~60% and ~25%, respectively, the antiallodynic effect of 5-HT (100 nmol) or 5-CT (0.3 nmol). Moreover, both selective 5-HT1A and 5-HT1B/1D receptor antagonists, WAY-100635 (0.3-1 nmol) and GR-127935 (0.3-1 nmol), respectively, partially diminished the antiallodynic effect of 5-HT or 5-CT by about 30%. Injection of antagonists, by themselves, did not affect allodynia. 5-HT5A receptors were expressed in the ipsilateral dorsal lumbar spinal cord and DRG and L5/L6 spinal nerve ligation did not modify 5-HT5A receptor protein expression in those sites. Results suggest that 5-HT5A receptors reduce pain processing in the spinal cord and that 5-HT and 5-CT reduce neuropathic pain through activation of 5-HT5A and 5-HT1A/1B/1D receptors. These receptors could be an important part of the descending pain inhibitory system.

  7. The function and structural influence of selective relaxed constraint at functional intracellular loop3 of 5-HT(1A) serotonin-1 receptor family.

    PubMed

    Dass, J Febin Prabhu; Sudandiradoss, C

    2012-10-25

    Serotonin (5-HT) and its receptors have been involved in critical signal transduction mechanism and deregulation implicated in mood-related disorders. 5-HT activities are mediated through a family of transmembrane spanning serotonin receptors. Both within the family and species, 5-HT receptor protein sequence diversity and 7-transmembrane structural homogeneity have long been intriguing. In this study, we have analyzed the codon site constraint in 5-HT1 subclass receptors from 13 orthologous mammalian mRNA coding sequence. Further, the study was extended to computationally investigate the impact of non-synonymous sites with respect to function and structural significance through sequence homology algorithm and molecular dynamics simulation (MDS). Codon sites with significant posterior probability were observed in 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor indicating variations in site constraint within the 5-HT1 sub-class genes. In 5-HT(1A) receptor, seven sites were detected at the functional intracellular loop(3) (ICL(3)) with higher substitution rate through Codeml program. Sequence homology algorithm identifies that these sites were functionally tolerant within the mammals representing a selectively relaxed constraint at this domain. On the other hand, the root mean square deviation (rmsd) values from MDS suggest differences in structural conformation of ICL(3) models among the species. Specifically, the human ICL(3) model fluctuation was comparatively more stable than other species. Hence, we argue that these sites may have varying influence in G-proteins coupling and activation of effectors systems through downstream interacting accessory proteins of cell among the species. However, further experimental studies are required to elucidate the precise role and the seeming difference of these sites in 5-HT receptors between species.

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

    PubMed

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

    2015-09-01

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

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

    PubMed

    Katsidoni, Vicky; Anagnostou, Ilektra; Panagis, George

    2013-03-01

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

  10. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy

    PubMed Central

    Ward, Sara Jane; McAllister, Sean D; Kawamura, Rumi; Murase, Ryuchi; Neelakantan, Harshini; Walker, Ellen A

    2014-01-01

    Background and Purpose Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy. Experimental Approach The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay. Key Results PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 – 10 mg·kg−1) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT1A antagonist WAY 100635, but not the CB1 antagonist SR141716 or the CB2 antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability. Conclusions and Implications Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT1A receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN. PMID:24117398

  11. Differential effects of protein kinase C activation on 5-HT1A receptor coupling to Ca2+ and K+ currents in rat serotonergic neurones.

    PubMed Central

    Chen, Y; Penington, N J

    1996-01-01

    1. Activation of the enzyme protein kinase C (PKC) partially uncouples receptors from the inhibition of Ca2+ current. We have studied the effect of PKC activation on 5-HT1A receptor coupling of Ca2+ currents and 5-HT-induced K+ current (IK,5-HT) in acutely isolated adult rat dorsal raphe neurones. 2. The phorbol ester 4 beta-phorbol 12-myristate, 13-acetate (PMA; 1 microM) did not significantly alter the peak Ca2+ current. A maximal dose of 5-HT inhibited Ca2+ current on average by 52%; after application of PMA, the inhibition was only 30% and the effect was irreversible for the duration of the experiment. 3. The inactive phorbol ester 4 alpha-phorbol (1 microM) did not reduce the effectiveness of 5-HT. When the kinase inhibitor staurosporine (ST; 200 nM) was added, PMA reduced the effect of 5-HT by only 13.9%. ST partially prevented or reversed the effect of PMA, depending on the order of addition. 4. The voltage-dependent rate or re-inhibition by 5-HT was reduced by PMA, suggesting that fewer activated G-protein subunits are available to interact with Ca2+ channel after the action of PMA. 5. In contrast, PMA (1 microM) did not have a significant effect on IK,5-HT. 6. PKC activation has an inhibitory effect on one branch of the 5-HT1A receptor transduction fork, namely inhibition of Ca2+ influx, but not on the activation of IK,5-HT. PMID:8910201

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

    PubMed

    Meneses, A; Terrón, J A

    2001-06-01

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

  13. The spleen is required for 5-HT1A receptor agonist-mediated increases in mean circulatory filling pressure during hemorrhagic shock in the rat.

    PubMed

    Tiniakov, Ruslan; Scrogin, Karie E

    2009-05-01

    The 5-HT(1A) receptor agonist, 8- OH-DPAT, increases whole body venous tone (mean circulatory filling pressure; MCFP), and attenuates metabolic acidosis in a rat model of unresuscitated hemorrhagic shock. To determine whether improved acid-base balance was associated with sympathetic activation and venous constriction, MCFP, sympathetic activity (SA), and blood gases were compared in hemorrhaged rats following administration of 5-HT(1A) receptor agonist 8-OH-DPAT, the arterial vasoconstrictor arginine vasopressin (AVP), or saline. To further determine whether protection of acid-base balance was dependent on splenic contraction and blood mobilization, central venous pressure (CVP), MCFP, and blood gases were determined during hemorrhage and subsequent 8-OH-DPAT-administration in rats subjected to real or sham splenectomy. Subjects were hemorrhaged to an arterial pressure of 50 mmHg for 25 min and subsequently were treated with 8-OH-DPAT (30 nmol/kg iv), AVP titrated to match the pressor effect of 8-OH-DPAT (approximately 2 ng/min iv), or infusion of normal saline. 8-OH-DPAT increased MAP, CVP, MCFP, and SA, and decreased lactate accumulation. AVP did not affect CVP or SA, but raised MCFP slightly to a level intermediate between 8-OH-DPAT- and saline-treated rats. Infusion of AVP also produced a modest protection against metabolic acidosis. Splenectomy prevented the rise in CVP, MCFP, and protection against metabolic acidosis produced by 8-OH-DPAT but had no effect on the immediate pressor response to the drug. Together, the data indicate that 8-OH-DPAT produces a pattern of cardiovascular responses consistent with a sympathetic-mediated venoconstriction that is, in part, responsible for the drug's beneficial effect on acid-base balance. Moreover, blood mobilization stimulated by the spleen is required for the beneficial effects of 8-OH-DPAT.

  14. 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.

  15. 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

  16. 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.

  17. 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

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

    PubMed

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

    2011-01-01

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

  19. Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation.

    PubMed

    Cosi, Cristina; Waget, Aurelie; Rollet, Karin; Tesori, Valentina; Newman-Tancredi, Adrian

    2005-05-10

    Excessive activation of non-NMDA receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT(1A) receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT(1A) receptor, with those of haloperidol, which is devoid of 5-HT(1A) agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT(1A) receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT(1A) receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 x 10 mg/kg), ziprasidone (2 x 20 mg/kg) and aripiprazole (2 x 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 x 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 x 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT(1A) receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT(1A) agonist properties may protect against excitotoxic injury, in vivo.

  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. 5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

    PubMed Central

    Wu, Hua-Li; Pang, Si-Lin; Liu, Qiong-Zhen; Wang, Qian; Cai, Min-Xuan; Shang, Jing

    2014-01-01

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

  2. Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia.

    PubMed

    Tirgar, F; Rezayof, A; Zarrindast, M-R

    2014-09-26

    The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3-7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1-2-μg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-μg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1-2-μg/rat) or (S)-WAY 100135 (0.25-1-μg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.

  3. Activation of 5-HT1A receptors in the rat dorsomedial hypothalamus inhibits stress-induced activation of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Stamper, Christopher E; Hassell, James E; Kapitz, Adam J; Renner, Kenneth J; Orchinik, Miles; Lowry, Christopher A

    2017-03-27

    Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticosteroid hormones into the circulation, is an adaptive response to perceived threats. Persistent activation of the HPA axis can lead to impaired physiological or behavioral function with maladaptive consequences. Thus, efficient control and termination of stress responses is essential for well-being. However, inhibitory control mechanisms governing the HPA axis are poorly understood. Previous studies suggest that serotonergic systems, acting within the medial hypothalamus, play an important role in inhibitory control of stress-induced HPA axis activity. To test this hypothesis, we surgically implanted chronic jugular cannulae in adult male rats and conducted bilateral microinjection of vehicle or the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT; 8 nmol, 0.2 μL, 0.1 μL/min, per side) into the dorsomedial hypothalamus (DMH) immediately prior to a 40 min period of restraint stress. Repeated blood sampling was conducted using an automated blood sampling system and plasma corticosterone concentrations were determined using enzyme-linked immunosorbent assay. Bilateral intra-DMH microinjections of 8-OH-DPAT suppressed stress-induced increases in plasma corticosterone within 10 min of the onset of handling prior to restraint and, as measured by area-under-the-curve analysis of plasma corticosterone concentrations, during the 40 min period of restraint. These data support an inhibitory role for serotonergic systems, acting within the DMH, on stress-induced activation of the HPA axis. Lay summary: Inhibitory control of the hypothalamic-pituitary-adrenal (HPA) stress hormone response is important for well-being. One neurochemical implicated in inhibitory control of the HPA axis is serotonin. In this study we show that activation of serotonin receptors, specifically inhibitory 5-HT1A receptors in the dorsomedial

  4. Citrus aurantium L. essential oil exhibits anxiolytic-like activity mediated by 5-HT1A-receptors and reduces cholesterol after repeated oral treatment

    PubMed Central

    2013-01-01

    Background The current treatments for anxiety disorders and depression have multiple adverse effects in addition to a delayed onset of action, which has prompted efforts to find new substances with potential activity in these disorders. Citrus aurantium was chosen based on ethnopharmacological data because traditional medicine refers to the Citrus genus as useful in diminishing the symptoms of anxiety or insomnia, and C. aurantium has more recently been proposed as an adjuvant for antidepressants. In the present work, we investigated the biological activity underlying the anxiolytic and antidepressant effects of C. aurantium essential oil (EO), the putative mechanism of the anxiolytic-like effect, and the neurochemical changes in specific brain structures of mice after acute treatment. We also monitored the mice for possible signs of toxicity after a 14-day treatment. Methods The anxiolytic-like activity of the EO was investigated in a light/dark box, and the antidepressant activity was investigated in a forced swim test. Flumazenil, a competitive antagonist of benzodiazepine binding, and the selective 5-HT1A receptor antagonist WAY100635 were used in the experimental procedures to determine the mechanism of action of the EO. To exclude false positive results due to motor impairment, the mice were submitted to the rotarod test. Results The data suggest that the anxiolytic-like activity observed in the light/dark box procedure after acute (5 mg/kg) or 14-day repeated (1 mg/kg/day) dosing was mediated by the serotonergic system (5-HT1A receptors). Acute treatment with the EO showed no activity in the forced swim test, which is sensitive to antidepressants. A neurochemical evaluation showed no alterations in neurotransmitter levels in the cortex, the striatum, the pons, and the hypothalamus. Furthermore, no locomotor impairment or signs of toxicity or biochemical changes, except a reduction in cholesterol levels, were observed after treatment with the EO. Conclusion

  5. Alcohol intake in high alcohol drinking (HAD) rats is suppressed by FG5865, a novel 5-HT1A agonist/5-HT2 antagonist.

    PubMed

    Long, T A; Kalmus, G W; Björk, A; Myers, R D

    1996-01-01

    Both the 5-HT2 antagonist, FG5606 (amperozide), and the mixed 5-HT1 agonist/5-HT2 antagonist, FG5893, attenuate significantly the volitional intake of alcohol in the cyanamide treated rat. The purpose of the present study was to investigate the effect on alcohol drinking in the selectively bred, high alcohol drinking (HAD) rat of a new and novel 5-HT1A agonist/5-HT2 antagonist, FG5865 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3-pyridinecarboxy lic acid methyl ester), which shares pharmacological properties with FG5893. Initially, a standard three bottle preference test for water vs. 3% to 30% alcohol solutions was given over 11 days to determine the maximally preferred concentration for each animal. Then water and this solution, which ranged between 9% and 20% with an overall mean absolute intake of 6.3 +/- 0.5 g/kg per day, was offered over three consecutive 4-day test sequences: (1) predrug control; (2) SC injections b.i.d. of either 1.0 mg/kg or 2.5 mg/kg FG5865 or saline control vehicle; and (3) postdrug. Whereas saline failed to alter alcohol consumption of the HAD rats, FG5865 caused a significant dose dependent reduction by as much as 75% in the intakes of alcohol during its administration in terms of both g/kg (p < 0.01) and proportion of alcohol to total fluid intake (p < 0.01). During the administration of 2.5 mg/kg FG5865, alcohol drinking declined from 6.5 +/- 0.3 g/kg to as low as 2.3 +/- 0.2 g/kg per day. Neither the body weight of the HAD animals nor their intake of food was affected by either dose of FG5865. These results uphold the concept that the 5-HT1A and 5-HT2 receptor subtypes in the brain play a part in the aberrant drinking of alcohol of the HAD rat. Because FG5865 influences the activity of serotonergic neurons in the mesolimbic system of the rat, it is envisaged that the drug suppresses alcohol drinking by way of its action on these neurons.

  6. Contribution of the Striatum to the Effects of 5-HT1A Receptor Stimulation in L-DOPA-treated Hemiparkinsonian Rats

    PubMed Central

    Bishop, Christopher; Krolewski, David M.; Eskow, Karen L.; Barnum, Christopher J.; Dupre, Kristin B.; Deak, Terrence; Walker, Paul D.

    2009-01-01

    Clinical and experimental studies implicate the use of serotonin (5-HT)1A receptor agonists for the reduction of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Although raphe nuclei likely play a role in these antidyskinetic effects, an unexplored population of striatal 5-HT1A receptors (5-HT1AR) may also contribute. To better characterize this mechanism, L-DOPA-primed hemiparkinsonian rats received the 5-HT1AR agonist ±8-OH-DPAT (0, 0.1, 1.0 mg/kg, i.p.) with or without cotreatment with the 5-HT1AR antagonist WAY100635 (0.5 mg/kg, i.p.) 5 min after L-DOPA, after which abnormal involuntary movements (AIMs), rotations, and forelimb akinesia were quantified. To establish the effects of 5-HT1AR stimulation on L-DOPA-induced c-fos and preprodynorphin (PPD) mRNA within the dopamine-depleted striatum, immunohistochemistry and real-time reverse transcription polymerase chain reaction, respectively, were used. Finally, to determine the contribution of striatal 5-HT1AR to these effects, L-DOPA-primed hemiparkinsonian rats received bilateral intrastriatal microinfusions of ±8-OH-DPAT (0, 5, or 10 μg/side), WAY100635 (5 μg/side), or both (10 μg + 5 μg/side) 5 min after L-DOPA, after which AIMs and rotations were examined. Systemic ±8-OH-DPAT dose- and receptor-dependently attenuated L-DOPA-mediated AIMs and improved forelimb akinesia. Striatal c-fos immuno-reactivity and PPD mRNA ipsilateral to the lesion were strongly induced by L-DOPA, while ±8-OH-DPAT suppressed these effects. Finally, intrastriatal infusions of ±8-OH-DPAT reduced AIMs while coinfusion of WAY100635 reversed its antidyskinetic effect. Collectively, these results support the hypothesis that the cellular and behavioral properties of 5-HT1AR agonists are conveyed in part via a population of functional 5-HT1AR within the striatum. PMID:19115412

  7. 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.

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

    PubMed

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

    2010-09-01

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

  9. Effect of mouse chromosome 13 terminal fragment on liability to catalepsy and expression of tryptophane hydroxylase-2, serotonin transporter, and 5-HT1A receptor genes in the brain.

    PubMed

    Kulikov, A V; Naumenko, V S; Bazovkina, D V; Dee, V Yu; Osipova, D V; Popova, N K

    2009-05-01

    Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool for studies of the molecular mechanisms of behavioral mutations. The 59-70 cM fragment of chromosome 13 containing the locus determining predisposition to freezing reaction (catalepsy) and the gene encoding 5-HT(1A) receptor were transferred from cataleptic CBA/Lac mice into the genome of catalepsy-resistant AKR/J mice. The impact of this fragment for the severity of catalepsy and expression of genes encoding tryptophane hydroxylase-2, serotonin transporter, and 5-HT(1A) receptor was studied. Half of mice of the resultant congenic AKR.CBA-D13Mit76 strain exhibited pronounced catalepsy, similarly to donor CBA animals. The expression of 5-HT(1A) receptor gene in the midbrain of AKR animals was significantly higher than in CBA. The level of 5-HT(1A) receptor mRNA in AKR.CBA-D13Mit76 animals was significantly higher than in the donor strain. Mice of parental AKR and CBA strains did not differ from each other and from AKR.CBA-D13Mit76 animals by the levels of tryptophane hydroxylase-2 and serotonin transporter genes mRNA. These data prove the location of catalepsy regulating gene in the distal fragment of chromosome 13. The recipient strain genome enhanced the expression of 5-HT(1A) receptor gene in the brain without modulating the expression of catalepsy gene.

  10. 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

  11. Effect of dopaminergic D1 receptors on plasticity is dependent of serotoninergic 5-HT1A receptors in L5-pyramidal neurons of the prefrontal cortex.

    PubMed

    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.

  12. Systemic modulation of serotonergic synapses via reuptake blockade or 5HT1A receptor antagonism does not alter perithreshold taste sensitivity in rats.

    PubMed

    Mathes, Clare M; Spector, Alan C

    2014-09-01

    Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration-response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior.

  13. Systemic Modulation of Serotonergic Synapses via Reuptake Blockade or 5HT1A Receptor Antagonism Does Not Alter Perithreshold Taste Sensitivity in Rats

    PubMed Central

    Spector, Alan C.

    2014-01-01

    Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration–response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior. PMID:25056731

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

    PubMed

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

    2009-07-29

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

  15. Structure-activity relationships of a series of substituted benzamides: potent D2/5-HT2 antagonists and 5-HT1a agonists as neuroleptic agents.

    PubMed

    Norman, M H; Rigdon, G C; Hall, W R; Navas, F

    1996-03-01

    A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) ddemonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)ben zamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent.

  16. 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.

  17. Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat

    PubMed Central

    Dupre, Kristin B.; Eskow, Karen L.; Barnum, Christopher J.; Bishop, Christopher

    2008-01-01

    Summary Convergent evidence suggests that serotonin 5-HT1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesia by auto-regulating aberrant release of L-DOPA-derived dopamine (DA) from raphestriatal neurons. However, recent findings indicate that 5-HT1AR stimulation also modifies D1 receptor (D1R)-mediated dyskinesia and rotations implicating a previously unexplored extra-raphe mechanism. In order to characterize the contribution of the striatum to these effects, rats with medial forebrain bundle DA lesions were tested for abnormal involuntary movements (AIMs) and rotations following striatal microinfusions of the 5-HT1AR agonist ±8-OH-DPAT and systemic D1R agonist treatment with SKF81297. Additional rats with multi-site striatal DA lesions were tested for motor disability following systemic or intrastriatal ±8-OH-DPAT with or without systemic SKF81297. In rats with medial forebrain bundle lesions, striatal infusions of ±8-OH-DPAT dose-dependently reduced AIMs while conversely increasing rotations. In rats with striatal lesions, ±8-OH-DPAT alone, both systemic and intrastriatal administration, optimally reversed motor disability. Collectively, these results support an important functional interaction between 5-HT1AR and D1R in the striatum with implications for the improved treatment of Parkinson’s disease. PMID:18824001

  18. 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

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

    PubMed

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

    2011-10-01

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

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

    PubMed

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

    2005-06-01

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

  1. 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.

  2. Depressed GABA and glutamate synaptic signaling by 5-HT1A receptors in the nucleus tractus solitarii and their role in cardiorespiratory function

    PubMed Central

    Ostrowski, Tim D.; Ostrowski, Daniela; Hasser, Eileen M.

    2014-01-01

    Serotonin (5-HT), and its 5-HT1A receptor (5-HT1AR) subtype, is a powerful modulator of the cardiorespiratory system and its sensory reflexes. The nucleus tractus solitarii (nTS) serves as the first central station for visceral afferent integration and is critical for cardiorespiratory reflex responses. However, the physiological and synaptic role of 5-HT1ARs in the nTS is relatively unknown. In the present study, we examined the distribution and modulation of 5-HT1ARs on cardiorespiratory and synaptic parameters in the nTS. 5-HT1ARs were widely distributed to cell bodies within the nTS but not synaptic terminals. In anesthetized rats, activation of 5-HT1ARs by microinjection of the 5-HT1AR agonist 8-OH-DPAT into the caudal nTS decreased minute phrenic neural activity via a reduction in phrenic amplitude. In brain stem slices, 8-OH-DPAT decreased the amplitude of glutamatergic tractus solitarii-evoked excitatory postsynaptic currents, and reduced overall spontaneous excitatory nTS network activity. These effects persisted in the presence of GABAA receptor blockade and were antagonized by coapplication of 5-HT1AR blocker WAY-100135. 5-HT1AR blockade alone had no effect on tractus solitarii-evoked excitatory postsynaptic currents, but increased excitatory network activity. On the other hand, GABAergic nTS-evoked inhibitory postsynaptic currents did not change by activation of the 5-HT1ARs, but spontaneous inhibitory nTS network activity decreased. Blocking 5-HT1ARs tended to increase nTS-evoked inhibitory postsynaptic currents and inhibitory network activity. Taken together, 5-HT1ARs in the caudal nTS decrease breathing, likely via attenuation of afferent transmission, as well as overall nTS network activity. PMID:24671532

  3. 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.

