The Experts below are selected from a list of 431247 Experts worldwide ranked by ideXlab platform
Gary E. Pickard - One of the best experts on this subject based on the ideXlab platform.
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Photic entrainment is altered in the 5-HT1B Receptor knockout mouse.
Journal of biological rhythms, 2006Co-Authors: Patricia J. Sollars, Malcolm D. Ogilvie, Anne M. Simpson, Gary E. PickardAbstract:The hypothalamic suprachiasmatic nucleus (SCN) is a circadian oscillator that receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain. Activation of presynaptic serotonin 1B (5-HT1B) Receptors on retinal terminals in the SCN inhibits retinohypothalamic neurotransmission and light-induced behavioral phase shifts. To assess the role of 5-HT1B Receptors in photic entrainment, 5-HT1B Receptor knockout (5-HT1B KO) and wild-type (WT) mice were maintained in non-24 h L:D cycles (T cycles). WT mice entrained to T = 21 h and T = 22 h cycles, whereas 5-HT1B KO animals did not. 5-HT1B KO animals did entrain to T = 23 h and T = 26 h cycles, although their phase angle of entrainment was altered compared to WT animals. 5-HT1B KO mice were significantly more phase delayed under T = 23 h conditions and significantly more phase advanced under T = 26 h conditions compared to WT mice. When 5-HT1B KO mice were housed in a T = 23 h short-day photoperiod (9.5L:13.5D), the delayed phase angle of entrainment was more pronounced. Light-induced phase shifts were reduced in 5-HT1B KO mice, consistent with their behavior in T cycles, suggesting an attenuated response to light. Based on previous work, this attenuated response to light might not have been predicted but can be explained by consideration of GABAergic mechanisms within the SCN. Phase-delayed circadian rhythms during the short days of winter are characteristic of patients suffering from seasonal affective disorder, and 5-HT has been implicated in its pathophysiology. The 5-HT1B KO mouse may be useful for investigating the altered entrainment evident during this serious mood disorder.
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5-HT1B Receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus.
Journal of neurophysiology, 2005Co-Authors: Jayne R. Bramley, Patricia J. Sollars, Gary E. Pickard, F. Edward DudekAbstract:The suprachiasmatic nucleus (SCN) receives a dense serotonergic innervation that modulates photic input to the SCN via serotonin 1B (5-HT1B) presynaptic Receptors on retinal glutamatergic terminals. However, the majority of 5-HT1B binding sites in the SCN are located on nonretinal terminals and most axonal terminals in the SCN are GABAergic. We therefore tested the hypothesis that 5-HT1B Receptors might also be located on SCN GABAergic terminals by examining the effects of the highly selective 5-HT1B Receptor agonist CP-93,129 on SCN miniature inhibitory postsynaptic currents (mIPSCs). Whole cell patch-clamp recordings of mIPSCs were obtained from rat and mouse SCN neurons in hypothalamic slices. Using CsCl-containing microelectrodes with QX314, we isolated mPSCs that were sensitive to the GABAA Receptor antagonist, bicuculline. Bath application of CP-93,129 (1 μM) decreased the frequency of mIPSCs by an average of 22% (n = 7) in rat SCN neurons and by an average of 30% (n = 8) in mouse SCN neurons with n...