  4. Modulation of cholinergic functions by serotonin and possible implications in memory: general data and focus on 5-HT(1A) receptors of the medial septum.

    PubMed

    Jeltsch-David, Hélène; Koenig, Julie; Cassel, Jean-Christophe

    2008-12-16

    Cholinergic systems were linked to cognitive processes like attention and memory. Other neurotransmitter systems having minor influence on cognitive functions - as shown by the weakness of the effects of their selective lesions - modulate cholinergic functions. The serotonergic system is such a system. Conjoined functional changes in cholinergic and serotonergic systems may have marked cognitive consequences [Cassel JC, Jeltsch H. Serotoninergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69(1):1-41; Steckler T, Sahgal A. The role of serotoninergic-cholinergic interactions in the mediation of cognitive behaviour. Behav Brain Res 1995;67:165-99]. A crucial issue in that concern is the identification of the neuroanatomical and neuropharmacological substrates where functional effects of serotonergic/cholinergic interactions originate. Approaches relying on lesions and intracerebral cell grafting, on systemic drug-cocktail injections, or even on intracerebral drug infusions represent the main avenues on which our knowledge about the role of serotonergic/cholinergic interactions has progressed. The present review will visit some of these avenues and discuss their contribution to what is currently known on the potential or established implication(s) into memory functions of serotonergic/cholinergic interactions. It will then focus on a brain region and a neuropharmacological substrate that have been poorly studied as regards serotonergic modulation of memory functions, namely the medial septum and its 5-HT(1A) receptors. Based on recent findings of our laboratory, we suggest that these receptors, located on both cholinergic and GABAergic septal neurons, take part in a mechanism that controls encoding, to some extent consolidation, but not retrieval, of hippocampal-dependent memories. This control, however, does not occur by the way of an exclusive action of serotonin on cholinergic neurons.

  5. Traumatic Brain Injury-Induced Cognitive and Histological Deficits Are Attenuated by Delayed and Chronic Treatment with the 5-HT1A-Receptor Agonist Buspirone

    PubMed Central

    Olsen, Adam S.; Sozda, Christopher N.; Cheng, Jeffrey P.; Hoffman, Ann N.

    2012-01-01

    Abstract The aim of this study was to evaluate the potential efficacy of the serotonin1A (5-HT1A) receptor agonist buspirone (BUS) on behavioral and histological outcome after traumatic brain injury (TBI). Ninety-six isoflurane-anesthetized adult male rats were randomized to receive either a controlled cortical impact or sham injury, and then assigned to six TBI and six sham groups receiving one of five doses of BUS (0.01, 0.05, 0.1, 0.3, or 0.5 mg/kg) or saline vehicle (VEH, 1.0 mL/kg). Treatments began 24 h after surgery and were administered intraperitoneally once daily for 3 weeks. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative days 1–5 and 14–19, respectively. Morphologically intact CA1/CA3 cells and cortical lesion volume were quantified at 3 weeks. No differences were observed among the BUS and VEH sham groups in any end-point measure and thus the data were pooled. Regarding the TBI groups, repeated-measures ANOVAs revealed that the 0.3 mg/kg dose of BUS enhanced cognitive performance relative to VEH and the other BUS doses (p<0.05), but did not significantly impact motor function. Moreover, the same dose conferred selective histological protection as evidenced by smaller cortical lesions, but not greater CA1/CA3 cell survival. No significant behavioral or histological differences were observed among the other BUS doses versus VEH. These data indicate that BUS has a narrow therapeutic dose response, and that 0.3 mg/kg is optimal for enhancing spatial learning and memory in this model of TBI. BUS may have potential as a novel pharmacotherapy for clinical TBI. PMID:22416854

  6. 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…

  7. A new class of arylpiperazine derivatives: the library synthesis on SynPhase lanterns and biological evaluation on serotonin 5-HT(1A) and 5-HT(2A) receptors.

    PubMed

    Zajdel, Paweł; Subra, Gilles; Bojarski, Andrzej J; Duszyńska, Beata; Pawłowski, Maciej; Martinez, Jean

    2004-01-01

    An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide- and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT(1A) and 5-HT(2A) receptors (estimated K(i) = 24-4000 and 1-2130 nM, respectively). Several dual 5-HT(1A)/5-HT(2A) ligands were found, of which two (9(3,3) and 9(3,5)) displayed high 5-HT(2A) affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT(1A) and 5-HT(2A) affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT(1A) (chemset 17, R(2) = adamantyl) and 5-HT(2A) (chemset 9, R(2) = norborn-2-ylmethyl) binding sites.

  8. Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT(1A) receptors.

    PubMed

    Orús, Lara; Pérez-Silanes, Silvia; Oficialdegui, Ana-M; Martínez-Esparza, Javier; Del Castillo, Juan-C; Mourelle, Marisa; Langer, Thierry; Guccione, Salvatore; Donzella, Giuseppina; Krovat, Eva M; Poptodorov, Konstantin; Lasheras, Berta; Ballaz, Santiago; Hervías, Isabel; Tordera, Rosa; Del Río, Joaquín; Monge, Antonio

    2002-09-12

    It has been proposed that 5-HT(1A) receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT(1A) receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]thiophene derivatives to arylpiperazines, typical 5-HT(1A) receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT(1A) receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT(1A) receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K(i) < 50 nM) and the 5-HT(1A) receptors (K(i) < 20 nM) were further explored for their ability to stimulate [(35)S]GTPgammaS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [(35)]GTPgammaS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT(1A) receptors, respectively. Compound 8g exhibited agonist activity (EC(50) = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,l antagonized the R(+)-8-OH

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

    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.

  10. The theta-related firing activity of parvalbumin-positive neurons in the medial septum-diagonal band of Broca complex and their response to 5-HT1A receptor stimulation in a rat model of Parkinson's disease.

    PubMed

    Li, Li-Bo; Han, Ling-Na; Zhang, Qiao-Jun; Sun, Yi-Na; Wang, Yong; Feng, Jie; Zhang, Li; Wang, Tao; Chen, Li; Liu, Jian

    2014-03-01

    The parvalbumin (PV)-positive neurons in the medial septum-diagonal band of Broca complex (MS-DB) play an important role in the generation of hippocampal theta rhythm involved in cognitive functions. These neurons in this region express a high density of 5-HT1A receptors which regulate the neuronal activity and consequently affect the theta rhythm. In this study, we examined changes in the theta-related firing activity of PV-positive neurons in the MS-DB, their response to 5-HT1A receptor stimulation and the corresponding hippocampal theta rhythm, and the density of PV-positive neurons and their co-localization with 5-HT1A receptors in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc decreased the rhythmically bursting activity of PV-positive neurons and the peak frequency of hippocampal theta rhythm. Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.5-128 µg/kg, i.v.) inhibited the firing rate of PV-positive neurons and disrupted rhythmically bursting activity of the neurons and the theta rhythm in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition and disruption in the lesioned rats were higher than that of sham-operated rats. Furthermore, local application of 8-OH-DPAT (0.005 μg) in the MS-DB also inhibited the firing rate of PV-positive neurons and disrupted their rhythmically bursting activity in sham-operated rats, while having no effect on PV-positive neurons in the lesioned rats. The lesion of the SNc decreased the density of PV-positive neurons in the MS-DB, and percentage of PV-positive neurons expressing 5-HT1A receptors. These results indicate that the lesion of the SNc leads to suppression of PV-positive neurons in the MS-DB and hippocampal theta rhythm. Furthermore, the lesion decreases the response of these neurons to 5-HT1A receptor stimulation, which attributes to dysfunction and/or down-regulation of 5-HT1A receptor expression on these

  11. Effects of 5-HT1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

    PubMed Central

    2013-01-01

    Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia. PMID:23496922

  12. Aggression-reducing effects of F15599, a novel selective 5-HT1A receptor agonist, after microinjection into the ventral orbital prefrontal cortex, but not in infralimbic cortex in male mice

    PubMed Central

    Stein, Dirson João; Miczek, Klaus A.; Lucion, Aldo Bolten

    2014-01-01

    Background The 5-HT1A receptor subtype has been postulated to modulate aggressive behavior particularly when it is excessive. F15599 is a high affinity and selective 5-HT1A receptor agonist that exhibits biased agonism for postsynaptic receptors that are preferentially coupled to Gαi3 protein subunits, with more potent action in the cortex, and with potential for selectively reducing aggression. Objectives and methods The aims of the current study were to investigate the anti-aggressive effects of the novel 5-HT1A receptor agonist, F15599, microinjected into the ventral orbital prefrontal cortex (VO PFC) and into the infralimbic cortex (ILC) of CF-1 male mice that had been previously socially provoked and to confirm the specific action at this receptor by blocking its effects using the 5-HT1A receptor antagonist, WAY100,635. Results Microinjection of the lower doses of F15599 (0.03 and 0.1 μg) into the VO PFC, but not into the ILC, significantly reduced the frequency of attack bites and sideways threats, without affecting other elements of the behavioral repertoire related to aggression such as pursuing and sniffing the intruder and tail rattle. There were also no changes observed in the duration of walking and rearing. Pretreatment with WAY100,635 prevented the anti-aggressive effects of F15599 when microinjected into VO PFC. Conclusions The present results demonstrated that F15599 is effective in reducing the most intense behavioral elements of aggressive behavior in male mice, when microinjected into the VO PFC, but not into the ILC, without affecting nonaggressive behavior, and confirmed the critical role of this cortical region and specifically the 5-HT1A heteroreceptors in the modulation of escalated aggressive behavior. PMID:23828155

  13. Enhanced reactivity of 5-HT1A receptors in the rat dorsal periaqueductal gray matter after chronic treatment with fluoxetine and sertraline: evidence from the elevated T-maze.

    PubMed

    Zanoveli, Janaina Menezes; Nogueira, Regina Lúcia; Zangrossi, Hélio

    2007-03-01

    Behavioral evidence indicates that sensitization of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal gray (DPAG) may underlie the therapeutic effect of serotonin reuptake inhibitors (SRIs) in panic disorder. These results were obtained from studies using animal models that associate escape behavior with panic attacks, such as the elevated T-maze. In this test, chronic administration of the non-selective SRI imipramine enhances the inhibitory effect on escape caused by the intra-DPAG injection of the 5-HT1A receptor agonist 8-OH-DPAT. We here evaluated the generality of this finding by investigating the effect of chronic administration of two selective SRIs (SSRIs), fluoxetine and sertraline, on the reactivity of the rat DPAG 5-HT1A receptors. The results showed that both SSRIs inhibited escape behavior in the elevated T-maze, suggestive of a panicolytic-like effect. Whereas intra-DPAG injection of a low dose of 8-OH-DPAT (0.4nmol) had no effect on escape in control animals, it significantly enhanced the inhibitory effect caused by the SSRIs on this response. Microinjection of 8-OH-DPAT in SSRI-treated rats also inhibited the acquisition of inhibitory avoidance, another defensive response measured by the elevated T-maze. The results indicate that chronic administration of fluoxetine and sertraline sensitizes 5-HT1A receptors in the DPAG. Overall, they support the view that facilitation of 5-HT1A receptor-mediated neurotransmission in the DPAG is implicated in the therapeutic effect of SRIs on panic disorder.

  14. Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins.

    PubMed

    Raap, D K; Evans, S; Garcia, F; Li, Q; Muma, N A; Wolf, W A; Battaglia, G; Van De Kar, L D

    1999-01-01

    The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins.

  15. WB 4101-related compounds. 2. Role of the ethylene chain separating amine and phenoxy units on the affinity for alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors.

    PubMed

    Bolognesi, M L; Budriesi, R; Cavalli, A; Chiarini, A; Gotti, R; Leonardi, A; Minarini, A; Poggesi, E; Recanatini, M; Rosini, M; Tumiatti, V; Melchiorre, C

    1999-10-07

    WB 4101 (1)-related benzodioxanes were synthesized by replacing the ethylene chain separating the amine and the phenoxy units of 1 with a cyclopentanol moiety, a feature of 6, 7-dihydro-5-[[(cis-2-hydroxy-trans-3-phenoxycyclopentyl)amino]meth yl] -2-methylbenzo[b]thiophen-4(5H)-one that was reported to display an intriguing selectivity profile at alpha(1)-adrenoreceptors. This synthesis strategy led to 4 out of 16 possible stereoisomers, which were isolated in the case of (-)-3, (+)-3, (-)-4, and (+)-4 and whose absolute configuration was assigned using a chiral building block for the synthesis of (-)-3 starting from (+)-(2R)-2, 3-dihydro-1,4-benzodioxine-2-carboxylic acid ((+)-9) and (1S,2S, 5S)-2-amino-5-phenoxycyclopentan-1-ol ((+)-10). The aim of this project was to further investigate whether it is possible to differentiate between these compounds with respect to their affinity for alpha(1)-adrenoreceptor subtypes and the affinity for 5-HT(1A) receptors, as 1 binds with high affinity at both receptor systems. The biological profiles of reported compounds at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO and HeLa cells membranes expressing the human cloned alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors, respectively. Furthermore, the functional activity of (-)-3, (+)-3, (-)-4, and (+)-4 toward 5-HT(1A) receptors was evaluated by determining the induced stimulation of [(35)S]GTPgammaS binding in cell membranes from HeLa cells transfected with human cloned 5-HT(1A) receptors. The configuration of the cyclopentane unit determined the affinity profile: a 1R configuration, as in (+)-3 and (-)-4, conferred higher affinity at alpha(1)-adrenoreceptors, whereas a 1S configuration, as in (-)-3 and (+)-4, produced higher affinity for 5-HT(1A) receptors. For the enantiomers (+)-4 and (-)-4 also a remarkable selectivity was

  16. 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.

  17. Synthesis, docking studies and biological evaluation of benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives on 5-HT1A serotonin receptors.

    PubMed

    Pessoa-Mahana, Hernán; Recabarren-Gajardo, Gonzalo; Temer, Jenny Fiedler; Zapata-Torres, Gerald; Pessoa-Mahana, C David; Barría, Claudio Saitz; Araya-Maturana, Ramiro

    2012-02-03

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

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

    PubMed

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

    2015-10-01

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

  19. The highly-selective 5-HT(1A) agonist F15599 reduces L-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque.

    PubMed

    Huot, Philippe; Johnston, Tom H; Fox, Susan H; Newman-Tancredi, Adrian; Brotchie, Jonathan M

    2015-10-01

    L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective anti-parkinsonian agent available, but upon chronic administration, patients with Parkinson's disease (PD) experience abnormal involuntary movements, dyskinesia. Modulation of serotonin 1A (5-HT1A) receptors is regarded as an effective way to alleviate dyskinesia, yet this approach has been marred by a reduction of the therapeutic effectiveness of L-DOPA. We hypothesised that highly-selective 5-HT1A stimulation might be a way to alleviate dyskinesia without compromising L-DOPA anti-parkinsonian action. F15599 (also known as NLX-101) is a highly-selective 5-HT1A agonist that displays over 1000 × selectivity over off-target receptors. Seven cynomolgus macaques were administered MPTP and developed severe parkinsonism. Following chronic administration of L-DOPA, they developed severe and reproducible dyskinesia. F15599 (0.003, 0.01, 0.03 and 0.1 mg/kg) or vehicle was administered in combination with L-DOPA and its effect on dyskinesia and L-DOPA anti-parkinsonian was assessed. In combination with L-DOPA, F15599 (0.1 mg/kg) reduced the severity of peak-dose dyskinesia, by ≈45% (P < 0.001), compared to L-DOPA alone. F15599 (any dose) had no effect on duration of on-time or motor activity counts compared to L-DOPA alone. F15599 at 0.03 and 0.1 mg/kg significantly reduced duration of on-time with disabling dyskinesia (by ≈49% and ≈71%, P < 0.05 and P < 0.001, respectively). These results suggest that F15599, a highly-selective 5-HT1A receptor agonist, alleviates dyskinesia without exerting a deleterious effect on L-DOPA anti-parkinsonian action.

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

    PubMed

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

    2017-02-01

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

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

  2. 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

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

    PubMed

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

    2006-06-01

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

  4. 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.

  5. Social instigation and aggression in postpartum female rats: role of 5-Ht1A and 5-Ht1B receptors in the dorsal raphé nucleus and prefrontal cortex

    PubMed Central

    da Veiga, Caroline Perinazzo; Miczek, Klaus A.; Lucion, Aldo Bolten

    2013-01-01

    Rationale 5-HT1A and 5-HT1B receptor agonists effectively reduce aggressive behavior in males that has been escalated by social instigation. Important sites of action for these drugs are the receptors in dorsal raphé nuclei (DRN) and the ventral–orbital prefrontal cortex (VO PFC). DRN and VO PFC areas are particularly relevant in the inhibitory control of escalated aggressive and impulsive behavior. Objectives The objectives of this study are to assess the anti-aggressive effects of 5-HT1A (8-OH-DPAT) and 5-HT1B (CP-93,129) receptor agonists microinjected into DRN and VO PFC, respectively, and to study the aggressive behavior in postpartum female Wistar rats using the social instigation protocol to increase aggression. Methods and Results 8-OH-DPAT (0.56 µg) in the DRN increased aggressive behavior in postpartum female rats. By contrast, CP-93,129 (1.0 µg) microinjected into VO PFC decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming and the latter increasing these acts. When 8-OH-DPAT was microinjected into DRN and CP-93,129 was microinjected into VO PFC in female rats at the same time, maternal aggression decreased. Specific participation of 5-HT1B receptors was verified by reversal of the anti-aggressive effects using the selective antagonist SB-224,289 (1.0 µg). Conclusions The decrease in maternal aggressive behavior after microinjections of 5-HT1B receptor agonists into the VO PFC and DRN of female postpartum rats that were instigated socially supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner, due to activation of 5-HT1B receptors at the soma and terminals. PMID:21107539

  6. Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635.

    PubMed

    Bagdy, G; Graf, M; Anheuer, Z E; Modos, E A; Kantor, S

    2001-12-01

    The possible role of 5-HT1A and 5-HT2C receptors in the anxiety induced by fear, acute treatment with SSRI antidepressants or the 5-HT receptor agonist m-CPP were tested in the social interaction anxiety test in male Sprague-Dawley rats. Fluoxetine (2.5-10 mg/kg, i.p.), sertraline (15 mg/kg, i.p.) and m-CPP (0.5-2.0 mg/kg, i.p.) all had an anxiogenic-like profile (decrease in time of total social interaction and increase in self-grooming compared to vehicle) under low-light, familiar arena test conditions. All these effects were reversed by pretreatment with the highly subtype-selective 5-HT2C receptor antagonist, SB-242084 at doses of either 0.05 or 0.2 mg/kg, i.p. In contrast, the selective 5-HT1A receptor antagonist WAY-100635 (0.05 and 0.2 mg/kg, s.c.) failed to reverse SSRI-induced decrease in time of total social interaction, further, it augmented self-grooming response. SB-242084 (0.2 mg/kg) and WAY-100635 (0.05 and 0.2 mg/kg) reversed hypolocomotion caused by the SSRI antidepressants. SB-242084, tested alone against vehicle under high-light, unfamiliar arena test conditions associated with fear, caused significant anxiolysis at 0.2 mg/kg and higher doses. These results suggest that increased anxiety in rodents, and possibly, also in humans (e.g. agitation or jitteriness after SSRIs and panic after m-CPP), caused by acute administration of SSRI antidepressants or m-CPP, are mediated by activation of 5-HT2C receptors. Blockade of 5-HT1A autoreceptors may exacerbate certain acute adverse effects of SSRI antidepressants. Both 5-HT1A and 5-HT2C receptors are involved in the SSRI-induced decrease in locomotor activity. In addition, our studies confirm data that subtype-selective 5-HT2C receptor antagonists have strong anxiolytic actions.

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

    PubMed

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

    2017-01-05

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

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

    PubMed

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

    2009-05-16

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

  9. 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.

  10. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha 1-adrenoceptors.

    PubMed

    Tachibana, Kaori; Matsumoto, Machiko; Togashi, Hiroko; Kojima, Taku; Morimoto, Yuji; Kemmotsu, Osamu; Yoshioka, Mitsuhiro

    2004-03-04

    Pharmacological characteristics of a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI), milnacipran, in modulation of the synaptic plasticity were investigated. Milnacipran (30 mg/kg, i.p.) suppressed the long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Milnacipran-induced suppression was reversed by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, i.v.) or the alpha1-adrenoceptor antagonist prazosin (1 and 10 microg/rat, i.c.v.). The alpha2-adrenoceptor antagonist idazoxan (5 mg/kg, i.p.) did not influence the milnacipran-induced synaptic responses. These data suggest that the inhibitory effects of milnacipran on LTP induction are mediated via both 5-HT1A receptors and alpha1-adrenoceptors. In other words, functional interaction between the serotonergic and noradrenergic neuronal systems is involved in alteration of the hippocampal synaptic plasticity, which may be implicated in the SNRI-induced therapeutic effect on psychiatric disorders.

  11. Short-term effect on intestinal epithelial Na(+)/H(+) exchanger by Gi(alpha1,2)-coupled 5-HT(1A) and G(q/11)-coupled 5-HT(2) receptors.