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5-HT1B Receptor Knockout Mice Exhibit an Enhanced Response to Constant Light:
Journal of biological rhythms, 2002Co-Authors: Patricia J. Sollars, Malcolm D. Ogilvie, Michael A. Rea, Gary E. PickardAbstract:Serotonin (5-HT) can act presynaptically at 5-HT1B Receptors on retinal terminals in the suprachiasmatic nucleus (SCN) to inhibit glutamate release, thereby modulating the effects of light on circadian behavior. 5-HT1B Receptor agonists (1) inhibit light-induced phase shifts of circadian activity rhythms, (2) attenuate light-induced Fos expression in the SCN, and (3) reduce the amplitude of optic nerve-evoked excitatory postsynaptic currents in SCN neurons in vitro. To determine whether functional disruption of the 5-HT1B presynaptic Receptors would result in an amplified response of the SCN to light, the period (τ) of the cir- cadian rhythm of wheel-running activity was estimated under several different conditions in 5-HT1B Receptor knockout (KO) mice and genetically matched wild- type animals. Under constant light (LL) conditions, the τ of 5-HT1B Receptor KO mice was significantly greater than the τ of wild-type mice. A quantitative analy- sis of the wheel-running activity revealed no differences between wild-type and KO mice in either total activity or the temporal distribution of activity under LL conditions, suggesting that the observed increase in τ was not a function of reduced activity. Under constant dark conditions, the period of the circadian rhythm of wheel-running activity of wild-type and 5-HT1B Receptor KO mice was similar. In addition, no differences were noted between wild-type and 5-HT1B Receptor KO mice in the rate of reentrainment t oa6h phase advance in the 12:12 light:dark cycle or in phase shifts in response to a 10 min light pulse presented at circadian time 16. The enhanced response of the SCN circadian clock of the 5- HT1B Receptor KO mice to LL conditions is consistent with the hypothesis that the endogenous activation of 5-HT1B presynaptic Receptors modulates circadian behavior by attenuating photic input to the SCN.
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A 5-HT1B Receptor agonist inhibits light-induced suppression of pineal melatonin production
Brain research, 2000Co-Authors: Michael A. Rea, Gary E. PickardAbstract:Serotonin (5-HT) modulates the phase adjusting effects of light on the mammalian circadian clock through the activation of presynaptic 5-HT1B Receptors located on retinal terminals in the suprachiasmatic nucleus (SCN). The current study was conducted to determine whether activation of 5-HT1B Receptors also alters photic regulation of nocturnal pineal melatonin production. Systemic administration of the 5-HT1B Receptor agonist TFMPP attenuated the inhibitory effect of light on pineal melatonin synthesis in a dose-related manner with an apparent ED50 value of 0.9 mg/kg. The effect of TFMPP on light-induced melatonin suppression was blocked by the 5-HT1 Receptor antagonist, methiothepin, but not by the 5-HT1A antagonist, WAY 100,635, consistent with the involvement of 5-HT1B Receptors. The results are consistent with the interpretation that activation of presynaptic 5-HT1B Receptors on retinal terminals in the SCN attenuates the effect of light on pineal melatonin production, as well as on circadian phase.
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5 ht1b Receptor mediated presynaptic inhibition of retinal input to the suprachiasmatic nucleus
The Journal of Neuroscience, 1999Co-Authors: Gary E. Pickard, Bret N Smith, Michael Belenky, Edward F Dudek, Patricia J. SollarsAbstract:The suprachiasmatic nucleus (SCN) receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain, and serotonin (5-HT) can modify the response of the SCN circadian oscillator to light. 5-HT1B Receptor-mediated presynaptic inhibition has been proposed as one mechanism by which 5-HT modifies retinal input to the SCN ([Pickard et al., 1996][1]). This hypothesis was tested by examining the subcellular localization of 5-HT1BReceptors in the mouse SCN using electron microscopic immunocytochemical analysis with 5-HT1B Receptor antibodies and whole-cell patch-clamp recordings from SCN neurons in hamster hypothalamic slices. 5-HT1B Receptor immunostaining was observed associated with the plasma membrane of retinal terminals in the SCN. 1-[3-(Trifluoromethyl)phenyl]-piperazine HCl (TFMPP), a 5-HT1B Receptor agonist, reduced in a dose-related manner the amplitude of glutamatergic EPSCs evoked by stimulating selectively the optic nerve. Selective 5-HT1A or 5-HT7Receptor antagonists did not block this effect. Moreover, in cells demonstrating an evoked EPSC in response to optic nerve stimulation, TFMPP had no effect on the amplitude of inward currents generated by local application of glutamate. The effect of TFMPP on light-induced phase shifts was also examined using 5-HT1B Receptor knock-out mice. TFMPP inhibited behavioral responses to light in wild-type mice but was ineffective in inhibiting light-induced phase shifts in 5-HT1B Receptor knock-out mice. The results indicate that 5-HT can reduce retinal input to the circadian system by acting at presynaptic 5-HT1B Receptors located on retinal axons in the SCN. [1]: #ref-54
Katarina Varnas - One of the best experts on this subject based on the ideXlab platform.