    PubMed

    Magro, Fernando; Fraga, Sónia; Soares-da-Silva, Patrício

    2007-07-26

    The present study evaluated the effect of 5-hydroxytryptamine (5-HT) on intestinal Na(+)/H(+) exchanger (NHE) activity and the cellular signaling pathways involved in T84 cells. T84 cells express endogenous NHE1 and NHE2 proteins, detected by immunoblotting, but not NHE3. The rank order for inhibition of NHE activity in acid-loaded T84 cells was 5-(N-ethyl-N-isopropyl)-amiloride (EIPA; IC(50)=519 [465, 579] nM)>cariporide (IC(50)=630 [484, 819] nM)>amiloride (IC(50)=19 [16, 24] microM); the NHE3 inhibitor S3226 was found to be devoid of effect. This different inhibitory sensitivity indicates that both NHE1 and NHE2 isoforms may play an active role in Na(+)-dependent intracellular pH (pH(i)) recovery in T84 cells. Short-term exposure (0.5 h) of T84 cells to 5-HT increased NHE activity in a concentration-dependent manner. The stimulation induced by 5-HT (30 microM) was partially inhibited by both WAY 100135 (300 nM) and ketanserin (300 nM), antagonists of 5-HT(1A) and 5-HT(2) receptors, respectively. NHE activity was significantly increased by 8-OH-DPAT and alpha-methyl-5-HT, agonists of, respectively, 5-HT(1A) and 5-HT(2) receptors. An incubation of T84 cells with anti-G(s) and anti-G(beta) antibodies complexed with lipofectin did not prevent the 5-HT-induced stimulation of NHE activity. Overnight treatment with anti-G(ialpha1,2) and anti-G(q/11) antibodies complexed with lipofectin blocked the stimulatory effect induced by 8-OH-DPAT and alpha-methyl-5-HT, respectively. It is concluded that in T84 cells 5-HT enhances intestinal NHE activity through stimulation of G(ialpha1,2)-coupled 5-HT(1A) and G(q/11)-coupled 5-HT(2) receptors.

  12. The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

    PubMed

    Korte, S Mechiel; Prins, Jolanda; Van den Bergh, Filip S; Oosting, Ronald S; Dupree, Rudy; Korte-Bouws, Gerdien A H; Westphal, Koen G C; Olivier, Berend; Denys, Damiaan A; Garland, Alexis; Güntürkün, Onur

    2017-01-05

    The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.

  13. 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

    2015-10-05

    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.

  14. 5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus.

    PubMed

    Freitas, Renato Leonardo; Ferreira, Célio Marcos dos Reis; Urbina, Maria Angélica Castiblanco; Mariño, Andrés Uribe; Carvalho, Andressa Daiane; Butera, Giuseppe; de Oliveira, Ana Maria; Coimbra, Norberto Cysne

    2009-05-01

    Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 microg/0.2 microL) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception.

  15. Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors.

    PubMed

    Frick, Luciana Romina; Bernardez-Vidal, Micaela; Hocht, Christian; Zanutto, Bonifacio Silvano; Rapanelli, Maximiliano

    2015-01-15

    Serotonin (5-HT) has been proposed as a possible encoder of reward. Nevertheless, the role of this neurotransmitter in reward-based tasks is not well understood. Given that the major serotonergic circuit in the rat brain comprises the dorsal raphe nuclei and the medial prefrontal cortex (mPFC), and because the latter structure is involved in the control of complex behaviors and expresses 1A (5-HT1A), 2A (5-HT2A), and 3 (5-HT3) receptors, the aim was to study the role of 5-HT and of these receptors in the acquisition and extinction of a reward-dependent operant conditioning task. Long Evans rats were trained in an operant conditioning task while receiving fluoxetine (serotonin reuptake inhibitor, 10mg/kg), tianeptine (serotonin reuptake enhancer, 10mg/kg), buspirone (5-HT1A partial agonist, 10mg/kg), risperidone (5-HT2A antagonist, 1mg/kg), ondansetron (5-HT3 antagonist, 2mg/kg) or vehicle. Then, animals that acquired the operant conditioning without any treatment were trained to extinct the task in the presence of the pharmacological agents. Fluoxetine impaired acquisition but improved extinction. Tianeptine administration induced the opposite effects. Buspirone induced a mild deficit in acquisition and had no effects during the extinction phase. Risperidone administration resulted in learning deficits during the acquisition phase, although it promoted improved extinction. Ondansetron treatment showed a deleterious effect in the acquisition phase and an overall improvement in the extinction phase. These data showed a differential role of 5-HT in the acquisition and extinction of an operant conditioning task, suggesting that it may have a dual function in reward encoding.

  16. Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the “Two Hit” Hypothesis for the Development of Schizophrenia

    PubMed Central

    Dalton, Victoria S.; Verdurand, Mathieu; Walker, Adam; Hodgson, Deborah M.; Zavitsanou, Katerina

    2012-01-01

    Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia. PMID:23738203

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

    PubMed

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

    2017-01-05

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

  18. Galanin (1-15) enhances the antidepressant effects of the 5-HT1A receptor agonist 8-OH-DPAT: involvement of the raphe-hippocampal 5-HT neuron system.

    PubMed

    Millón, Carmelo; Flores-Burgess, Antonio; Narváez, Manuel; Borroto-Escuela, Dasiel O; Santín, Luis; Gago, Belen; Narváez, José Angel; Fuxe, Kjell; Díaz-Cabiale, Zaida

    2016-12-01

    Galanin N-terminal fragment (1-15) [GAL(1-15)] is associated with depression-related and anxiogenic-like effects in rats. In this study, we analyzed the ability of GAL(1-15) to modulate 5-HT1A receptors (5-HT1AR), a key receptor in depression. GAL(1-15) enhanced the antidepressant effects induced by the 5-HT1AR agonist 8-OH-DPAT in the forced swimming test. These effects were stronger than the ones induced by Galanin (GAL). This action involved interactions at receptor level since GAL(1-15) affected the binding characteristics and the mRNA levels of 5-HT1AR in the dorsal hippocampus and dorsal raphe. The involvement of the GALR2 was demonstrated with the GALR2 antagonist M871. Proximity ligation assay experiments indicated that 5-HT1AR are in close proximity with GALR1 and GALR2 in both regions and in raphe RN33B cells. The current results indicate that GAL(1-15) enhances the antidepressant effects induced by 8-OH-DPAT acting on 5-HT1AR operating as postjunctional or as autoreceptors. These results may give the basis for the development of drugs targeting potential GALR1-GALR2-5-HT1AR heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons for the treatment of depression.

  19. 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.

  20. A delayed and chronic treatment regimen with the 5-HT1A receptor agonist 8-OH-DPAT after cortical impact injury facilitates motor recovery and acquisition of spatial learning

    PubMed Central

    Cheng, Jeffrey P.; Hoffman, Ann N.; Zafonte, Ross D.; Kline, Anthony E.

    2008-01-01

    An early (i.e., 15 min) single systemic administration of the 5-HT1A receptor agonist 8-OH-DPAT enhances behavioral recovery after experimental traumatic brain injury (TBI). However, acute administration of pharmacotherapies after TBI may be clinically challenging and thus the present study sought to investigate the potential efficacy of a delayed and chronic 8-OH-DPAT treatment regimen. Forty-eight isoflurane-anesthetized adult male rats received either a controlled cortical impact or sham injury and beginning 24 hrs later were administered 8-OH-DPAT (0.1 or 0.5 mg/kg) or saline vehicle (1.0 mL/kg) intraperitoneally once daily until all behavioral assessments were completed. Neurobehavior was assessed by motor and cognitive tests on post-operative days 1–5 and 14–19, respectively. The lower dose of 8-OH-DPAT (0.1 mg/kg) enhanced motor performance, acquisition of spatial learning, and memory retention vs. both the higher dose (0.5 mg/kg) and vehicle treatment (p < 0.05). These data replicate previous findings from our laboratory showing that 8-OH-DPAT improves neurobehavior after TBI, and extend those results by demonstrating that the benefits can be achieved even when treatment is withheld for 24 hrs. A delayed and chronic treatment regimen may be more clinically feasible. PMID:18638506

  1. Effects of GABA(B), 5-HT(1A), and 5-HT(2) receptor stimulation on activation and inhibition of the rat lateral amygdala following medial geniculate nucleus stimulation in vivo.

    PubMed

    Sokal, David M; Giarola, Alessandra S; Large, Charles H

    2005-01-07

    The input from the medial geniculate nucleus of the thalamus (MGN) to the lateral amygdala is known to be important in the regulation of fear and anxiety. Modulation of this pathway may be useful for the treatment of anxiety disorders. We set out to determine whether simple extracellular electrophysiological techniques could be used to study pharmacological modulation of this pathway in vivo. We studied the effects of GABA(B), 5-HT(1), and 5-HT(2) receptor agonists on activity in the lateral amygdala following stimulation of the MGN in isoflurane-anaesthetised rats. Electrical stimulation of the MGN evoked a characteristic biphasic field potential in the lateral amygdala. Baclofen (10 mg kg(-1), iv) inhibited the evoked potential with an effect that was most marked on the positive-going component (80+/-9% inhibition; P<0.05). Baclofen also significantly reduced paired-pulse inhibition of the negative-going component at short interpulse intervals (<200 ms). The 5-HT(1A) receptor ligands, 8-OH-DPAT (60 microg kg(-1), iv) and WAY-100635 (0.5 mg kg(-1), iv) were without effect on evoked responses or paired-pulse relationship. In contrast, the 5-HT(2) receptor agonist, DOI, caused a rapid inhibition of the field potential (to 59.33+/-11.41% of the baseline response; P<0.05). This effect was blocked by ketanserin, either following systemic (0.5 mg kg(-1), iv) or intra-amygdala administration. These results show that GABA(B) and 5-HT(2) receptor agonists can modulate activation of the lateral amygdala following MGN stimulation; furthermore, GABA(B) receptor agonists appear to have a profound effect on local circuit inhibition within the lateral amygdala. The results support the use of in vivo field potential recording within the MGN-lateral amygdala pathway to evaluate this as a possible site of action for novel anxiolytic drugs.

  2. Omega-3 Fatty Acid Deficient Male Rats Exhibit Abnormal Behavioral Activation in the Forced Swim Test Following Chronic Fluoxetine Treatment: Association with Altered 5-HT1A and Alpha2A Adrenergic Receptor Expression

    PubMed Central

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

    2014-01-01

    Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n=34) or without (DEF, n=30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n=14) and DEF (n=12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (−26%, p=0.0001) and DEF+FLX (−32%, p=0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF+FLX rats exhibited significantly greater climbing behavior compared with CON+FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF+FLX rats exhibited significant elevations in climbing behavior. DEF+FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON+FLX rats. DEF+FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats. PMID:24360505

  3. (6aR)-11-amino-N-propyl-noraporphine, a new dopamine D2 and serotonin 5-HT1A dual agonist, elicits potent antiparkinsonian action and attenuates levodopa-induced dyskinesia in a 6-OHDA-lesioned rat model of Parkinson's disease.

    PubMed

    Zhao, Rui; Lu, Weijian; Fang, Xing; Guo, Lin; Yang, Zhi; Ye, Na; Zhao, Jiahao; Liu, Zhili; Jia, Jia; Zheng, Longtai; Zhao, Bin; Zhang, Ao; Zhen, Xuechu

    2014-09-01

    Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa-induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT1A receptors may provide a novel approach for drug development in PD and LID.

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

    PubMed

    Meneses, Alfredo

    2007-11-22

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

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2011-08-01

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

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

    PubMed

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

    2015-04-01

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

  8. Genetic Polymorphism of 1019C/G (rs6295) Promoter of Serotonin 1A Receptor and Catechol-O-Methyltransferase in Panic Disorder

    PubMed Central

    Ishiguro, Shin; Aoki, Akiko; Ueda, Mikito; Hayashi, Yuki; Akiyama, Kazufumi; Kato, Kazuko; Shimoda, Kazutaka

    2017-01-01

    Objective Family and twin studies have suggested genetic liability for panic disorder (PD) and therefore we sought to determine the role of noradrenergic and serotonergic candidate genes for susceptibility for PD in a Japanese population. Methods In this age- and gender-matched case-control study involving 119 PD patients and 119 healthy controls, we examined the genotype distributions and allele frequencies of the serotonin transporter gene linked polymorphic region (5-HTTLPR), −1019C/G (rs6295) promoter polymorphism of the serotonin receptor 1A (5-HT1A), and catechol-O-methyltransferase (COMT) gene polymorphism (rs4680) and their association with PD. Results No significant differences were evident in the allele frequencies or genotype distributions of the COMT (rs4680), 5-HTTLPR polymorphisms or the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients and controls. Although there were no significant associations of these polymorphisms with in subgroups of PD patients differentiated by gender or in subgroup comorbid with agoraphobia (AP), significant difference was observed in genotype distributions of the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients without AP and controls (p=0.047). Conclusion In this association study, the 1019C/G (rs6295) promoter polymorphism of the 5-HT1A receptor G/G genotype was associated with PD without AP in a Japanese population. PMID:28096880

  9. Effect of serotonin-related gene polymorphisms on pathogenesis and treatment response in Korean schizophrenic patients.

    PubMed

    Kim, Yong-Ku; Yoon, Ho-Kyoung

    2011-09-01

    Serotonin has been implicated in the pathophysiology of several psychiatric disorders including schizophrenia. Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. We aimed to investigate the associations of HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T variants with schizophrenia. A total of 202 patients with schizophrenia and 165 normal controls were genotyped for HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T single nucleotide polymorphisms (SNPs). In order to assess the severity of a patient's psychiatric symptoms, the brief psychiatric rating scale (BPRS), the positive and negative symptom scale (PANSS), and the Calgary depression scale for Schizophrenia (CDSS) were administered. Genotype and allele frequencies were compared between groups via χ(2) statistics. Associations between the genotypes of candidate SNPs with the severity of symptoms were examined with ANOVA by comparing the mean scores of BPRS, PANSS, and CDSS according to genotype. No significant differences in the genotype distributions and allele frequencies of four SNPs were found between patients with schizophrenia and normal controls. There was a trend towards association of HTR1A C-1019G polymorphism with negative symptom. Negative symptom score of PANSS was lower in the patients with CC genotype than in the G allele carriers. These results suggested that C allele might be associated with lesser negative symptom. More studies are needed to confirm these findings. In the future, we plan to study the associations between schizophrenia and other genetic polymorphisms.

  10. Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.

    PubMed

    Masellis, M; Basile, V S; Meltzer, H Y; Lieberman, J A; Sevy, S; Goldman, D A; Hamblin, M W; Macciardi, F M; Kennedy, J L

    2001-01-15

    The affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group (n=185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT6 (HTR6), 5-HT1A (HTR1A) and 5-HT7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi(2)=0.06, 1 df, P=0.80; genotype: chi(2)=1.21, 2 df, P=0.55). The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes. With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype). This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T-->C 267 polymorphism of the 5-HT6 receptor gene in response to clozapine, although replication is required to confirm this finding.

  11. Single nucleotide polymorphisms and suicidal behaviour.

    PubMed

    Pregelj, Peter

    2012-09-01

    The World Health Organization estimates that almost one million deaths each year are attributable to suicide, and suicide attempt is close to 10 times more common than suicide completion. Suicidal behaviour has multiple causes that are broadly divided into proximal stressors or triggers and predisposition such as genetic. It is also known that single nucleotide polymorphisms (SNPs) occur throughout a human DNA influencing the structure, quantity and the function of proteins and other molecules. Abnormalities of the serotonergic system were observed in suicide victims. Beside 5-HT1A and other serotonin receptors most studied are the serotonin transporter 5' functional promoter variant, and monoamine oxidase A and the tryptophan-hydroxylase 1 and 2 (TPH) polymorphisms. It seems that especially genes regulating serotoninergic system and neuronal systems involved in stress response are associated with suicidal behaviour. Most genetic studies on suicidal behaviour have considered a small set of functional polymorphisms relevant mostly to monoaminergic neurotransmission. However, genes involved in regulation of other factors such as brain-derived neurotropic factor seems to be even more relevant for further research.

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

    PubMed

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

    2015-01-01

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

  13. Potentiation of the time-dependent, antidepressant-induced changes in the agonistic behaviour of resident rats by the 5-HT1A receptor antagonist, WAY-100635.

    PubMed

    Mitchell, P J; Redfern, P H

    1997-11-01

    Acute and chronic antidepressant drug treatments respectively decrease and increase the aggressive behaviour of resident rats during encounters with unfamiliar conspecifics. We have now examined the effect of the 5-hydroxytryptamine1A receptor antagonist, WAY-100635, on fluoxetine-, paroxetine- or venlafaxine-induced changes in aggression. WAY-100635 (0.1 mg/kg), which did not modify behaviour when given alone, potentiated the venlafaxine (5.54 mg/kg)-induced reduction in aggression after acute treatment and, during chronic treatment, accelerated the fluoxetine (0.34 mg/kg/day)-induced increase in aggression, from day 5 to day 2. A similar change in time course was seen with paroxetine (0.33 mg/kg/day), although the increase in aggression was smaller. Venlafaxine (5.54 mg/kg/day, alone or co-administered with WAY-100635) increased aggression by day 2. During chronic treatment, therefore, venlafaxine, at the dose used, had a more rapid onset of action than either fluoxetine or paroxetine, whereas the fluoxetine- and paroxetine-, but not the venlafaxine-, induced increase in aggression was accelerated by WAY-100635. These studies further support the hypothesis that selective blockade of the 5-hydroxytryptamine1A receptor augments the effects of antidepressant drugs in an animal model predictive of antidepressant activity, presumably by concomitant blockade of the somatodendritic 5-hydroxytryptamine1A autoreceptor-mediated negative feedback system of serotonergic neurones.

  14. RU 24969-induced emesis in the cat - 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1C implicated

    NASA Technical Reports Server (NTRS)

    Lucot, James B.

    1990-01-01

    RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of nonspecific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (-)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect argument is presented that implicates a role for 5-HT1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.

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

    PubMed Central

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

    2015-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA) are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes. PMID:26300776

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

    PubMed

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

    2015-01-01

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

  17. Suicide, stress and serotonin receptor 1A promoter polymorphism -1019C>G in Slovenian suicide victims.

    PubMed

    Videtic, Alja; Zupanc, Tomaz; Pregelj, Peter; Balazic, Joze; Tomori, Martina; Komel, Radovan

    2009-06-01

    Implication of serotonergic system in suicide and suicide attempts has been discussed for several years. One of the most abundant serotonin receptors in the mammalian brain is the receptor 1A (5-HT1A); studies of its polymorphisms and suicide have provided very inconsistent results so far. The suggestion that the G allele depresses HTR1A autoreceptor expression, and therefore reduces serotonergic neurotransmission that might predispose to depression and suicide, made the promoter polymorphism -1019C>G a very promising candidate gene. In our study we analyzed promoter polymorphism -1019C>G on 323 suicide victims and 190 controls (all of Slovenian origin), taking into account sex, suicide method, and in case of suicide victims also stressful life events. Differences in the distributions of genotype and allele frequencies were not statistically significant between suicide victims and control group, and the same was found for distributions according to sex and suicide method. For 62 suicide victims information about stressful life events in the month prior to the suicide and in childhood was provided. For analysis we combined CG/GG genotypes and compared them to the CC genotype. More stressful life events in the month prior to the suicide were reported for the subgroup with CC genotype (mean number of events = 2.53; SD = 1.50) in comparison to subgroup with CG/GG genotypes (mean number of events = 1.58; SD = 1.32; P < 0.05). However, subgroups of suicide victims with CC or CG/GG genotypes did not differ regarding numbers of reported stressful life events in childhood (P > 0.05). Our study provides no evidence for the implication of HTR1A promoter polymorphism in suicide in general, but it suggests further studies that would take into account the interconnected network of suicide completion, genetic background and stress, beside other risk factors.

  18. Marmoset Serotonin 5-HT1A Receptor Mapping with a Biased Agonist PET Probe 18F-F13714: Comparison with an Antagonist Tracer 18F-MPPF in Awake and Anesthetized States

    PubMed Central

    Yokoyama, Chihiro; Mawatari, Aya; Kawasaki, Akihiro; Takeda, Chiho; Onoe, Kayo; Doi, Hisashi; Newman-Tancredi, Adrian; Zimmer, Luc

    2016-01-01

    Background: In vivo mapping by positron emission tomography of the serotonin 1A receptors has been hindered by the lack of suitable agonist positron emission tomography probes. 18F-labeled F13714 is a recently developed biased agonist positron emission tomography probe that preferentially targets subpopulations of serotonin 1A receptors in their “active state,” but its brain labeling pattern in nonhuman primate has not been described. In addition, a potential confound in the translatability of PET data between nonhuman animal and human arise from the use of anesthetics that may modify the binding profiles of target receptors. Methods: Positron emission tomography scans were conducted in a cohort of common marmosets (n=4) using the serotonin 1A receptor biased agonist radiotracer, 18F-F13714, compared with a well-characterized 18F-labeled antagonist radiotracer, 18F-MPPF. Experiments on each animal were performed under both consciousness and isoflurane-anesthesia conditions. Results: 18F-F13714 binding distribution in marmosets by positron emission tomography differs markedly from that of the 18F-MPPF. Whereas 18F-MPPF showed highest binding in hippocampus and amygdala, 18F-F13714 showed highest labeling in other regions, including insular and cingulate cortex, thalamus, raphe, caudate nucleus, and putamen. The binding potential values of 18F-F13714 were about one-third of those observed with 18F-MPPF, with marked individual- and region-specific differences under isoflurane-anesthetized vs conscious conditions. Conclusions: These findings highlight the importance of investigating the brain imaging of serotonin 1A receptors using agonist probes such as 18F-F13714, which may preferentially target subpopulations of serotonin 1A receptors in specific brain regions of nonhuman primate as a biased agonist. PMID:27608810

  19. Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by L-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease.

    PubMed

    Lindenbach, David; Dupre, Kristin B; Eskow Jaunarajs, Karen L; Ostock, Corinne Y; Goldenberg, Adam A; Bishop, Christopher

    2013-11-06

    Motor symptoms of Parkinson's disease are commonly treated using l-DOPA although long-term treatment usually causes debilitating motor side effects including dyskinesias. A putative source of dyskinesia is abnormally high levels of phosphorylated extracellular-regulated kinase (pERK) within the striatum. In animal models, the serotonin 1A receptor agonist ±8-OH-DPAT reduces dyskinesia, suggesting it may exhibit efficacy through the pERK pathway. The present study investigated the effects of ±8-OH-DPAT on pERK density in rats treated with l-DOPA or the D1 receptor agonist SKF81297. Rats were given a unilateral dopamine lesion with 6-hydroxydopamine and primed with a chronic regimen of l-DOPA, SKF81297 or their vehicles. On the final test day, rats were given two injections: first with ±8-OH-DPAT, the D1 receptor antagonist SCH23390 or their vehicles, and second with l-DOPA, SKF81297 or their vehicles. Rats were then transcardially perfused for immunohistological analysis of pERK expression in the striatum and primary motor cortex. Rats showed greater dyskinesia in response to l-DOPA and SKF81297 after repeated injections. Although striatal pERK induction was similar between acute and chronic l-DOPA, SKF81297 caused the largest increase in striatal pERK after the first exposure. Neither compound alone affected motor cortex pERK. Surprisingly, in the ventromedial striatum, ±8-OH-DPAT potentiated l-DOPA-induced pERK; in the motor cortex, ±8-OH-DPAT potentiated pERK with l-DOPA or SKF81297. Our results support previous work that the striatal pERK pathway is dysregulated after dopamine depletion, but call into question the utility of pERK as a biomarker of dyskinesia expression.

  20. Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: new data from the Patch in Practice trial and pooled analyses.

    PubMed

    David, Sean P; Johnstone, Elaine C; Murphy, Michael F G; Aveyard, Paul; Guo, Boliang; Lerman, Caryn; Munafò, Marcus R

    2008-11-01

    The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A45-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p=0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p=0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p=0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p=0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p=0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p=0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N=1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR)=1.25, 95% CI 0.89, 1.74, p=0.19; SS: OR=1.31, 95% CI 0.86, 1.98, p=0.21) or 26-week follow-up (Reference LL; SL: OR=0.93, 95% CI 0.64, 1.33, p=0.68; SS: OR=1.00, 95% CI 0.63, 1.58, p=1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.

  1. Polymorphism in Energetic Materials

    DTIC Science & Technology

    2008-01-01

    2008 NRL REVIEW 71 Polymorphism in Energetic Materials J.R. Deschamps,1 D.A. Parrish,1 and R.J. Butcher2 1Laboratory for Structure of Matter...can lead to substantial alterations in stability and performance. The authors recently reported on the crystal structures of five polymorphs of picryl...cally distinct forms. Since the properties of a solid sub- stance are determined by its composition and structure , polymorphs, although chemically

  2. Polymorphous computing fabric

    DOEpatents

    Wolinski, Christophe Czeslaw [Los Alamos, NM; Gokhale, Maya B [Los Alamos, NM; McCabe, Kevin Peter [Los Alamos, NM

    2011-01-18

    Fabric-based computing systems and methods are disclosed. A fabric-based computing system can include a polymorphous computing fabric that can be customized on a per application basis and a host processor in communication with said polymorphous computing fabric. The polymorphous computing fabric includes a cellular architecture that can be highly parameterized to enable a customized synthesis of fabric instances for a variety of enhanced application performances thereof. A global memory concept can also be included that provides the host processor random access to all variables and instructions associated with the polymorphous computing fabric.

  3. Polymorphism and solvatomorphism 2008.

    PubMed

    Brittain, Harry G

    2010-09-01

    Papers and patents that deal with polymorphism and solvatomorphism have been summarized in an annual review. The review is divided into sections that cover articles of general interest, computational and theoretical studies, preparative and isolation methods, structural characterization and properties of polymorphic and solvatomorphic systems, studies of phase transformations, effects associated with secondary processing, and United States patents issued during 2008.

  4. Disappearing Polymorphs Revisited

    PubMed Central

    Bučar, Dejan-Krešimir; Lancaster, Robert W; Bernstein, Joel

    2015-01-01

    Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law. PMID:26031248

  5. Polymorphism of sorbitol

    NASA Astrophysics Data System (ADS)

    Nezzal, Amale; Aerts, Luc; Verspaille, Marleen; Henderickx, Geert; Redl, Andreas

    2009-07-01

    The polymorphism of sorbitol was investigated, confirming the existence of four anhydrous crystalline phases plus the hydrate. The crystallised melt (CM), the alpha form, and the gamma form were obtained via a dry route. The CM was confirmed to be a crystalline state with a spherulite morphology. The alpha form was obtained via direct conversion from the CM, in contrast to more complicated routes previously reported, and was found to have a very high crystallinity. Gamma crystals were obtained by seeding the melt at high temperature; however, crystallinity was clearly less than for alpha crystals. Despite its lower crystallinity, the gamma polymorph was found to be the most stable of the anhydrous crystalline forms; this was confirmed by its high melting point and low hygroscopicity. In contrast, the alpha polymorph has a relatively high melting point but lacks moisture stability at high relative humidity. The hydrate form has the same resistance to moisture as the gamma form, but melts at a lower temperature. The combination of both a high melting point and high stability in the presence of water makes the gamma polymorph best suited for confectionary applications.

  6. Investigation of Uranium Polymorphs

    SciTech Connect

    Sweet, Lucas E.; Henager, Charles H.; Hu, Shenyang Y.; Johnson, Timothy J.; Meier, David E.; Peper, Shane M.; Schwantes, Jon M.

    2011-08-01

    The UO3-water system is complex and has not been fully characterized, even though these species are common throughout the nuclear fuel cycle. As an example, most production schemes for UO3 result in a mixture of up to six or more different polymorphic phases, and small differences in these conditions will affect phase genesis that ultimately result in measureable changes to the end product. As a result, this feature of the UO3-water system may be useful as a means for determining process history. This research effort attempts to better characterize the UO3-water system with a variety of optical techniques for the purpose of developing some predictive capability for estimating process history in polymorphic phases of unknown origin. Three commercially relevant preparation methods for the production of UO3 were explored. Previously unreported low temperature routes to β- and γ-UO3 were discovered. Raman and fluorescence spectroscopic libraries were established for pure and mixed polymorphic forms of UO3 in addition to the common hydrolysis products of UO3. An advantage of the sensitivity of optical fluorescence microscopy over XRD has been demonstrated. Preliminary aging studies of the α and γ forms of UO3 have been conducted. In addition, development of a 3-D phase field model used to predict phase genesis of the system was initiated. Thermodynamic and structural constants that will feed the model have been gathered from the literature for most of the UO3 polymorphic phases.

  7. Enzyme polymorphisms in Canarium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fifty-two accessions of Canarium involving seven species, C. ovatum, C. album, C. megalanthum, C. harveyi, C. indicum, C. mehenbethene, and C. odontophyllum were studied for isozyme polymorphisms. Starch gel electrophoresis with a histidine-citrate buffer system (pH 6.5) was employed to assay six en...

  8. Polymorphism of phosphoric oxide

    USGS Publications Warehouse

    Hill, W.L.; Faust, G.T.; Hendricks, S.B.

    1943-01-01

    The melting points and monotropic relationship of three crystalline forms of phosphoric oxide were determined by the method of quenching. Previous vapor pressure data are discussed and interpreted to establish a pressure-temperature diagram (70 to 600??) for the one-component system. The system involves three triple points, at which solid, liquid and vapor (P4O10) coexist in equilibrium, namely: 420?? and 360 cm., 562?? and 43.7 cm. and 580?? and 55.5 cm., corresponding to the hexagonal, orthorhombic and stable polymorphs, respectively, and at least two distinct liquids, one a stable polymer of the other, which are identified with the melting of the stable form and the hexagonal modification, respectively. Indices of refraction of the polymorphs and glasses were determined. The density and the thermal, hygroscopic and structural properties of the several phases are discussed.

  9. Stability of Polymeric Crystalline Polymorphs

    NASA Astrophysics Data System (ADS)

    Sinkovits, Daniel W.; Kumar, Sanat K.

    2014-03-01

    In the search for polymeric materials with novel properties, such as high dielectric constant and low loss, an important attribute of a material is its crystal structure. Most polymers can crystallize into multiple polymorphs whose properties vary. Therefore, the question of which polymorphs are thermodynamically preferred under what conditions is of great importance. We generate polymorphs using atomistic molecular dynamics simulations and tackle the question of stability using a combination of molecular dynamics and Monte Carlo techniques. Multidisciplinary University Research Initiative (MURI).

  10. Energetics of kaolin polymorphs

    SciTech Connect

    Ligny, D. de; Navrotsky, A.

    1999-04-01

    The enthalpy of formation of kaolin polymorphs at 298 K has been determined by drop-solution calorimetry into molten lead borate at 975 K. Corrections have been made for impurities in the samples. The standard enthalpy of formation from the elements is: kaolinite {minus}4120.2 {+-} 6.6 kJ/mol, dickite {minus}4107.6 {+-} 5.7 kJ/mol, nacrite {minus}4104.0 {+-} 7.6 kJ/mol, and halloysite {minus}4097.5 {+-} 5.6 kJ/mol. Using entropy data from the literature, the standard free energy of formation from the elements at 298 K is /{minus}3799.4 {+-} 6.4 kJ/mol for kaolinite, {minus}3785.1 {+-} 5.6 kJ/mol for dickite, and {minus}3776.8 {+-} 5.8 kJ/mol for halloysite. The effect of crystallinity (Hinckley index ranging from 1.6 to 0.4) on the enthalpy of formation of kaolinite is smaller than 5 kJ/mol, the experimental error. The relative stability of the polymorphs probably does not change significantly with pressure and temperature over their range of occurrence. Thus the geological occurrence of halloysite, nacrite, and dickite, which are metastable phases, must be interpreted in terms of kinetics or as the result of a specific synthesis path, rather than as resulting from changes in the thermodynamically stable phase assemblage.

  11. Polymorphic Evolutionary Games.

    PubMed

    Fishman, Michael A

    2016-06-07

    In this paper, I present an analytical framework for polymorphic evolutionary games suitable for explicitly modeling evolutionary processes in diploid populations with sexual reproduction. The principal aspect of the proposed approach is adding diploid genetics cum sexual recombination to a traditional evolutionary game, and switching from phenotypes to haplotypes as the new game׳s pure strategies. Here, the relevant pure strategy׳s payoffs derived by summing the payoffs of all the phenotypes capable of producing gametes containing that particular haplotype weighted by the pertinent probabilities. The resulting game is structurally identical to the familiar Evolutionary Games with non-linear pure strategy payoffs (Hofbauer and Sigmund, 1998. Cambridge University Press), and can be analyzed in terms of an established analytical framework for such games. And these results can be translated into the terms of genotypic, and whence, phenotypic evolutionary stability pertinent to the original game.

  12. SOD2 polymorphisms: unmasking the effect of polymorphism on splicing

    PubMed Central

    Shao, Jing; Chen, Lishan; Marrs, Brian; Lee, Lin; Huang, Hai; Manton, Kenneth G; Martin, George M; Oshima, Junko

    2007-01-01

    Background The SOD2 gene encodes an antioxidant enzyme, mitochondrial superoxide dismutase. SOD2 polymorphisms are of interest because of their potential roles in the modulation of free radical-mediated macromolecular damage during aging. Results We identified a new splice variant of SOD2 in human lymphoblastoid cell lines (LCLs). The alternatively spliced product was originally detected by exon trapping of a minigene in order to examine the consequences of an intronic polymorphism found upstream of exon 4 (nucleotide 8136, 10T vs 9T). Examination of the transcripts derived from the endogenous loci in five LCLs with or without the intron 3 polymorphism revealed low levels of an in-frame deletion of exon 4 that were different from those detected by the exon trap assay. This suggested that exon trapping of the minigene unmasked the effect of the 10T vs 9T polymorphism on the splicing of the adjacent exon. We also determined the frequencies of single nucleotide polymorphisms in a sample of US African-Americans and non-African-Americans ages 65 years and older who participated in the 1999 wave of the National Long Term Care Survey (NLTCS). Particularly striking differences between African-Americans and non-African-Americans were found for the frequencies of genotypes at the 10T/9T intron 3 polymorphism. Conclusion Exon trapping can unmask in vitro splicing differences caused by a 10T/9T intron 3 polymorphism. Given the recent evidence that SOD2 is in a region on chromosome 6 linked to susceptibility to hypertension, it will be of interest to investigate possible associations of this polymorphism with cardiovascular disorders. PMID:17331249

  13. Preferential Nucleation during Polymorphic Transformations

    PubMed Central

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-01-01

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and therefore nucleation more probable - with increasing number of special OR’s. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material. PMID:27484579

  14. Preferential Nucleation during Polymorphic Transformations.

    PubMed

    Sharma, H; Sietsma, J; Offerman, S E

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR's) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR's with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller - and therefore nucleation more probable - with increasing number of special OR's. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  15. 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.

  16. Polymorphous light eruption.

    PubMed

    Hölzle, E; Plewig, G; von Kries, R; Lehmann, P

    1987-03-01

    Polymorphous light eruption (PLE) is a common photodermatosis of unknown etiology. It afflicts mainly fair-skinned patients, with a preponderance of young females. There is, however, no absolute restriction as to age, sex, or race. Clinical variants include the papular, vesiculo-bullous, and hemorrhagic variety, as well as plaque, erythema multiforme-like, and insect bite (strophulus)-like types. Skin lesions appear only in certain exposed areas hours or a few days after intense sunshine, and are nearly always monomorphous in the same patient. The rash subsides spontaneously within several days without leaving scars. The histopathologic picture is characteristic and shows a perivascular lymphocytic infiltrate in the upper and middle corium with subepidermal edema, vacuolization of basal cells, and spongiosis in the lower epidermis. The most important differential diagnoses are solar urticaria, photosensitive erythema multiforme, and lupus erythematosus. The action spectrum of PLE is under debate. Reproduction of skin lesions has been reported with UVB, UVA, and, rarely, visible light, with UVA probably being the most effective part of the spectrum. More important than treatment of PLE is prophylaxis. UVA- and UVB-effective sunscreens are of some help. Phototherapy and especially photochemotherapy (psoralen + UVA; PUVA) offer effective ways to decrease light sensitivity. Systemic treatment with chloroquine or beta-carotene has been disappointing.

  17. New polymorphous computing fabric.

    SciTech Connect

    Wolinski, C.; Gokhale, M.; McCabe, K. P.

    2002-01-01

    This paper introduces a new polymorphous computing Fabric well suited to DSP and Image Processing and describes its implementation on a Configurable System on a Chip (CSOC). The architecture is highly parameterized and enables customization of the synthesized Fabric to achieve high performance for a specific class of application. For this reason it can be considered to be a generic model for hardware accelerator synthesis from a high level specification. Another important innovation is the Fabric uses a global memory concept, which gives the host processor random access to all the variables and instructions on the Fabric. The Fabric supports different computing models including MIMD, SPMD and systolic flow and permits dynamic reconfiguration. We present a specific implementation of a bank of FIR filters on a Fabric composed of 52 cells on the Altera Excalibur ARM running at 33 MHz. The theoretical performance of this Fabric is 1.8 GMACh. For the FIR application we obtain 1.6 GMAC/s real performance. Some automatic tools have been developed like the tool to provide a host access utility and assembler.

  18. Selective breeding for catalepsy changes the distribution of microsatellite D13Mit76 alleles linked to the 5-HT serotonin receptor gene in mice.

    PubMed

    Kondaurova, E M; Bazovkina, D V; Kulikov, A V; Popova, N K

    2006-11-01

    Catalepsy (pronounced motor inhibition) is a natural defensive reaction against predator. Recently, the quantitative trait locus for catalepsy was mapped on mouse chromosome 13 near the 5-HT(1A) serotonin receptor gene. Here, the linkage between catalepsy and the 5-HT(1A) receptor gene was verified using breeding experiment. Selective breeding for high predisposition to catalepsy was started from backcross BC[CBA x (CBA x AKR)] generation between catalepsy-prone (CBA) and catalepsy-resistant (AKR) mouse strains. CBA and AKR strains also differed in the 5-HT(1A) receptor functional activity. A rapid increase of cataleptic percentage from 21.2% in the backcrosses to 71% in the third generation of selective breeding (S3) was shown. The fragment of chromosome 13 including the 5-HT(1A) receptor gene was marked with D13Mit76 microsatellite. Breeding for catalepsy increased the concentration of CBA-derived and decreased the concentration of AKR-derived alleles of microsatellite D13Mit76 in the S1 and S2. All mice of the S9 and S12 were homozygous for CBA-derived allele of D13Mit76 marker. Mice of the S12 showed CBA-like receptor activity. These findings indicate that selective breeding for behavior can involve selection of polymorphic variants of the 5-HT(1A) receptor gene.

  19. Polymorphic light eruption sine eruption.

    PubMed

    Dover, J S; Hawk, J L

    1988-01-01

    We describe seven patients, four female and three male, who developed intense pruritus on sun-exposed skin without visible change. The clinical features resembled those of polymorphic light eruption (PLE) without rash. Four patients also occasionally developed typical PLE upon sun exposure, but sun-induced pruritus alone occurred most frequently. No patient was taking any drug therapy. One patient developed similar pruritus following solar simulated irradiation, and one following PUVA therapy. All other laboratory investigations were negative. Treatment with low dose UVB phototherapy or PUVA therapy was effective. The condition, which we have called polymorphic light eruption sine eruptione (PLESE), appears to be a variant of PLE not previously reported.

  20. Crystal Polymorphs of Barbital: News about a Classic Polymorphic System

    PubMed Central

    2013-01-01

    Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I0, III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I0, III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I0/III, I0/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I0 > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N–H···O=C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV. PMID:24283960

  1. Triclinic polymorph of dibenzotetra-thia-fulvalene.

    PubMed

    Mamada, Masashi; Yamashita, Yoshiro

    2009-08-08

    Crystals of the title compound (DBTTF), C(14)H(8)S(4), feature a triclinic polymorph different from two known monoclinic polymorphs. In this form, there are two independent centrosymmetric half-mol-ecules in the asymmetric unit. Although the mol-ecular orientations are relatively similar to one of monoclinic polymorphs, the packing motif is different.

  2. Preferential nucleation during polymorphic transformations

    DOE PAGES

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and thereforemore » nucleation more probable - with increasing number of special OR’s. As a result, these insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.« less

  3. Preferential nucleation during polymorphic transformations

    SciTech Connect

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and therefore nucleation more probable - with increasing number of special OR’s. As a result, these insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  4. Characterization of polymorphic ampicillin forms.

    PubMed

    Baraldi, C; Tinti, A; Ottani, S; Gamberini, M C

    2014-11-01

    In this work polymorphs of α-aminobenzylpenicillin (ampicillin), a β-lactamic antibiotic, were prepared and investigated by several experimental and theoretical methods. Amorphous monohydrate and three crystalline forms, the trihydrate, the crystal form I and the crystal form II, were investigated by FT-IR and micro-Raman. Also data obtained by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) and hot-stage Raman spectroscopy are reported. Finally, quantum mechanical calculations were performed by density functional theory (DFT) to assist the assignment of spectroscopic experimental bands. For the first time, the ampicillin molecule in its zwitterionic form was studied at the B3LYP/aug-cc-pVDZ level and the corresponding theoretical vibrational spectra were computed. In fact, ampicillin in the crystal is in zwitterionic form and concentrations of this same form are quite relevant in solutions at physiological pH. Experimental and theoretical results allowed identification of specific features for polymorph characterization. Bands typical of the different polymorphs are identified both in IR and Raman spectra: in particular in the NH stretching region (IR), in the amide I+δNH region (both techniques), in the 1520-1490cm(-1) region (IR), in the 1320-1300cm(-1) and 1280-1220cm(-1) (IR), in the 1200-1170cm(-1) (Raman), in the amide V region (IR), and, finally, in the 715-640cm(-1) and 220-200cm(-1) (Raman). Interconversion among different polymorphs was investigated by hot-stage Raman spectroscopy and thermal analysis, clarifying the complex pattern of transformations undergone as a function of temperature and heating rate. In particular, DSC scans show how the trihydrate crystals transform into anhydrous forms on heating. Finally, stability tests demonstrated, after a two years period, that no transformation or degradation of the polymorphs occurred.

  5. IPD: the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Marsh, Steven G E

    2007-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer cell immunoglobulin-like receptors (KIRs); IPD-MHC, a database of sequences of the major histocompatibility complex (MHC) of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTAB, which provides access to the European Searchable Tumour Cell Line Database, a cell bank of immunologically characterized melanoma cell lines. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. Those sections with similar data, such as IPD-KIR and IPD-MHC, share the same database structure.

  6. Lipid Polymorphisms and Membrane Shape

    PubMed Central

    Frolov, Vadim A.; Shnyrova, Anna V.; Zimmerberg, Joshua

    2011-01-01

    Morphological plasticity of biological membrane is critical for cellular life, as cells need to quickly rearrange their membranes. Yet, these rearrangements are constrained in two ways. First, membrane transformations may not lead to undesirable mixing of, or leakage from, the participating cellular compartments. Second, membrane systems should be metastable at large length scales, ensuring the correct function of the particular organelle and its turnover during cellular division. Lipids, through their ability to exist with many shapes (polymorphism), provide an adequate construction material for cellular membranes. They can self-assemble into shells that are very flexible, albeit hardly stretchable, which allows for their far-reaching morphological and topological behaviors. In this article, we will discuss the importance of lipid polymorphisms in the shaping of membranes and its role in controlling cellular membrane morphology. PMID:21646378

  7. Superhard monoclinic polymorph of carbon.

    PubMed

    Li, Quan; Ma, Yanming; Oganov, Artem R; Wang, Hongbo; Wang, Hui; Xu, Ying; Cui, Tian; Mao, Ho-Kwang; Zou, Guangtian

    2009-05-01

    We report a novel phase of carbon possessing a monoclinic C2/m structure (8 atoms/cell) identified using an ab initio evolutionary structural search. This polymorph, which we call M-carbon, is related to the (2x1) reconstruction of the (111) surface of diamond and can also be viewed as a distorted (through sliding and buckling of the sheets) form of graphite. It is stable over cold-compressed graphite above 13.4 GPa. The simulated x-ray diffraction pattern and near K-edge spectroscopy are in satisfactory agreement with the experimental data [W. L. Mao, Science 302, 425 (2003)10.1126/science.1089713] on overcompressed graphite. The hardness and bulk modulus of this new carbon polymorph are calculated to be 83.1 and 431.2 GPa, respectively, which are comparable to those of diamond.