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The 5-HT1B Receptor - a potential target for antidepressant treatment.
Psychopharmacology, 2018Co-Authors: Mikael Tiger, Katarina Varnas, Yoshiro Okubo, Johan LundbergAbstract:Major depressive disorder (MDD) is the leading cause of disability worldwide. The serotonin hypothesis may be the model of MDD pathophysiology with the most support. The majority of antidepressants enhance synaptic serotonin levels quickly, while it usually takes weeks to discern MDD treatment effect. It has been hypothesized that the time lag between serotonin increase and reduction of MDD symptoms is due to downregulation of inhibitory Receptors such as the serotonin 1B Receptor (5-HT1BR). The research on 5-HT1BR has previously been hampered by a lack of selective ligands for the Receptor. The last extensive review of 5-HT1BR in the pathophysiology of depression was published 2009, and based mainly on findings from animal studies. Since then, selective radioligands for in vivo quantification of brain 5-HT1BR binding with positron emission tomography has been developed, providing new knowledge on the role of 5-HT1BR in MDD and its treatment. The main focus of this review is the role of 5-HT1BR in relation to MDD and its treatment, although studies of 5-HT1BR in obsessive-compulsive disorder, alcohol dependence, and cocaine dependence are also reviewed. The evidence outlined range from animal models of disease, effects of 5-HT1B Receptor agonists and antagonists, case-control studies of 5-HT1B Receptor binding postmortem and in vivo, with positron emission tomography, to clinical studies of 5-HT1B Receptor effects of established treatments for MDD. Low 5-HT1BR binding in limbic regions has been found in MDD patients. When 5-HT1BR ligands are administered to animals, 5-HT1BR agonists most consistently display antidepressant-like properties, though it is not yet clear how 5-HT1BR is best approached for optimal MDD treatment.
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a pet study with 11c az10419369 to determine brain 5 ht1b Receptor occupancy of zolmitriptan in healthy male volunteers
Cephalalgia, 2013Co-Authors: Katarina Varnas, Aurelija Jucaitė, Dennis J Mccarthy, Per Stenkrona, Magdalena Nord, Christer Halldin, Lars Farde, Stephen KanesAbstract:AIM: To investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B Receptors in human subjects after administration of the antimigraine drug zolmitriptan. METHODS: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment. RESULTS: After administration of 10 mg zolmitriptan, mean Receptor occupancy was 4-5%. No consistent changes in 5-HT1B Receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential ( BP ND) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline. CONCLUSION: This is the first demonstration of CNS 5-HT1B Receptor occupancy of a triptan. The findings are consistent with the low Receptor occupancy previously reported in PET studies with agonists at other G protein coupled Receptors.
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Dose-dependent binding of AZD3783 to brain 5-HT1B Receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369.
Psychopharmacology, 2011Co-Authors: Katarina Varnas, M. Edward Pierson, Dennis J Mccarthy, Svante Nyberg, Per Karlsson, Matts Kågedal, Zsolt Cselényi, Alan Xiao, Minli Zhang, Christer HalldinAbstract:Rationale The serotonin 5-HT1B Receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT1B Receptor occupancy with drug candidates targeting this Receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT1B Receptor antagonist with potential antidepressant properties.
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[11C]AZ10419369: a selective 5-HT1B Receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain.
NeuroImage, 2008Co-Authors: M. Edward Pierson, Katarina Varnas, Dennis J Mccarthy, Jan Andersson, Svante Nyberg, Sjoerd J. Finnema, Akihiro Takano, Per Karlsson, Balázs Gulyás, Amy MeddAbstract:The 5-HT1B Receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. Here we report the synthesis of a novel PET radioligand, [11C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide), for in vivo visualization of 5-HT1B Receptors in the brains of macaques and humans subjects. [11C