  8. Superhard Monoclinic Polymorph of Carbon

    SciTech Connect

    Li, Quan; Ma, Yanming; Oganov, Artem R.; Wang, Hongbo; Wang, Hui; Xu, Ying; Cui, Tian; Mao, Ho-Kwang; Zou, Guangtian; Jilin; SBU; CIW

    2009-05-08

    We report a novel phase of carbon possessing a monoclinic C2/m structure (8 atoms/cell) identified using an ab initio evolutionary structural search. This polymorph, which we call M-carbon, is related to the (2x1) reconstruction of the (111) surface of diamond and can also be viewed as a distorted (through sliding and buckling of the sheets) form of graphite. It is stable over cold-compressed graphite above 13.4 GPa. The simulated x-ray diffraction pattern and near K-edge spectroscopy are in satisfactory agreement with the experimental data [W.L. Mao et al., Science 302, 425 (2003)] on overcompressed graphite. The hardness and bulk modulus of this new carbon polymorph are calculated to be 83.1 and 431.2 GPa, respectively, which are comparable to those of diamond.

  9. The Single Nucleotide Polymorphism Consortium

    NASA Technical Reports Server (NTRS)

    Morgan, Michael

    2003-01-01

    I want to discuss both the Single Nucleotide Polymorphism (SNP) Consortium and the Human Genome Project. I am afraid most of my presentation will be thin on law and possibly too high on rhetoric. Having been engaged in a personal and direct way with these issues as a trained scientist, I find it quite difficult to be always as objective as I ought to be.

  10. Chemical substitution in silica polymorph

    NASA Technical Reports Server (NTRS)

    Smith, J. V.; Steele, I. M.

    1984-01-01

    Ion and electron probe analyses are presented for trace elements (Al, Na, K, Li, Ti) in quartz, tridymite, cristobalite and melanophlogite. Quartz and melanophlogite show low levels of trace elements relative to tridymite and cristobalite. The previously determined alpha-beta inversion temperature decreases as the Al content of quartz increases. For all silica polymorphs, Al is greater than or equal to Na + K + Li on an atom basis, with the excess Al probably balanced by H.

  11. Chromosomal polymorphism in mammals: an evolutionary perspective.

    PubMed

    Dobigny, Gauthier; Britton-Davidian, Janice; Robinson, Terence J

    2017-02-01

    Although chromosome rearrangements (CRs) are central to studies of genome evolution, our understanding of the evolutionary consequences of the early stages of karyotypic differentiation (i.e. polymorphism), especially the non-meiotic impacts, is surprisingly limited. We review the available data on chromosomal polymorphisms in mammals so as to identify taxa that hold promise for developing a more comprehensive understanding of chromosomal change. In doing so, we address several key questions: (i) to what extent are mammalian karyotypes polymorphic, and what types of rearrangements are principally involved? (ii) Are some mammalian lineages more prone to chromosomal polymorphism than others? More specifically, do (karyotypically) polymorphic mammalian species belong to lineages that are also characterized by past, extensive karyotype repatterning? (iii) How long can chromosomal polymorphisms persist in mammals? We discuss the evolutionary implications of these questions and propose several research avenues that may shed light on the role of chromosome change in the diversification of mammalian populations and species.

  12. Parasitic polymorphism of Coccidioides spp

    PubMed Central

    2014-01-01

    Background Coccidioides spp. is the ethiological agent of coccidioidomycosis, an infection that can be fatal. Its diagnosis is complicated, due to that it shares clinical and histopathological characteristics with other pulmonary mycoses. Coccidioides spp. is a dimorphic fungus and, in its saprobic phase, grows as a mycelium, forming a large amount of arthroconidia. In susceptible persons, arthroconidia induce dimorphic changes into spherules/endospores, a typical parasitic form of Coccidioides spp. In addition, the diversity of mycelial parasitic forms has been observed in clinical specimens; they are scarcely known and produce errors in diagnosis. Methods We presented a retrospective study of images from specimens of smears with 15% potassium hydroxide, cytology, and tissue biopsies of a histopathologic collection from patients with coccidioidomycosis seen at a tertiary-care hospital in Mexico City. Results The parasitic polymorphism of Coccidioides spp. observed in the clinical specimens was as follows: i) spherules/endospores in different maturation stages; ii) pleomorphic cells (septate hyphae, hyphae composed of ovoid and spherical cells, and arthroconidia), and iii) fungal ball formation (mycelia with septate hyphae and arthroconidia). Conclusions The parasitic polymorphism of Coccidioides spp. includes the following: spherules/endospores, arthroconidia, and different forms of mycelia. This knowledge is important for the accurate diagnosis of coccidioidomycosis. In earlier studies, we proposed the integration of this diversity of forms in the Coccidioides spp. parasitic cycle. The microhabitat surrounding the fungus into the host would favor the parasitic polymorphism of this fungus, and this environment may assist in the evolution toward parasitism of Coccidioides spp. PMID:24750998

  13. Calcium acamprosate: a triclinic polymorph.

    PubMed

    Maccaroni, Elisabetta; Panzeri, Walter; Malpezzi, Luciana

    2011-12-01

    The title compound, poly[bis-(μ(3)-4-acetamido-propane-sulfon-ato)-calcium], [Ca(C(5)H(10)NO(4)S)(2)](n), is a triclinic polymorph of the previously reported monoclinic structure [Toffoli et al. (1988 ▶). Acta Cryst. C44, 1493-1494]. The triclinic modification was found to have an all-trans configuration of the acetamido-propane chain, in contrast with the monoclinic polymorph which shows an angle of 74.66 (8)° between the S-C-C-C chain plane and that of the amide group. The Ca(2+) cation is situated on an inversion centre and is hexa-coordinated by six O atoms belonging to different anions in a distorted octa-hedral geometry. This arrangement leads to a layered structure parallel to (011). The layers are held together by N-H⋯O hydrogen bonds and by short C-H⋯O inter-actions, both involving the sulfonate O atoms not coordinated to the Ca(2+) cations. The structure was determined from a crystal twinned by non-merohedry [twin law ([Formula: see text]00, 0[Formula: see text]0, -0.335 -0.85 1), with a fractional contribution of the minor twin domain of 46.7 (1)%].

  14. Spinning up the polymorphs of calcium carbonate

    PubMed Central

    Boulos, Ramiz A.; Zhang, Fei; Tjandra, Edwin S.; Martin, Adam D.; Spagnoli, Dino; Raston, Colin L.

    2014-01-01

    Controlling the growth of the polymorphs of calcium carbonate is important in understanding the changing environmental conditions in the oceans. Aragonite is the main polymorph in the inner shells of marine organisms, and can be readily converted to calcite, which is the most stable polymorph of calcium carbonate. Both of these polymorphs are significantly more stable than vaterite, which is the other naturally occurring polymorph of calcium carbonate, and this is reflected in its limited distribution in nature. We have investigated the effect of high shear forces on the phase behaviour of calcium carbonate using a vortex fluidic device (VFD), with experimental parameters varied to explore calcium carbonate mineralisation. Variation of tilt angle, rotation speed and temperature allow for control over the size, shape and phase of the resulting calcium carbonate. PMID:24448077

  15. Investigation of the riddle of sulfathiazole polymorphism.

    PubMed

    Abu Bakar, Mohd R; Nagy, Zoltan K; Rielly, Chris D; Dann, Sandy E

    2011-07-29

    Since the discovery of sulfathiazole as an antimicrobial agent in 1939, numerous works in the screening for its different polymorphic forms, which is an essential part of drug development, have been conducted and published. These works consequently result in the availability of various methods for generating a particular polymorph. By following these methods, however, one cannot be guaranteed to obtain the intended pure polymorph because most of the methods do not clearly and adequately describe the crystallisation conditions, such as cooling rates and initial solute concentrations. In this paper, the available methods for generating all the known polymorphs of sulfathiazole are reviewed and selected methods for generating certain polymorphs, performed with their processes monitored using process analytical technology tools, i.e. focussed beam reflectance measurement and attenuated total reflectance ultraviolet spectroscopy, are presented. The properties of the obtained crystals, examined using various characterisation methods, are also presented and whenever possible, are compared with those of other workers.

  16. Vibrational study of tamoxifen citrate polymorphism

    NASA Astrophysics Data System (ADS)

    Gamberini, M. C.; Baraldi, C.; Tinti, A.; Palazzoli, F.; Ferioli, V.

    2007-09-01

    The trans isomer of ( Z)-2-[ p-(1,2-diphenyl-butenyl)phenoxy]- N, N-dimethyletylamine (tamoxifen) is well known for its endocrine activity as an antiestrogenic agent. Its citrate salt, a widely used pharmaceutical agent, appears in three main polymorphic forms, two of which are well known (I and II) and another form not yet well evidenced. A vibrational study has been conducted for identifying the two known polymorphic forms of tamoxifen citrate (I and II) and for characterising the other form (form III) examined in this study. Other techniques for the characterization of the different polymorphs, such as XRDP, have been used.

  17. Rivastigmine hydrogen tartrate polymorphs: Solid-state characterisation of transition and polymorphic conversion via milling

    NASA Astrophysics Data System (ADS)

    Amaro, Maria Inês; Simon, Alice; Cabral, Lúcio Mendes; de Sousa, Valéria Pereira; Healy, Anne Marie

    2015-11-01

    Rivastigmine (RHT) is an active pharmaceutical ingredient that is used for the treatment of mild to moderately severe dementia in Alzheimer's disease, and is known to present two polymorphic forms and to amorphise upon granulation. To date there is no information in the scientific or patent literature on polymorphic transition and stability. Hence, the aim of the current study was to gain a fundamental understanding of the polymorphic forms by (1) evaluating RHT thermodynamic stability (monotropy or enantiotropy) and (2) investigating the potential for polymorphic transformation upon milling. The two polymorphic and amorphous forms were characterised using X-ray powder diffractometry, thermal analyses, infra-red spectroscopy and water sorption analysis. The polymorphic transition was found to be spontaneous (ΔG0 < 0) and exothermic (ΔH0 < 0), indicative of a monotropic polymorph pair. The kinetic studies showed a fast initial polymorphic transition characterised by a heterogeneous nucleation, followed by a slow crystal growth. Ball milling can be used to promote the polymorphic transition and for the production of RHT amorphous form.

  18. Polymorphism Control of Poly(vinylidene fluoride)

    NASA Astrophysics Data System (ADS)

    Zheng, Jianfen; He, Aihua; Li, Junxing; Han, Charles C.

    2008-03-01

    Poly(vinylidene fluoride) (PVDF) is well-known for its polymorphism, and can exhibit five different polymorphs depending on its processing conditions. The α-phase is the most common and stable polymorph and the β-phase is the most important one due to its piezoelectric and pyroelectric properties. Polymorphism control of PVDF has been realized through electrospinning. PVDF fibrous membranes with fiber diameter in the range of 100 nm to several micrometers were produced by electrospinning and the crystal phase of electrospun PVDF fibers can be adjusted at the same time. Through the control of electrospinning parameters such as the solvent and electrospinning temperature, PVDF fibrous membranes containing mainly α- or β- or γ-phase could be fabricated successfully.

  19. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, M.

    1988-01-21

    A method for processing related subject and reference macromolecule composed of complementary strand into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 fig.

  20. Gene polymorphisms and chronic obstructive pulmonary disease.

    PubMed

    Wu, Xiaodan; Yuan, Bowei; López, Elena; Bai, Chunxue; Wang, Xiangdong

    2014-01-01

    The genetic component was suggested to contribute to the development of chronic obstructive pulmonary disease (COPD), a major and growing public health burden. The present review aims to characterize the evidence that gene polymorphisms contribute to the aetiology of COPD and related traits, and explore the potential relationship between certain gene polymorphisms and COPD susceptibility, severity, lung function, phenotypes, or drug effects, even though limited results from related studies lacked consistency. Most of these studies were association studies, rather than confirmatory studies. More large-sized and strictly controlled studies are needed to prove the relationship between gene polymorphisms and the reviewed traits. More importantly, prospective confirmatory studies beyond initial association studies will be necessary to evaluate true relationships between gene polymorphisms and COPD and help individualized treatment for patients with COPD.

  1. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, M.

    1991-07-16

    A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 figure.

  2. Polymorph Discrimination using Low Wavenumber Raman Spectroscopy

    PubMed Central

    Roy, Saikat; Chamberlin, Brianna; Matzger, Adam J.

    2016-01-01

    Characterization of crystalline polymorphs and their quantitation has become an integral part of the pre-clinical drug development process. Raman spectroscopy is a powerful technique for the rapid identification of phases of pharmaceuticals. In the present work we demonstrate the use of low wavenumber Raman vibrational spectroscopy (including phonon measurement) for discrimination among polymorphs. A total of 10 polymorphic pharmaceuticals were employed to conduct a critical assessment. Raman scattering in the low frequency region (10–400 cm−1), which includes crystal lattice vibrations, has been analyzed and the results indicate lattice phonon Raman scattering can be used for rapid discrimination of polymorphic phases with additional discriminating power compared to conventional collection strategies. Moreover structural insight and conformational changes can be detected with this approach. PMID:27642248

  3. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, Marvin

    1991-01-01

    A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments.

  4. Crystal Polymorphism and Multiple Crystal Forms

    NASA Astrophysics Data System (ADS)

    Braga, Dario; Grepioni, Fabrizia; Maini, Lucia; Polito, Marco

    This chapter discusses the phenomenon of polymorphism in organic and organometallic compounds. Polymorphism is first introduced and then, to give the work some context, background information is given concerning properties and techniques for characterizing the solid phases. In particular, desolvation and interconverstion are examined, and the gas-solid reactions are presented as a successful route to obtaining new crystalline phases. Co-crystal definition is then described and the problem in distinguishing co-crystals and salts is evaluated.

  5. DNA polymorphism identity determination using flow cytometry

    DOEpatents

    Nolan, John P.; White, P. Scott; Cai, Hong

    2001-01-01

    DNA polymorphism identity determination using flow cytometry. Primers designed to be immobilized on microspheres are allowed to anneal to the DNA strand under investigation, and are extended by either DNA polymerase using fluorescent dideoxynucleotides or ligated by DNA ligase to fluorescent reporter oligonucleotides. The fluorescence of either the dideoxynucleotide or the reporter oligonucleotide attached to the immobilized primer is measured by flow cytometry, thereby identifying the nucleotide polymorphism on the DNA strand.

  6. Tetrazolium Oxidase Polymorphism in Rainbow Trout

    PubMed Central

    Cederbaum, Stephen D.; Yoshida, Akira

    1972-01-01

    Tetrazolium oxidase from the blood and liver of rainbow trout was found to be genetically polymorphic. The inheritance pattern of the liver enzyme was compatible only with a one locus-two allele hypothesis. The enzymes in the blood while having an electrophoretically identical polymorphism could differ genotypically from that of the liver in a given fish. The significance of these findings to the understanding of the evolution of the salmonid genome is discussed. PMID:4675090

  7. Polymorphic crystals selected in the nucleation stage

    NASA Astrophysics Data System (ADS)

    Zhang, Hui-Jun; Peng, Shu-Ming; Zhou, Xiao-Song; Ju, Xin

    2014-08-01

    Molecular dynamics simulations are used to explore the atomic mechanism of formation of polymorphic crystals. Cooling the Lennard-Jones systems, we observe that the system almost always evolves into a polymorphic crystal with either fivefold-symmetric stacking faults or single-direction stacking faults. The detailed analysis reveals that such an evolution depends on the configuration of fcc/hcp concomitance in the nucleation stage. A defect-induced model is then introduced to illustrate these two evolution routes. Through calculating the formation energies of the defective critical nuclei, we find that the polymorphic crystals seem to be determined by their critical nuclei, in which the relatively lower formation energy ensures the preponderance of the fivefold-symmetric cluster. Before the nucleation, we observe that thermal fluctuations prefer hcp-like particles over fcc-like ones while in the nucleation and growth stage this preference reverses. Notably, an extended step rule of Ostwald is seemingly suitable to characterise the growth process because of the temporary hcp layers appearing among fcc layers in the growth stage. Although the crystalline cluster with single-direction stacking faults has higher growth rate and structural order than its competitor, the component (fcc and hcp) proportion of the final crystals is almost always constant regardless of the polymorphic type. Our finding renews the understanding of the polymorphism of crystals, and possibly draws more attention of people intending to control the polymorphic structures through nucleation.

  8. Cytochrome P450 gene polymorphism and cancer.

    PubMed

    Agundez, Jose A G

    2004-06-01

    Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs and environmental chemicals. Several CYP enzymes metabolically activate procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an association between CYP enzyme activity and the risk to develop several forms of cancer. Research carried out in the last decade demonstrated that several CYP enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications and deletions. As genotyping procedures became available for most human CYP, an impressive number of association studies on CYP polymorphisms and cancer risk were conducted. Here we review the findings obtained in these studies regarding CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent evidences for association between CYP polymorphisms and lung, head and neck, and liver cancer were reported. Controversial findings suggest that colorectal and prostate cancers may be associated to CYP polymorphisms, whereas no evidences for a relevant association with breast or bladder cancers were reported. We summarize the available information related to the association of CYP polymorphisms with leukaemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This review discusses on causes of heterogeneity in the proposed associations, controversial findings on cancer risk, and identifies topics that require further investigation. In addition, some recommendations on study design, in order to obtain more conclusive findings in further studies, are provided.

  9. MHC polymorphism under host-pathogen coevolution.

    PubMed

    Borghans, José A M; Beltman, Joost B; De Boer, Rob J

    2004-02-01

    The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change.

  10. Prdm9 polymorphism unveils mouse evolutionary tracks.

    PubMed

    Kono, Hiromitsu; Tamura, Masaru; Osada, Naoki; Suzuki, Hitoshi; Abe, Kuniya; Moriwaki, Kazuo; Ohta, Kunihiro; Shiroishi, Toshihiko

    2014-06-01

    PR/SET domain containing 9 (Prdm9) mediates histone modifications such as H3K4me3 and marks hotspots of meiotic recombination. In many mammalian species, the Prdm9 gene is highly polymorphic. Prdm9 polymorphism is assumed to play two critical roles in evolution: to diversify the spectrum of meiotic recombination hotspots and to cause male hybrid sterility, leading to reproductive isolation and speciation. Nevertheless, information about Prdm9 sequences in natural populations is very limited. In this study, we conducted a comprehensive population survey on Prdm9 polymorphism in the house mouse, Mus musculus. Overall M. musculus Prdm9 displays an extraordinarily high level of polymorphism, particularly in regions encoding zinc finger repeats, which recognize recombination hotspots. Prdm9 alleles specific to various M. musculus subspecies dominate in subspecies territories. Moreover, introgression into other subspecies territories was found for highly divergent Prdm9 alleles associated with t-haplotype. The results of our phylogeographical analysis suggest that the requirement for hotspot diversity depends on geographical range and time span in mouse evolution, and that Prdm9 polymorphism has not been maintained by a simple balanced selection in the population of each subspecies.

  11. Solvable model for polymorphic dynamics of biofilaments.

    PubMed

    Mohrbach, Hervé; Kulić, Igor M

    2012-03-01

    We investigate an analytically tractable toy model for thermally induced polymorphic dynamics of cooperatively rearranging biofilaments-like microtubules. The proposed four-block model, which can be seen as a coarse-grained approximation of the full polymorphic tube model, permits a complete analytical treatment of all thermodynamic properties including correlation functions and angular Fourier mode distributions. Due to its mathematical tractability the model straightforwardly leads to some physical insights in recently discussed phenomena like the "length dependent persistence length." We show that a polymorphic filament can disguise itself as a classical worm-like chain on small and on large scales and yet display distinct anomalous tell-tale features indicating an inner switching dynamics on intermediate length scales.

  12. Human FcR Polymorphism and Disease

    PubMed Central

    Li, Xinrui; Gibson, Andrew W.; Kimberly, Robert P.

    2014-01-01

    Fc receptors play a central role in maintaining the homeostatic balance in the immune system. Our knowledge of the structure and function of these receptors and their naturally occurring polymorphisms, including single nucleotide polymorphisms and/or copy number variations, continues to expand. Through studies of their impact on human biology and clinical phenotype, the contributions of these variants to the pathogenesis, progression, and/or treatment outcome of many diseases that involve immunoglobulin have become evident. They affect susceptibility to bacterial and viral pathogens, constitute as risk factors for IgG or IgE mediated inflammatory diseases, and impact the development of many autoimmune conditions. In this chapter, we will provide an overview of these genetic variations in classical FcγRs, FcRLs, and other Fc receptors, as well as challenges in achieving an accurate and comprehensive understanding of the FcR polymorphisms and genomic architecture. PMID:25116105

  13. Novel polymorphisms in ovine prion protein gene.

    PubMed

    Meydan, H; Ozkan, M M; Yildiz, M A; Goldmann, W

    2013-08-01

    The aim of this study was to identify the PRNP polymorphisms outside the standard codons 136, 154 and 171 in 1110 sheep with no clinical sign of scrapie from all 18 Turkish native sheep breeds and compare our results with published data on ovine PRNP polymorphism from other regions of the world. Among the 22 amino acid polymorphisms and three silent mutations, 10 were novel for ovine PRNP: p.Gly94Gly, p.Leu128Ile, p.Met132Leu, p.Ser135Arg, p.Met137Val, p.Asn146Lys, p.Arg159Arg, p.Tyr160Asn, p.Gln163His and p.Thr193Ser. These data reveal that sheep breeds close to the historic center of small ruminant domestication have remained highly diverse in the prion gene locus, with distinctive genetic similarities to both Asian and European sheep breeds.

  14. Single Nucleotide Polymorphisms and Osteoarthritis

    PubMed Central

    Wang, Ting; Liang, Yuting; Li, Hong; Li, Haibo; He, Quanze; Xue, Ying; Shen, Cong; Zhang, Chunhua; Xiang, Jingjing; Ding, Jie; Qiao, Longwei; Zheng, Qiping

    2016-01-01

    Abstract Osteoarthritis (OA) is a complex disorder characterized by degenerative articular cartilage and is largely attributed to genetic risk factors. Single nucleotide polymorphisms (SNPs) are common DNA variants that have shown promising and efficiency, compared with positional cloning, to map candidate genes of complex diseases, including OA. In this study, we aim to provide an overview of multiple SNPs from a number of genes that have recently been linked to OA susceptibility. We also performed a comprehensive meta-analysis to evaluate the association of SNP rs7639618 of double von Willebrand factor A domains (DVWA) gene with OA susceptibility. A systematic search of studies on the association of SNPs with susceptibility to OA was conducted in PubMed and Google scholar. Studies subjected to meta-analysis include human and case-control studies that met the Hardy–Weinberg equilibrium model and provide sufficient data to calculate an odds ratio (OR). A total of 9500 OA cases and 9365 controls in 7 case-control studies relating to SNP rs7639618 were included in this study and the ORs with 95% confidence intervals (CIs) were calculated. Over 50 SNPs from different genes have been shown to be associated with either hip (23), or knee (20), or both (13) OA. The ORs of these SNPs for OA and the subtypes are not consistent. As to SNP rs7639618 of DVWA, increased knee OA risk was observed in all genetic models analyzed. Specifically, people from Asian with G-allele showed significantly increased risk of knee OA (A versus G: OR = 1.28, 95% CI 1.13–1.46; AA versus GG: OR = 1.60, 95% CI 1.25–2.05; GA versus GG: OR = 1.31, 95% CI 1.18–1.44; AA versus GA+GG: OR = 1.34, 95% CI 1.12–1.61; AA+GA versus GG: OR = 1.40, 95% CI 1.19–1.64), but not in Caucasians or with hip OA. Our results suggest that multiple SNPs play different roles in the pathogenesis of OA and its subtypes; SNP rs7639618 of DVWA gene is associated with a significantly increased

  15. Clinical applications of Genome Polymorphism Scans

    PubMed Central

    Weber, James L

    2006-01-01

    Applications of Genome Polymorphism Scans range from the relatively simple such as gender determination and confirmation of biological relationships, to the relatively complex such as determination of autozygosity and propagation of genetic information throughout pedigrees. Unlike nearly all other clinical DNA tests, the Scan is a universal test – it covers all people and all genes. In balance, I argue that the Genome Polymorphism Scan is the most powerful, affordable clinical DNA test available today. Reviewers: This article was reviewed by Scott Weiss (nominated by Neil Smalheiser), Roberta Pagon (nominated by Jerzy Jurka) and Val Sheffield (nominated by Neil Smalheiser). PMID:16756678

  16. TNF-alpha polymorphisms and breast cancer.

    PubMed

    Yang, Yu; Feng, Rennan; Bi, Sheng; Xu, Yuqing

    2011-09-01

    Tumor necrosis factor-α (TNF-α) is an important pro-inflammatory cytokine in the development and progress in human cancer. TNF-α polymorphisms have been confirmed to influence the risk for several types of cancer, however, the associations between TNF-α polymorphisms and breast cancer (BC) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations regarding this point. Electronic searches of several databases were conducted for all online publications on the associations between TNF-α-238, -308, -857, -863, -1031, -1210 polymorphisms and BC through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated to assess the strength of these associations in fixed- and random-effect models with Review manager 5.0. A total of 17 studies with 44,442 BC patients and 49,926 controls involved were identified. This meta-analysis showed no significant association between TNF-α-308 polymorphism and BC (AA + GA vs. GG: OR = 0.95, 95% CI = 0.82-1.09) in overall and (OR = 1.44, 95% CI = 0.61-3.40) Asian populations, however, a negative association was shown in Caucasian subgroup (OR = 0.91, 95% CI = 0.85-0.97). As regards the TNF-α-238 polymorphism, the OR values (95% CI) were 0.99 (0.94-1.05), 0.94 (0.78-1.14), and 1.00 (0.95-1.05) for the overall, Asian, and Caucasian studies, respectively. No significant associations were found for other polymorphisms. Furthermore, there was a coincidence in the sensitivity analysis of these associations. No publication bias was detected in this study. To sum up, no significant associations were found between the TNF-α-308, -238, -857, -863, -1031, -1210 polymorphisms and the risk for BC in overall populations, whereas a negative association was found between TNF-α-308 polymorphism and BC in Caucasian populations.

  17. Polymorphs calcium carbonate on temperature reaction

    SciTech Connect

    Chong, Kai-Yin; Chia, Chin-Hua; Zakaria, Sarani

    2014-09-03

    Calcium carbonate (CaCO{sub 3}) has three different crystal polymorphs, which are calcite, aragonite and vaterite. In this study, effect of reaction temperature on polymorphs and crystallite structure of CaCO{sub 3} was investigated. X-ray powder diffraction (XRD), fourier transform infrared (FTIR), and variable pressure scanning electron microscope (VPSEM) were used to characterize the obtained CaCO{sub 3} particles. The obtained results showed that CaCO{sub 3} with different crystal and particle structures can be formed by controlling the temperature during the synthesis process.

  18. Polymorphic transformation of helical flagella of bacteria

    NASA Astrophysics Data System (ADS)

    Lim, Sookkyung; Howard Berg Collaboration; William Ko Collaboration; Yongsam Kim Collaboration; Wanho Lee Collaboration; Charles Peskin Collaboration

    2016-11-01

    Bacteria such as E. coli swim in an aqueous environment by utilizing the rotation of flagellar motors and alternate two modes of motility, runs and tumbles. Runs are steady forward swimming driven by bundles of flagellar filaments whose motors are turning CCW; tumbles involve a reorientation of the direction of swimming triggered by motor reversals. During tumbling, the helical flagellum undergoes polymorphic transformations, which is a local change in helical pitch, helical radius, and handedness. In this work, we investigate the underlying mechanism of structural conformation and how this polymorphic transition plays a role in bacterial swimming. National Science Foundation.

  19. Mitochondrial DNA polymorphism in mitochondrial myopathy.

    PubMed

    Holt, I J; Harding, A E; Morgan-Hughes, J A

    1988-05-01

    In order to test the hypothesis that mitochondrial myopathy may be caused by mutation of the mitochondrial (mt) genome, restriction fragment length polymorphism in leucocyte mt DNA has been studied in 38 patients with mitochondrial myopathy, 44 of their unaffected matrilineal relatives, and 35 normal control subjects. Previously unreported mt DNA polymorphisms were identified in both patients and controls. No differences in restriction fragment patterns were observed between affected and unaffected individuals in the same maternal line, and there was no evidence of major deletion of mt DNA in patients. This study provides no positive evidence of mitochondrial inheritance in mitochondrial myopathy, but this has not been excluded.

  20. Simultaneous detection of the exon 10 polymorphism and a novel intronic single base insertion polymorphism in the XPD gene using single strand conformation polymorphism.

    PubMed

    Kumar, Rajiv; Angelini, Sabrina; Hemminki, Kari

    2003-03-01

    We developed a new method based on the single strand conformation polymorphism (SSCP) technique for the detection of a G23591A (Asp312Asn) polymorphism in exon 10 of the XPD gene. In the process we also identified a novel polymorphism 23623C-ins (IVS10+17C-ins) in intron 10 of the same gene. With this newly developed SSCP-based method of genotyping we could detect both polymorphisms in the same assay and thus consequently determine the haplotype. In order to determine the population frequency of the novel polymorphism and the haplotype frequency, 302 healthy individuals were genotyped. The allelic frequency of the 23623C-ins intronic polymorphism was 0.16, whereas the frequency of the variant allele for the G23591A polymorphism was 0.39. Forty-three individuals (14%) were heterozygous for both polymorphisms but none carried polymorphic variants for both G23591A and 23623C-ins on the same allele. The effect of the novel intronic insertion polymorphism, which is located 16 nt downstream of the 3'-end of exon 10 of the XPD gene and involves a mononucleotide C repeat sequence, on expression remains to be determined.

  1. Idealized powder diffraction patterns for cellulose polymorphs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cellulose samples are routinely analyzed by X-ray diffraction to determine their crystal type (polymorph) and crystallinity. However, the connection is seldom made between those efforts and the crystal structures of cellulose that have been determined with synchrotron X-radiation and neutron diffrac...

  2. Treatment of asymptomatic catecholaminergic polymorphic ventricular tachycardia.

    PubMed

    Obeyesekere, Manoj N; Sy, Raymond W; Leong-Sit, Peter; Gula, Lorne J; Yee, Raymond; Skanes, Allan C; Klein, George J; Krahn, Andrew D

    2012-05-01

    Catecholaminergic polymorphic ventricular tachycardia is a rare genetic disorder caused by mutations in genes involved in the intracellular calcium homeostasis of cardiac cells. Affected patients typically present with life-threatening ventricular arrhythmias precipitated by emotional/physical stress. The diagnosis is based on the demonstration of polymorphic or bidirectional ventricular tachycardia associated with adrenergic stress. Genetic testing can be confirmatory in some patients. Treatment for catecholaminergic polymorphic ventricular tachycardia includes medical and surgical efforts to suppress the effects of epinephrine at the myocardial level and/or modulation of calcium homeostasis. Mortality is high when untreated and sudden cardiac death may be the first manifestation of the disease. First-degree relatives of a proband should be offered genetic testing if the causal mutation is known. If the family mutation is not known, relatives should be clinically evaluated with provocative testing. In the absence of rigorous trials, prophylactic treatment of the asymptomatic catecholaminergic polymorphic ventricular tachycardia patient appears to reduce morbidity and mortality.

  3. Difficulties in Learning Inheritance and Polymorphism

    ERIC Educational Resources Information Center

    Liberman, Neomi; Beeri, Catriel; Kolikant, Yifat Ben-David

    2011-01-01

    This article reports on difficulties related to the concepts of inheritance and polymorphism, expressed by a group of 22 in-service CS teachers with an experience with the procedural paradigm, as they coped with a course on OOP. Our findings are based on the analysis of tests, questionnaires that the teachers completed in the course, as well as on…

  4. ARH missense polymorphisms and plasma cholesterol levels.

    PubMed

    Hubacek, Jaroslav A; Hyatt, Tommy

    2004-01-01

    Mutations in a putative low-density lipoprotein (LDL) receptor adaptor protein called ARH have been recently described in patients with autosomal recessive hypercholesterolemia (ARH). ARH plays a tissue-specific role in determination of LDL receptor function. In the ARH gene three mismatched polymorphisms have been detected: Pro202Ser, Pro202His and Arg238Trp. These are of putative interest in plasma cholesterol level determination. To evaluate the effect of polymorphisms on plasma cholesterol levels, all polymorphisms were analyzed by PCR and restriction enzyme analysis by MnII, HpyCH4IV and SacII in 100 Caucasian males with high (>90%, 6.29 +/- 0.89 mmol/l), and 100 males with low (<10%, 3.60 +/- 0.57 mmol/l), total plasma cholesterol levels. No significant differences were observed in frequencies of ARH genotypes or alleles between these two extreme groups. These results suggest that ARH polymorphisms are unlikely to be important genetic determinants of plasma cholesterol levels.

  5. Molecular basis for amyloid-[beta] polymorphism

    SciTech Connect

    Colletier, Jacques-Philippe; Laganowsky, Arthur; Landau, Meytal; Zhao, Minglei; Soriaga, Angela B.; Goldschmidt, Lukasz; Flot, David; Cascio, Duilio; Sawaya, Michael R.; Eisenberga, David

    2011-10-19

    Amyloid-beta (A{beta}) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A{beta} molecules form {beta}-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of A{beta} has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A{beta} polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A{beta}. These structures, all of short, self-complementing pairs of {beta}-sheets termed steric zippers, reveal a variety of modes of self-association of A{beta}. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to A{beta}. These structures and molecular models contribute fundamental information for understanding A{beta} polymorphic nature and pathogenesis.

  6. The Effect of Polymorphism on Surface Energetics of D-Mannitol Polymorphs.

    PubMed

    Smith, Robert R; Shah, Umang V; Parambil, Jose V; Burnett, Daniel J; Thielmann, Frank; Heng, Jerry Y Y

    2017-01-01

    The aim of this work was to assess the effect of different crystalline polymorphism on surface energetics of D-mannitol using finite dilution inverse gas chromatography (FD-IGC). Pure α, β and δ polymorphs were prepared via solution crystallisation and characterised by powder X-ray diffraction (P-XRD). The dispersive surface energies were found to range from 43 to 34 mJ/m(2), 50 to 41 mJ/m(2), and 48 to 38 mJ/m(2), for α, β, and δ, respectively, for surface coverage ranging from 0.006 to 0.095. A deconvolution modelling approach was employed to establish their energy sites. The primary sites corresponded to maxima in the dispersive surface energy of 37.1 and 33.5; 43.3 and 39.5; and 38.6, 38.4 and 33.0; for α, β, and δ, respectively. This methodology was also extended to an α-β polymorph mixture to estimate the amount of the constituent α and β components present in the sample. The dispersive surface energies of the α-β mixture were found to be in the range of 48 to 37 mJ/m(2) with 40.0, 42.4, 38.4 and 33.1 mJ/m(2) sites. The deconvolution modelling method extracted the energy contribution of each of the polymorphs from data for the polymorphic mixture. The mixture was found to have a β-polymorph surface content of ∼19%. This work shows the influence of polymorphism on surface energetics and demonstrates that FD-IGC coupled with a simple modelling approach to be a powerful tool for assessing the specific nature of this energetic distribution including the quantification of polymorphic content on the surface.

  7. Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine.

    PubMed

    Du, Yong; Zhang, Huili; Xue, Jiadan; Tang, Wenjian; Fang, Hongxia; Zhang, Qi; Li, Yafang; Hong, Zhi

    2015-02-25

    Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm(-1) represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields.

  8. Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine

    NASA Astrophysics Data System (ADS)

    Du, Yong; Zhang, Huili; Xue, Jiadan; Tang, Wenjian; Fang, Hongxia; Zhang, Qi; Li, Yafang; Hong, Zhi

    2015-02-01

    Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm-1 represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields.

  9. Wnt antagonist gene polymorphisms and renal cancer

    PubMed Central

    Hirata, Hiroshi; Hinoda, Yuji; Nakajima, Koichi; Kikuno, Nobuyuki; Yamamura, Soichiro; Kawakami, Kazumori; Suehiro, Yutaka; Tabatabai, Z. Laura; Ishii, Nobuhisa; Dahiya, Rajvir

    2014-01-01

    Purpose Epigenetic silencing of several Wnt pathway related genes has been reported in renal cancer. Except for the TCF4 gene, there are no reports regarding Wnt pathway gene polymorphisms in renal cancer. Therefore, we hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer. Experimental Design A total of 210 patients (145 male and 65 female) with pathologically confirmed renal cell carcinoma (RCC), and 200 age- and sex-matched control individuals were enrolled in this study. We genotyped 14 SNPs in six genes including DKK2 (rs17037102, rs419558, rs447372), DKK3 (rs3206824, rs11022095, rs1472189, rs7396187, rs2291599), DKK4 (rs2073664), sFRP4 (rs1802073, rs1802074), SMAD7 (rs12953717), DAAM2 (rs6937133, rs2504106) using PCR-RFLP and direct sequencing in RCC and age-matched healthy subjects. We also tested the relationship between these polymorphisms and clinicopathologic data including gender, grade, tumor stage, lymph-node involvement, distant metastasis, and overall survival. Results A significant decrease in the frequency of the G/A+A/A genotypes in the DKK3 codon335 rs3206824 was observed in RCC patients compared with controls. The frequency of the rs3206824 (G/A) A- rs7396187 (G/C) C haplotype was significantly lower in RCC compared with other haplotypes. We also found that DKK3 rs1472189 C/T is associated with distant metastasis and furthermore, DKK2 rs17037102 G homozygous patients had a decreased risk for death by multivariate Cox regression analysis. Conclusions This is the first report documenting that DKK3 polymorphisms are associated with RCC and that the DKK2 rs17037102 polymorphism may be a predictor for survival in RCC patients after radical nephrectomy. PMID:19562778

  10. IPD--the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Mistry, Kavita; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G E

    2010-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors, IPD-MHC, is a database of sequences of the Major Histocompatibility Complex of different species; IPD-human platelet antigens, alloantigens expressed only on platelets and IPD-ESTDAB, which provides access to the European Searchable Tumour cell-line database, a cell bank of immunologically characterised melanoma cell lines. The data is currently available online from the website and ftp directory.

  11. IPD--the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Halliwell, Jason A; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G E

    2013-01-01

    The Immuno Polymorphism Database (IPD), http://www.ebi.ac.uk/ipd/ is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer-cell immunoglobulin-like receptors, IPD-MHC, a database of sequences of the major histocompatibility complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTDAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The data is currently available online from the website and FTP directory. This article describes the latest updates and additional tools added to the IPD project.

  12. Carbon nitride frameworks and dense crystalline polymorphs

    NASA Astrophysics Data System (ADS)

    Pickard, Chris J.; Salamat, Ashkan; Bojdys, Michael J.; Needs, Richard J.; McMillan, Paul F.

    2016-09-01

    We used ab initio random structure searching (AIRSS) to investigate polymorphism in C3N4 carbon nitride as a function of pressure. Our calculations reveal new framework structures, including a particularly stable chiral polymorph of space group P 43212 containing mixed s p2 and s p3 bonding, that we have produced experimentally and recovered to ambient conditions. As pressure is increased a sequence of structures with fully s p3 -bonded C atoms and three-fold-coordinated N atoms is predicted, culminating in a dense P n m a phase above 250 GPa. Beyond 650 GPa we find that C3N4 becomes unstable to decomposition into diamond and pyrite-structured CN2.

  13. Gene polymorphisms, apoptotic capacity and cancer risk.

    PubMed

    Imyanitov, Evgeny N

    2009-04-01

    Programmed cell death has been implicated in various aspects of cancer development. Apoptotic capacity is a subject of significant interindividual variations, which are largely attributed to hereditary traits. Single nucleotide polymorphisms (SNPs) located within cell death genes may influence cancer risk in various ways. Low activity of apoptosis may favor cancer development because of the failure to eliminate cellular clones carrying DNA damage and propensity to inflammation, but may also protect against malignancy due to preservation of antitumor immune cells. Phenotyping studies assessing cell death rate in cancer patients versus healthy controls are limited in number and produced controversial results. TP53 R72P polymorphism is the only SNP whose functional impact on apoptotic response has been replicated in independent investigations. Intriguingly, meta-analysis of TP53 genotyping studies has provided evidence for the association between apoptosis-deficient TP53 genotype and tumor susceptibility. Systematic analysis of cancer-predisposing relevance of other apoptotic gene SNPs remains to be done.

  14. IPD—the Immuno Polymorphism Database

    PubMed Central

    Robinson, James; Mistry, Kavita; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G. E.

    2010-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors, IPD-MHC, is a database of sequences of the Major Histocompatibility Complex of different species; IPD-human platelet antigens, alloantigens expressed only on platelets and IPD-ESTDAB, which provides access to the European Searchable Tumour cell-line database, a cell bank of immunologically characterised melanoma cell lines. The data is currently available online from the website and ftp directory. PMID:19875415

  15. Kinetics versus Thermodynamics in Virus Capsid Polymorphism.

    PubMed

    Moerman, Pepijn; van der Schoot, Paul; Kegel, Willem

    2016-07-07

    Virus coat proteins spontaneously self-assemble into empty shells in aqueous solution under the appropriate physicochemical conditions, driven by an interaction free energy per bond on the order of 2-5 times the thermal energy kBT. For this seemingly modest interaction strength, each protein building block nonetheless gains a very large binding free energy, between 10 and 20 kBT. Because of this, there is debate about whether the assembly process is reversible or irreversible. Here we discuss capsid polymorphism observed in in vitro experiments from the perspective of nucleation theory and of the thermodynamics of mass action. We specifically consider the potential contribution of a curvature free energy term to the effective interaction potential between the proteins. From these models, we propose experiments that may conclusively reveal whether virus capsid assembly into a mixture of polymorphs is a reversible or an irreversible process.

  16. APOE gene polymorphisms and diabetic peripheral neuropathy.

    PubMed

    Monastiriotis, Christodoulos; Papanas, Nikolaos; Veletza, Stavroula; Maltezos, Efstratios

    2012-09-08

    Genetic factors may influence the natural course of diabetic peripheral neuropathy and explain some of its variability. The aim of this review was to examine the association between apolipoprotein E (apoE) gene polymorphisms and diabetic peripheral neuropathy. Four relevant studies were identified. The two earlier works provided evidence that the ɛ4 allele is a risk factor for this complication, while the two more recent studies were negative. Important differences in the methodology used and in the populations included are obvious, rendering difficult the comparison between studies. In conclusion, the association between APOE gene polymorphisms and diabetic peripheral neuropathy is still unclear. Available evidence is rather limited and results have so far been contradictory. Future studies should employ more robust methodology, adjusting for potential confounders and for the prevalence of neuropathy in the general population with diabetes.

  17. New polymorphic variants of human blood clotting factor IX

    SciTech Connect

    Surin, V.L.; Luk`yanenko, A.V.; Tagiev, A.F.; Smirnova, O.V.; Plutalov, O.V.; Berlin, Yu.A.

    1995-04-01

    The polymorphism of Alu-repeats, which are located in the introns of the human factor IX gene (copies 1-3), was studied. To identify polymorphic variants, direct sequencing of PCR products that contained appropriate repeats was used. In each case, 20 unrelated X chromosomes were studied. A polymorphic Dra I site was found near the 3{prime}-end of Alu copy 3 within the region of the polyA tract. A PCR-based testing system with internal control of restriction hydrolysis was suggested. Testing 81 unrelated X chromosomes revealed that the frequency of the polymorphic Dra I site is 0.23. Taq I polymorphism, which was revealed in Alu copy 4 of factor IX gene in our previous work, was found to be closely linked to Dra I polymorphism. Studies in linkage between different types of polymorphisms of the factor IX gene revealed the presence of a rare polymorphism in intron a that was located within the same minisatellite region as the known polymorphic insertion 50 bp/Dde I. However, the size of the insertion in our case was 26 bp. Only one polymorphic variant was found among over 150 unrelated X chromosomes derived from humans from Moscow and its vicinity. 10 refs., 4 figs., 1 tab.

  18. Calorimetric determinations and theoretical calculations of polymorphs of thalidomide

    NASA Astrophysics Data System (ADS)

    Lara-Ochoa, F.; Pérez, G. Espinosa; Mijangos-Santiago, F.

    2007-09-01

    The analysis of the thermograms of thalidomide obtained for the two reported polymorphs α and β by differential scanning calorimetry (DSC) shows some inconsistencies that are discussed in the present work. The conception of a new polymorph form, named β ∗, allowed us to explain the observed thermal behavior more satisfactorily. This new polymorph shows enantiotropy with both α and β polymorphs, reflected in the unique endotherm obtained in the DSC-thermograms, when a heating rate of 10 °C/min is applied. Several additional experiments, such as re-melting of both polymorph forms, showed that there is indeed a new polymorph with an endotherm located between the endotherms of α and β. IR, Raman, and powder X-ray permit us to characterize the isolated compound, resulting from the re-melting of both polymorph forms. Mechanical calculations were performed to elucidate the conformations of each polymorph, and ab initio quantum chemical calculations were performed to determine the energy of the more stable conformers and the spatial cell energy for both polymorphs α and β. These results suggested a possible conformation for the newly discovered polymorph β ∗.

  19. Introgressive hybridization in a trophically polymorphic cichlid

    PubMed Central

    Hulsey, C Darrin; García-de-León, Francisco J

    2013-01-01

    Trophically polymorphic species could represent lineages that are rapidly diverging along an ecological axis or could phenotypically mark the collapse of species through introgressive hybridization. We investigated patterns of introgression between the trophically polymorphic cichlid fish Herichthys minckleyi and its relative H. cyanoguttatus using a combination of population genetics and species tree analyses. We first examined the distribution of mitochondrial haplotypes within the alternative H. minckleyi pharyngeal jaw morphotypes that are endemic to the small desert valley of Cuatro Ciénegas. We recovered two clusters of mitochondrial haplotypes. The first contained a number of slightly differentiated cytochrome b (cytb) haplotypes that showed some phylogeographic signal and were present in both jaw morphotypes. The other haplotype was monomorphic, highly differentiated from the other cluster, present in equal frequencies in the morphotypes, and identical to H. cyanoguttatus haplotypes found outside Cuatro Ciénegas. Then, we investigated whether H. minckleyi individuals with the H. cyanoguttatus cytb were more evolutionarily similar to H. cyanoguttatus or other H. minckleyi using a species tree analysis of 84 nuclear loci. Both H. minckleyi pharyngeal morphotypes, regardless of their cytb haplotype, were quite distinct from H. cyanoguttatus. However, hybridization could be blurring subdivision within H. minckleyi as the alternative jaw morphotypes were not genetically distinct from one another. Accounting for introgression from H. cyanoguttatus will be essential to understand the evolution of the trophically polymorphic cichlid H. minckleyi. PMID:24340193

  20. Polymorphisms within inflammatory genes and colorectal cancer

    PubMed Central

    Landi, Stefano; Gemignani, Federica; Bottari, Fabio; Gioia-Patricola, Lydie; Guino, Elisabet; Cambray, María; Biondo, Sebastiano; Capella, Gabriel; Boldrini, Laura; Canzian, Federico; Moreno, Victor

    2006-01-01

    Background Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). Results There was no statistically significant association between the SNPs investigated and colorectal cancer risk. Conclusion The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size. PMID:17062130

  1. An orthorhombic polymorph of mulinic acid.

    PubMed

    Brito, Iván; Bórquez, Jorge; Loyola, Luis Alberto; López-Rodríguez, Matías; Cárdenas, Alejandro

    2010-01-09

    THE TITLE COMPOUND [SYSTEMATIC NAME: (3S,3aS,10bR)-3-isopropyl-5a,8-dimethyl-2,3,4,5,5a,6,7,10,10a,10b-deca-hydro-endo-epidioxy-cyclo-hepta-[e]indene-3a(1H)-carboxylic acid], C(20)H(30)O(4), is a polymorphic form of a previously reported structure [Loyola et al. (1990 ▶). Tetra-hedron, 46, 5413-5420]. The newly found ortho-rhom-bic polymorph crystallizes in P2(1)2(1)2(1) with two mol-ecules in the asymmetric unit. The mol-ecules are linked into discrete D(2) chains by simple O-H⋯O inter-actions. There are only slight variations in the mol-ecular geometry and supra-molecular organization in the crystal structures of the two polymorphs. The densities are 1.145 (monoclinic, P2(1)) and 1.155 Mg m(-3) (ortho-rhom-bic, P2(1)2(1)2(1)).

  2. Polymorphic growth rates in myrmecophilous insects.

    PubMed

    Schönrogge, K; Wardlaw, J C; Thomas, J A; Elmes, G W

    2000-04-22

    A polymorphism in growth rates was recently described affecting the larval development of the myrmecophilous butterfly Maculinea rebeli, spanning different years in a single insect population. The close integration of M. rebeli into the host ant colonies, facilitated by adaptations in behaviour and chemical mimicry, make extended larval development a successful strategy. Here we present additional data for M. rebeli and new data for Maculinea alcon (another cuckoo-feeding lycaenid) and the two myrmecophilous predators Maculinea arion and Microdon mutabilis (Diptera: Syrphidae). As predicted, M. alcon shows the same growth pattern as M. rebeli with a proportion of caterpillars developing in one year and the remainder over two years. This pattern holds in both northern and southern European populations, where M. alcon exploits different species of host. Against expectation, the same bimodal distribution of pre-pupation body weights, indicating one and two year developers, was found for the larvae of M. arion and M. mutabilis. As predators, both species are less closely integrated in their host ant colonies, suggesting that the polymorphism in growth rates is a more general adaptation to a myrmecophilous life style, arrived at by convergent evolution between the Maculinea and Microdon species. For predatory species we suggest that biennialism is an adaptation to the migratory behaviour of the host made possible by the predators' ability to fast over extended periods. We also hypothesize that M. arion represents an ancestral strategy in Maculinea butterflies and that the growth polymorphism might have become genetically fixed in the cuckoo-feeding species.

  3. Genetic polymorphisms linked to susceptibility to malaria.

    PubMed

    Driss, Adel; Hibbert, Jacqueline M; Wilson, Nana O; Iqbal, Shareen A; Adamkiewicz, Thomas V; Stiles, Jonathan K

    2011-09-19

    The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature.Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.

  4. Colour Polymorphism Protects Prey Individuals and Populations Against Predation.

    PubMed

    Karpestam, Einat; Merilaita, Sami; Forsman, Anders

    2016-02-23

    Colour pattern polymorphism in animals can influence and be influenced by interactions between predators and prey. However, few studies have examined whether polymorphism is adaptive, and there is no evidence that the co-occurrence of two or more natural prey colour variants can increase survival of populations. Here we show that visual predators that exploit polymorphic prey suffer from reduced performance, and further provide rare evidence in support of the hypothesis that prey colour polymorphism may afford protection against predators for both individuals and populations. This protective effect provides a probable explanation for the longstanding, evolutionary puzzle of the existence of colour polymorphisms. We also propose that this protective effect can provide an adaptive explanation for search image formation in predators rather than search image formation explaining polymorphism.

  5. N-Acetyltransferase 1 Polymorphism and Breast Cancer Risk

    DTIC Science & Technology

    2011-10-01

    analysis of the N-acetyltransferase 1 gene (NAT1*) using polymerase chain reaction-restriction fragment- single strand conformation polymorphism assay...risk of smoking-induced lung cancer (Bouchardy et al., 1998). NAT1*14B is characterized by a single nucleotide polymorphism (SNP) G560A (rs4986782...Structure-function analyses of single nucleotide polymorphisms in human N-acetyltransferase 1. Drug Metab Rev 40, 169-184. Zheng, W., Deitz, A.C., Campbell

  6. Genetic Polymorphisms, Hormone Levels, and Hot Flashes in Midlife Women

    PubMed Central

    Schilling, Chrissy; Gallicchio, Lisa; Miller, Susan R.; Langenberg, Patricia; Zacur, Howard; Flaws, Jodi A.

    2007-01-01

    Objective Hot flashes disrupt the lives of millions of women each year. Although hot flashes are a public health concern, little is known about risk factors that predispose women to hot flashes. Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes. Methods In a cross-sectional study design, midlife women aged 45 to 54 years (n=639) were recruited from Baltimore and its surrounding counties. Participants completed a questionnaire and donated a blood sample for steroid hormone analysis and genotyping. The associations between genetic polymorphisms and hormone levels, as well as the associations between genetic polymorphisms, hormone levels, and hot flashes were examined using statistical models. Results A polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, while a polymorphism in CYP19 (aromatase) was associated with higher testosterone and DHEA-S levels. Lower progesterone and sex hormone binding globulin levels, lower free estradiol index, and a higher ratio of total androgens to total estrogens were associated with the experiencing of hot flashes. A polymorphism in CYP1B1 and a polymorphism in 3βHSD were both associated with hot flashes. Conclusion Some genetic polymorphisms may be associated with altered levels of hormones in midlife women. Further, selected genetic polymorphisms and altered hormone levels may be associated with the risk of hot flashes in midlife women. PMID:17187946

  7. Single-nucleotide polymorphism discovery by targeted DNA photocleavage.

    PubMed

    Hart, Jonathan R; Johnson, Martin D; Barton, Jacqueline K

    2004-09-28

    Single-nucleotide polymorphisms are the largest source of genetic variation in humans. We report a method for the discovery of single-nucleotide polymorphisms within genomic DNA. Pooled genomic samples are amplified, denatured, and annealed to generate mismatches at polymorphic DNA sites. Upon photoactivation, these DNA mismatches are then cleaved site-specifically by using a small molecular probe, a bulky metallointercalator, Rhchrysi or Rhphzi. Fluorescent labeling of the cleaved products and separation by capillary electrophoresis permits rapid identification with single-base resolution of the single-nucleotide polymorphism site. This method is remarkably sensitive and minor allele frequencies as low as 5% can be readily detected.

  8. Persistence of neutral polymorphisms in Lake Victoria cichlid fish

    PubMed Central

    Nagl, Sandra; Tichy, Herbert; Mayer, Werner E.; Takahata, Naoyuki; Klein, Jan

    1998-01-01

    Phylogenetic trees for groups of closely related species often have different topologies, depending on the genes used. One explanation for the discordant topologies is the persistence of polymorphisms through the speciation phase, followed by differential fixation of alleles in the resulting species. The existence of transspecies polymorphisms has been documented for alleles maintained by balancing selection but not for neutral alleles. In the present study, transspecific persistence of neutral polymorphisms was tested in the endemic haplochromine species flock of Lake Victoria cichlid fish. Putative noncoding region polymorphisms were identified at four randomly selected nuclear loci and tested on a collection of 12 Lake Victoria species and their putative riverine ancestors. At all loci, the same polymorphism was found to be present in nearly all the tested species, both lacustrine and riverine. Different polymorphisms at these loci were found in cichlids of other East African lakes (Malawi and Tanganyika). The Lake Victoria polymorphisms must have therefore arisen after the flocks now inhabiting the three great lakes diverged from one another, but before the riverine ancestors of the Lake Victoria flock colonized the Lake. Calculations based on the mtDNA clock suggest that the polymorphisms have persisted for about 1.4 million years. To maintain neutral polymorphisms for such a long time, the population size must have remained large throughout the entire period. PMID:9826684

  9. Persistence of neutral polymorphisms in Lake Victoria cichlid fish.

    PubMed

    Nagl, S; Tichy, H; Mayer, W E; Takahata, N; Klein, J

    1998-11-24

    Phylogenetic trees for groups of closely related species often have different topologies, depending on the genes used. One explanation for the discordant topologies is the persistence of polymorphisms through the speciation phase, followed by differential fixation of alleles in the resulting species. The existence of transspecies polymorphisms has been documented for alleles maintained by balancing selection but not for neutral alleles. In the present study, transspecific persistence of neutral polymorphisms was tested in the endemic haplochromine species flock of Lake Victoria cichlid fish. Putative noncoding region polymorphisms were identified at four randomly selected nuclear loci and tested on a collection of 12 Lake Victoria species and their putative riverine ancestors. At all loci, the same polymorphism was found to be present in nearly all the tested species, both lacustrine and riverine. Different polymorphisms at these loci were found in cichlids of other East African lakes (Malawi and Tanganyika). The Lake Victoria polymorphisms must have therefore arisen after the flocks now inhabiting the three great lakes diverged from one another, but before the riverine ancestors of the Lake Victoria flock colonized the Lake. Calculations based on the mtDNA clock suggest that the polymorphisms have persisted for about 1.4 million years. To maintain neutral polymorphisms for such a long time, the population size must have remained large throughout the entire period.

  10. 2-Quinolinecarboxaldehyde: Polymorphic behavior of a small rigid molecule

    NASA Astrophysics Data System (ADS)

    Maria, Teresa M. R.; Ermelinda S. Eusébio, M.; Almeida e Silva, J.; Sobral, Abílio J. F. N.; Cardoso, C.; Paixão, J. A.; Ramos Silva, M.

    2012-12-01

    This work reports an investigation on the polymorphism of 2-quinolinecarboxaldehyde, a quinoline derivative, frequently used as a ligand in the synthesis of metal complexes. 2-Quinolinecarboxaldehyde lacks both molecular flexibility and the ability to form strong hydrogen bonds, two characteristics often seen as driving forces for the occurrence of polymorphism. Nevertheless, a rich polymorphic behavior was found for this substance. Polymorphic forms were generated by crystallization from solutions, and by melt cooling. Four polymorphic forms could be clearly identified by thermal analysis investigation and the crystalline structures of forms I and III were solved by single-crystal X-ray diffraction, at room temperature. In polymorph I, molecules are joined by π-π and weak C-H⋯O interactions while in polymorph III helicoidal chiral chains are formed and very weak C-H⋯O intermolecular interactions can be identified. Neither of these intermolecular interactions involves the formyl hydrogen atom. Concomitant polymorph crystallization from the melt was often observed. XRPD diffractograms which showed similarities to that of polymorph I but presented striking differences were obtained in some experiments. In certain cases the discrepancies may be ascribed to effects of preferential orientation. However, the existence of multiple but slightly different structures with small differences seems to be a better explanation for these experimental observations.

  11. Adrenergic Polymorphism and the Human Stress Response

    PubMed Central

    Rao, Fangwen; Zhang, Lian; Wessel, Jennifer; Zhang, Kuixing; Wen, Gen; Kennedy, Brian P.; Rana, Brinda K.; Das, Madhusudan; Rodriguez-Flores, Juan L.; Smith, Douglas W.; Cadman, Peter E.; Salem, Rany M.; Mahata, Sushil K.; Schork, Nicholas J.; Taupenot, Laurent; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case–control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key

  12. Polymorphism in silicate-postperovskite reviewed (Invited)

    NASA Astrophysics Data System (ADS)

    Tschauner, O. D.

    2010-12-01

    Early on in the examination of postperovskite(ppv)-type magnesium metasilicate it had been debated if this potential deep mantle mineral can be subject to further structural transformation as function of composition, pressure, and temperature within the range of conditions in the lower mantle. MgSiO3-perovskite accommodates minor elements through local lattice distortions by tilt of the corner-sharing octahedral framework. The CaIrO3-type ppv structure does not seem to possess a similar mechanism of local relaxation of lattice strain. Instead minor elements may rather be accommodated by periodic kinks in this layered structure (1). This kinking-mechanism allows for generating a plethora of polymorphs similar in structure and free energy (1,2). However, the elastic properties of ppv may be strongly affected by this type of structural modification. While structural analogues of silicate-ppv exhibit this type of polymorphism (3,4) previous attempts to examine polymorphism in silicate-ppv remained suggestive (2,5). This is mostly owed to the severe constraints imposed on powder diffraction studies conducted under the extreme conditions of stability of MgSiO3-ppv. Here I present new results on silicate-ppv based on different experimental strategies which shed more light on this complex yet important issue of structural modifications in minor-element bearing silicate-ppv. (1) Oganov et al. Nature 438, 1142 (2005);(2) Tschauner et al. Am. Min. 93, 533 (2008); (3) Shirako et al. Phys. Chem. Min. 36, 455 (2009); Yakovlev et al. J. Sol. Stat. Chem. 182, 1545 (2009) Work supported through NNSA Cooperative Agreement DOE-FC88-01NV14049

  13. What Determines the Ice Polymorph in Clouds?

    PubMed

    Hudait, Arpa; Molinero, Valeria

    2016-07-20

    Ice crystals in the atmosphere nucleate from supercooled liquid water and grow by vapor uptake. The structure of the ice polymorph grown has strong impact on the morphology and light scattering of the ice crystals, modulates the amount of water vapor in ice clouds, and can impact the molecular uptake and reactivity of atmospheric aerosols. Experiments and molecular simulations indicate that ice nucleated and grown from deeply supercooled liquid water is metastable stacking disordered ice. The ice polymorph grown from vapor has not yet been determined. Here we use large-scale molecular simulations to determine the structure of ice that grows as a result of uptake of water vapor in the temperature range relevant to cirrus and mixed-phase clouds, elucidate the molecular mechanism of the formation of ice at the vapor interface, and compute the free energy difference between cubic and hexagonal ice interfaces with vapor. We find that vapor deposition results in growth of stacking disordered ice only under conditions of extreme supersaturation, for which a nonequilibrium liquid layer completely wets the surface of ice. Such extreme conditions have been used to produce stacking disordered frost ice in experiments and may be plausible in the summer polar mesosphere. Growth of ice from vapor at moderate supersaturations in the temperature range relevant to cirrus and mixed-phase clouds, from 200 to 260 K, produces exclusively the stable hexagonal ice polymorph. Cubic ice is disfavored with respect to hexagonal ice not only by a small penalty in the bulk free energy (3.6 ± 1.5 J mol(-1) at 260 K) but also by a large free energy penalty at the ice-vapor interface (89.7 ± 12.8 J mol(-1) at 260 K). The latter originates in higher vibrational entropy of the hexagonal-terminated ice-vapor interface. We predict that the free energy penalty against the cubic ice interface should decrease strongly with temperature, resulting in some degree of stacking disorder in ice grown from

  14. Placental glucose dehydrogenase polymorphism in Koreans.

    PubMed

    Kim, Y J; Paik, S G; Park, H Y

    1994-12-01

    The genetic polymorphism of placental glucose dehydrogenase (GDH) was investigated in 300 Korean placentae using horizontal starch gel electrophoresis. The allele frequencies for GDH1, GDH2 and GDH3 were 0.537, 0.440 and 0.005, respectively, which were similar to those in Japanese. We also observed an anodal allele which was similar to the GDH4 originally reported in Chinese populations at a low frequency of 0.015. An additional new cathodal allele (named GDH6) was observed in the present study with a very low frequency of 0.003.

  15. Genetic salivary protein polymorphism in Mexican population.

    PubMed

    Banderas Tarabay, J A; González Begné, M

    1996-01-01

    Genetic polymorphism is the major contributor that affects human salivary composition. In order to determine the molecular phenotypes in saliva, it is important to know the distribution of proteins with specific functions which allows the clinical diagnosis of specific diseases. Unstimulated human whole saliva samples from 120 subjects were subjected to sodium dodecyl sulfate polyacrylamide slab gel electrophoresis (SDS-PAGE). The phenotype distribution of several molecules including MG1, MG2, alpha-Amylase, PRP-I and cystatins were similar. Qualitative and quantitative characteristics were specific in each subject.

  16. Polymorphisms in Autophagy Genes and Susceptibility to Tuberculosis

    PubMed Central

    Alisjahbana, Bachti; Sahiratmadja, Edhyana; Parwati, Ida; Oosting, Marije; Plantinga, Theo S.; Joosten, Leo A. B.; Netea, Mihai G.; Ottenhoff, Tom H. M.; van de Vosse, Esther; van Crevel, Reinout

    2012-01-01

    Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02) and MTOR (p = 0.02) and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04). All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production. PMID:22879892

  17. Human lymphocyte polymorphisms detected by quantitative two-dimensional electrophoresis

    SciTech Connect

    Goldman, D.; Merril, C.R.

    1983-09-01

    A survey of 186 soluble lymphocyte proteins for genetic polymorphism was carried out utilizing two-dimensional electrophoresis of /sup 14/C-labeled phytohemagglutinin (PHA)-stimulated human lymphocyte proteins. Nineteen of these proteins exhibited positional variation consistent with independent genetic polymorphism in a primary sample of 28 individuals. Each of these polymorphisms was characterized by quantitative gene-dosage dependence insofar as the heterozygous phenotype expressed approximately 50% of each allelic gene product as was seen in homozygotes. Patterns observed were also identical in monozygotic twins, replicate samples, and replicate gels. The three expected phenotypes (two homozygotes and a heterozygote) were observed in each of 10 of these polymorphisms while the remaining nine had one of the homozygous classes absent. The presence of the three phenotypes, the demonstration of gene-dosage dependence, and our own and previous pedigree analysis of certain of these polymorphisms supports the genetic basis of these variants. Based on this data, the frequency of polymorphic loci for man is: P . 19/186 . .102, and the average heterozygosity is .024. This estimate is approximately 1/3 to 1/2 the rate of polymorphism previously estimated for man in other studies using one-dimensional electrophoresis of isozyme loci. The newly described polymorphisms and others which should be detectable in larger protein surveys with two-dimensional electrophoresis hold promise as genetic markers of the human genome for use in gene mapping and pedigree analyses.

  18. Impact of host genetic polymorphisms on vaccine induced antibody response

    PubMed Central

    Linnik, Janina E.; Egli, Adrian

    2016-01-01

    ABSTRACT Many host- and vaccine-specific factors modulate an antibody response. Host genetic polymorphisms, in particular, modulate the immune response in multiple ways on different scales. This review article describes how information on host genetic polymorphisms and corresponding immune cascades may be used to generate personalized vaccine strategies to optimize the antibody response. PMID:26809773

  19. Association between Tryptophan Hydroxylase 2 Gene Polymorphism and Completed Suicide

    ERIC Educational Resources Information Center

    Fudalej, Sylwia; Ilgen, Mark; Fudalej, Marcin; Kostrzewa, Grazyna; Barry, Kristen; Wojnar, Marcin; Krajewski, Pawel; Blow, Frederic; Ploski, Rafal

    2010-01-01

    The association between suicide and a single nucleotide polymorphism (rs1386483) was examined in the recently identified tryptophan hydroxylase 2 (TPH2) gene. Blood samples of 143 suicide victims and 162 age- and sex-matched controls were examined. The frequency of the TT genotype in the TPH2 polymorphism was higher in suicide victims than in…

  20. Effects of functional polymorphisms on beef carcass merit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To develop a resource to identify polymorphisms present in common beef cattle breeds, and relate those polymorphisms to phenotypic differences, low-coverage genomic sequence was obtained on 186 purebred bulls from 15 predominant breeds in the United States, and 84 crossbred sons of these bulls. The...

  1. Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

    SciTech Connect

    White, Tommy E.; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos; Knowlton, Caitlin; Kim, Baek; Sawyer, Sara L.; Diaz-Griffero, Felipe

    2014-07-15

    SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition. - Highlights: • Human SAMHD1 single-nucleotide polymorphisms block HIV-1 and HIV-2 infection. • SAMHD1 polymorphisms do not affect its ability to block LINE-1 retrotransposition. • SAMHD1 polymorphisms decrease the cellular levels of dNTPs.

  2. Bitter Taste Receptor Polymorphisms and Human Aging

    PubMed Central

    Carrai, Maura; Crocco, Paolina; Montesanto, Alberto; Canzian, Federico; Rose, Giuseppina; Rizzato, Cosmeri

    2012-01-01

    Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association (p = 0.001) with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics. PMID:23133589

  3. Polymorphic collaboration in the global grid

    NASA Astrophysics Data System (ADS)

    McQuay, William K.

    2006-05-01

    Next generation collaborative systems must be able to represent the same information in different forms on a broad spectrum of devices and resources from low end personal digital assistants (PDA) to high performance computers (HPC). Users might be on a desktop then switch to a laptop and then to a PDA while accessing the global grid. The user preference profile for a collaboration session should be capable of moving with them as well as be automatically adjusted for the device type. Collaborative systems must be capable of representing the same information in many forms for different domains and on many devices and thus be polymorphic. Polymorphic collaboration will provide an ability for multiple heterogeneous resources (human to human, human to machine and machine to machine) to share information and activities, as well as the ability to regulate collaborative sessions based on client characteristics and needs; reuse user profiles, tool category choices, and settings in future collaboration session by same or different users; use intelligent agents to assist collaborative systems in learning user/resource preferences and behaviors, and autonomously derive optimal information to provide to users and decision makers. This paper discusses ongoing research in next generation collaborative environments with the goal of making electronic collaboration as easy to use as the telephone - collaboration at the touch of the screen.

  4. Salivary proteome and its genetic polymorphisms.

    PubMed

    Oppenheim, Frank G; Salih, Erdjan; Siqueira, Walter L; Zhang, Weimin; Helmerhorst, Eva J

    2007-03-01

    Salivary diagnostics for oral as well as systemic diseases is dependent on the identification of biomolecules reflecting a characteristic change in presence, absence, composition, or structure of saliva components found under healthy conditions. Most of the biomarkers suitable for diagnostics comprise proteins and peptides. The usefulness of salivary proteins for diagnostics requires the recognition of typical features, which make saliva as a body fluid unique. Salivary secretions reflect a degree of redundancy displayed by extensive polymorphisms forming families for each of the major salivary proteins. The structural differences among these polymorphic isoforms range from distinct to subtle, which may in some cases not even affect the mass of different family members. To facilitate the use of modern state-of-the-art proteomics and the development of nanotechnology-based analytical approaches in the field of diagnostics, the salient features of the major salivary protein families are reviewed at the molecular level. Knowledge of the structure and function of salivary gland-derived proteins/peptides has a critical impact on the rapid and correct identification of biomarkers, whether they originate from exocrine or non-exocrine sources.

  5. Functional relevance of human adh polymorphism.

    PubMed

    Eriksson, C J; Fukunaga, T; Sarkola, T; Chen, W J; Chen, C C; Ju, J M; Cheng, A T; Yamamoto, H; Kohlenberg-Müller, K; Kimura, M; Murayama, M; Matsushita, S; Kashima, H; Higuchi, S; Carr, L; Viljoen, D; Brooke, L; Stewart, T; Foroud, T; Su, J; Li, T K; Whitfield, J B

    2001-05-01

    This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were C. J. Peter Eriksson and Tatsushige Fukunaga. The presentations were (1) 4-Methylpyrazole as a tool in the investigation of the role of ADH in the actions of alcohol in humans, by Taisto Sarkola and C. J. Peter Eriksson; (2) ADH2 polymorphism and flushing in Asian populations, by Wei J. Chen, C. C. Chen, J. M. Ju, and Andrew T. A. Cheng; (3) Role of ADH3 genotypes in the acute effects of alcohol in a Finnish population, by Hidetaka Yamamoto, Kathrin Kohlenberg-Müller, and C. J. Peter Eriksson; (4) Clinical characteristics and disease course of alcoholics with different ADH2 genotypes, by Mitsuru Kimura, Masanobu Murayama, Sachio Matsushita, Haruo Kashima, and Susumu Higuchi; (5) ADH2 polymorphism, alcohol drinking, and birth defects, by Lucinda Carr, D. Viljoen, L. Brooke, T. Stewart, T. Foroud, J. Su, and Ting-Kai Li; and (6) ADH genotypes and alcohol use in Europeans, by John B. Whitfield.

  6. TNFA promoter polymorphism and susceptibility to brucellosis.

    PubMed

    Caballero, A; Bravo, M J; Nieto, A; Colmenero, J D; Alonso, A; Martín, J

    2000-09-01

    The aim of this study was to investigate the possible influence of the tumor necrosis factor alpha (TNFA) gene promoter polymorphisms and HLA class II genes on the susceptibility to or development of human brucellosis. TNFA genotypes (at positions -308 and -238) were determined in 59 patients with brucellosis and 160 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. There were no significant differences between the patients and the controls for the TNFA-238 genotypes. However, when the overall TNFA-308 genotype distribution of the brucella patients was compared with that of the control subjects, a significant skewing was observed (P = 0.02). The TNFA-308.1/2 genotype was present at significantly higher frequency in the total patient as a whole compared with control subjects (30% versus 15%; P = 0.01, odds ratio (OR) 2.49, 95% confidence interval (CI) 1.16-5.33). No statistically significant differences in the distribution of HLA-DRB1 or DQB1 alleles were observed between brucella patients and control subjects. Stratification to correct for interdependence of TNFA-308.2 and HLA-DR3 alleles confirmed that, in spite of their strong linkage disequilibrium, the association of TNFA-308.2 with brucellosis was independent of HLA-DR3.

  7. IPD--the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Waller, Matthew J; Stoehr, Peter; Marsh, Steven G E

    2005-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors; IPD-MHC, a database of sequences of the Major Histocompatibility Complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. Those sections with similar data, such as IPD-KIR and IPD-MHC share the same database structure. The sharing of a common database structure makes it easier to implement common tools for data submission and retrieval. The data are currently available online from the website and ftp directory; files will also be made available in different formats to download from the website and ftp server. The data will also be included in SRS, BLAST and FASTA search engines at the European Bioinformatics Institute.

  8. IPD—the Immuno Polymorphism Database

    PubMed Central

    Robinson, James; Halliwell, Jason A.; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G. E.

    2013-01-01

    The Immuno Polymorphism Database (IPD), http://www.ebi.ac.uk/ipd/ is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer-cell immunoglobulin-like receptors, IPD-MHC, a database of sequences of the major histocompatibility complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTDAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The data is currently available online from the website and FTP directory. This article describes the latest updates and additional tools added to the IPD project. PMID:23180793

  9. Plumage polymorphism and fitness in Swainson's hawks.

    PubMed

    Briggs, C W; Collopy, M W; Woodbridge, B

    2011-10-01

    We examine the maintenance of a plumage polymorphism, variation in plumages among the same age and sex class within a population, in a population of Swainson's Hawks. We take advantage of 32 years of data to examine two prevalent hypotheses used to explain the persistence of morphs: apostatic selection and heterozygous advantage. We investigate differences in fitness among three morph classes of a melanistic trait in Swainson's Hawks: light (7% of the local breeding population), intermediate (57%) and dark (36%). Specifically, we examined morph differences in adult apparent survival, breeding success, annual number of fledglings produced, probability of offspring recruitment into the breeding population and lifetime reproductive success (LRS). If apostatic selection were a factor in maintaining morphs, we would expect that individuals with the least frequent morph would perform best in one or more of these fitness categories. Alternatively, if heterozygous advantage played a role in the maintenance of this polymorphism, we would expect heterozygotes (i.e. intermediate morphs) to have one or more increased rates in these categories. We found no difference in adult apparent survival between morph classes. Similarly, there were no differences in breeding success, nest productivity, LRS or probability of recruitment of offspring between parental morph. We conclude that neither apostatic selection nor heterozygous advantage appear to play a role in maintaining morphs in this population.

  10. Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs.

    PubMed

    Khomane, Kailas S; More, Parth K; Bansal, Arvind K

    2012-07-01

    Being a density violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of molecular packing (true density) and thermodynamic properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examinations of the molecular packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of molecules in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true density and lower heat of fusion showed higher bonding strength. Hence, true density and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders.

  11. Dynamically Alterable Arrays of Polymorphic Data Types

    NASA Technical Reports Server (NTRS)

    James, Mark

    2006-01-01

    An application library package was developed that represents data packets for Deep Space Network (DSN) message packets as dynamically alterable arrays composed of arbitrary polymorphic data types. The software was to address a limitation of the present state of the practice for having an array directly composed of a single monomorphic data type. This is a severe limitation when one is dealing with science data in that the types of objects one is dealing with are typically not known in advance and, therefore, are dynamic in nature. The unique feature of this approach is that it enables one to define at run-time the dynamic shape of the matrix with the ability to store polymorphic data types in each of its indices. Existing languages such as C and C++ have the restriction that the shape of the array must be known in advance and each of its elements be a monomorphic data type that is strictly defined at compile-time. This program can be executed on a variety of platforms. It can be distributed in either source code or binary code form. It must be run in conjunction with any one of a number of Lisp compilers that are available commercially or as shareware.

  12. Polymorphism of the IGF-I System and Sports Performance.

    PubMed

    Ben-Zaken, Sigal; Meckel, Yoav; Nemet, Dan; Dror, Nitzan; Eliakim, Alon

    2016-06-01

    The potential use genetic polymorphism, and in particularly polymorphism of hormone genes, as tool to predict athletic performance is currently very challenging. Recent studies suggest that single nucleotide polymorphisms in IGF-I and myostatin may be beneficial for endurance and short distance running, and may even be associated with elite performance. Polymorphism in IGF-I receptor may differentiate between the two edges of the endurance-power athletic performance running spectrum suggesting beneficial effects for endurance and prevent from success in power events. In contrast, and despite similar metabolic demands, the myostatin-IGF-I-IGF-IR system seems not to play an important role in swimming excellence. This suggests that combining different sport disciplines for sports genetic research purposes should be done with extreme caution. Finally, since any phenotype reflects a complex relationship between genes, environment, epigenetic factors, and the interactions between them, consulting the young athlete regarding future success cannot be based solely on genetic polymorphism.

  13. The relative stability of xylazine hydrochloride polymorphous forms.

    PubMed

    Bērziņs, Agris; Krūkle, Kristīne; Actiņs, Andris; Kreismanis, Juris P

    2010-01-01

    All four known xylazine hydrochloride polymorphous forms were obtained and their relative stabilities were compared directly at three different temperatures. At higher temperatures, it is possible to determine the relative stability of all forms directly by measuring the changes in the composition of the mixtures of two polymorphous forms using powder x-ray diffraction methods. At lower temperatures, a solvent was added to the mixture and the changes in composition were determined. Polymorph transition temperatures were determined directly. To predict the transition temperature which was not found using the direct method, the polymorph melting data and determined transition temperatures were used. A phase stability diagram was constructed from the acquired data. The stability of all anhydrous polymorphous forms was compared in the presence of water vapor pressure that was higher than the equilibrium pressure.

  14. Assortative mating counteracts the evolution of dispersal polymorphisms.

    PubMed

    Fronhofer, Emanuel A; Kubisch, Alexander; Hovestadt, Thomas; Poethke, Hans-Joachim

    2011-09-01

    Polymorphic dispersal strategies are found in many plant and animal species. An important question is how the genetic variation underlying such polymorphisms is maintained. Numerous mechanisms have been discussed, including kin competition or frequency-dependent selection. In the context of sympatric speciation events, genetic and phenotypic variation is often assumed to be preserved by assortative mating. Thus, recently, this has been advocated as a possible mechanism leading to the evolution of dispersal polymorphisms. Here, we examine the role of assortative mating for the evolution of trade-off-driven dispersal polymorphisms by modeling univoltine insect species in a metapopulation. We show that assortative mating does not favor the evolution of polymorphisms. On the contrary, assortative mating favors the evolution of an intermediate dispersal type and a uni-modal distribution of traits within populations. As an alternative, mechanism dominance may explain the occurrence of two discrete morphs.

  15. Special considerations in prognostic research in cancer involving genetic polymorphisms

    PubMed Central

    2013-01-01

    Analysis of genetic polymorphisms may help identify putative prognostic markers and determine the biological basis of variable prognosis in patients. However, in contrast to other variables commonly used in the prognostic studies, there are special considerations when studying genetic polymorphisms. For example, variable inheritance patterns (recessive, dominant, codominant, and additive genetic models) need to be explored to identify the specific genotypes associated with the outcome. In addition, several characteristics of genetic polymorphisms, such as their minor allele frequency and linkage disequilibrium among multiple polymorphisms, and the population substructure of the cohort investigated need to be accounted for in the analyses. In addition, in cancer research due to the genomic differences between the tumor and non-tumor DNA, differences in the genetic information obtained using these tissues need to be carefully assessed in prognostic studies. In this article, we review these and other considerations specific to genetic polymorphism by focusing on genetic prognostic studies in cancer. PMID:23773794

  16. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

  17. An integrated restriction fragment length polymorphism--amplified fragment length polymorphism linkage map for cultivated sunflower.

    PubMed

    Gedil, M A; Wye, C; Berry, S; Segers, B; Peleman, J; Jones, R; Leon, A; Slabaugh, M B; Knapp, S J

    2001-04-01

    Restriction fragment length polymorphism (RFLP) maps have been constructed for cultivated sunflower (Helianthus annuus L.) using three independent sets of RFLP probes. The aim of this research was to integrate RFLP markers from two sets with RFLP markers for resistance gene candidate (RGC) and amplified fragment length polymorphism (AFLP) markers. Genomic DNA samples of HA370 and HA372, the parents of the F2 population used to build the map, were screened for AFLPs using 42 primer combinations and RFLPs using 136 cDNA probes (RFLP analyses were performed on DNA digested with EcoRI, HindIII, EcoRV, or DraI). The AFLP primers produced 446 polymorphic and 1101 monomorphic bands between HA370 and HA372. The integrated map was built by genotyping 296 AFLP and 104 RFLP markers on 180 HA370 x HA372 F2 progeny (the AFLP marker assays were performed using 18 primer combinations). The HA370 x HA372 map comprised 17 linkage groups, presumably corresponding to the 17 haploid chromosomes of sunflower, had a mean density of 3.3 cM, and was 1326 cM long. Six RGC RFLP loci were polymorphic and mapped to three linkage groups (LG8, LG13, and LG15). AFLP markers were densely clustered on several linkage groups, and presumably reside in centromeric regions where recombination is reduced and the ratio of genetic to physical distance is low. Strategies for targeting markers to euchromatic DNA need to be tested in sunflower. The HA370 x HA372 map integrated 14 of 17 linkage groups from two independent RFLP maps. Three linkage groups were devoid of RFLP markers from one of the two maps.

  18. Gene Polymorphisms and Pharmacogenetics in Rheumatoid Arthritis

    PubMed Central

    Rego-Pérez, Ignacio; Fernández-Moreno, Mercedes; Blanco, Francisco J

    2008-01-01

    Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown etiology with genetic predisposition. The advent of new biological agents, as well as the more traditional disease-modifying antirheumatic drugs, has resulted in highly efficient therapies for reducing the symptoms and signs of RA; however, not all patients show the same level of response in disease progression to these therapies. These variations suggest that RA patients may have different genetic regulatory mechanisms. The extensive polymorphisms revealed in non-coding gene-regulatory regions in the immune system, as well as genetic variations in drug-metabolizing enzymes, suggest that this type of variation is of functional and evolutionary importance and may provide clues for developing new therapeutic strategies. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patient’s genetic profile. PMID:19506728

  19. Polymorphic Alu insertions among Mayan populations.

    PubMed

    Herrera, R J; Rojas, D P; Terreros, M C

    2007-01-01

    The Mayan homeland within Mesoamerica spans five countries: Belize, El Salvador, Guatemala, Honduras and Mexico. There are indications that the people we call the Maya migrated from the north to the highlands of Guatemala as early as 4000 B.C. Their existence was village-based and agricultural. The culture of these Preclassic Mayans owes much to the earlier Olmec civilization, which flourished in the southern portion of North America. In this study, four different Mayan groups were examined to assess their genetic variability. Ten polymorphic Alu insertion (PAI) loci were employed to ascertain the genetic affinities among these Mayan groups. North American, African, European and Asian populations were also examined as reference populations. Our results suggest that the Mayan groups examined in this study are not genetically homogeneous.

  20. Androgen receptor gene mutation, rearrangement, polymorphism

    PubMed Central

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E.

    2013-01-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents. PMID:25045626

  1. Tubulin bistability and polymorphic dynamics of microtubules.

    PubMed

    Mohrbach, Hervé; Johner, Albert; Kulić, Igor M

    2010-12-31

    Based on the hypothesis that the GDP-tubulin dimer is a conformationally bistable molecule-rapidly fluctuating between a discrete curved and a straight state-we develop a model for polymorphic dynamics of the microtubule lattice. We show that GDP-tubulin bistability consistently explains unusual dynamic fluctuations, the apparent length-stiffness relation of grafted taxol-stabilized microtubules, and the curved-helical appearance of microtubules in general. When clamped by one end the microtubules undergo an unusual zero energy motion-in its effect reminiscent of a limited rotational hinge. We conclude that microtubules exist in highly cooperative energy-degenerate helical states and discuss possible implications in vivo.

  2. Single nucleotide polymorphism for animal fibre identification.

    PubMed

    Subramanian, Selvi; Karthik, T; Vijayaraaghavan, N N

    2005-03-16

    Animal fibres are highly valuable industrial products often adulterated during marketing. Currently, there is no precise method available to identify and differentiate the fibres. In this study, a PCR-RFLP technique was exploited to differentiate cashmere and wool fibres derived from goat and sheep, respectively. The presence of DNA in animal hair shafts has enabled the isolation of DNA from scoured cashmere and wool fibres. The mitochondrial cytochrome b sequences of both species were amplified by PCR using primers designed from conserved regions. The polymorphism observed between the two species was detected by restricting the amplified product by endonucleases viz., BamH1 and Ssp1. The RFLP profile clearly distinguishes the cashmere and wool fibres and this technique can also be exploited to test adulteration in animal fibres qualitatively.

  3. Identification of polymorphism in ethylone hydrochloride: synthesis and characterization

    PubMed Central

    Alarcon, Idralyn Q.; Copeland, Catherine R.; Cameron, T. Stanley; Linden, Anthony; Grossert, J. Stuart

    2015-01-01

    Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT‐Raman, powder XRD, GC‐MS, ESI‐MS/MS and NMR (13C CPMAS, 1H, 13C). The two polymorphs can be distinguished by vibrational spectroscopy, solid‐state nuclear magnetic resonance spectroscopy and X‐ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra’. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X‐ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism in ethylone hydrochloride. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. PMID:26344849

  4. Zoledronic acid: monoclinic and triclinic polymorphs from powder diffraction data.

    PubMed

    Chernyshev, Vladimir V; Shkavrov, Sergey V; Paseshnichenko, Ksenia A; Puryaeva, Tamara P; Velikodny, Yurii A

    2013-03-01

    The crystal structures of the monoclinic and triclinic polymorphs of zoledronic acid, C5H10N2O7P2, have been established from laboratory powder X-ray diffraction data. The molecules in both polymorphs are described as zwitterions, namely 1-(2-hydroxy-2-phosphonato-2-phosphonoethyl)-1H-imidazol-3-ium. Strong intermolecular hydrogen bonds (with donor-acceptor distances of 2.60 Å or less) link the molecules into layers, parallel to the (100) plane in the monoclinic polymorph and to the (1-10) plane in the triclinic polymorph. The phosphonic acid groups form the inner side of each layer, while the imidazolium groups lie to the outside of the layer, protruding in opposite directions. In both polymorphs, layers related by translation along [100] interact through weak hydrogen bonds (with donor-acceptor distances greater than 2.70 Å), forming three-dimensional layered structures. In the monoclinic polymorph, there are hydrogen-bonded centrosymmetric dimers linked by four strong O-H...O hydrogen bonds, which are not present in the triclinic polymorph.

  5. Identification of polymorphism in ethylone hydrochloride: synthesis and characterization.

    PubMed

    Maheux, Chad R; Alarcon, Idralyn Q; Copeland, Catherine R; Cameron, T Stanley; Linden, Anthony; Grossert, J Stuart

    2016-08-01

    Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT-Raman, powder XRD, GC-MS, ESI-MS/MS and NMR ((13) C CPMAS, (1) H, (13) C). The two polymorphs can be distinguished by vibrational spectroscopy, solid-state nuclear magnetic resonance spectroscopy and X-ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra'. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X-ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism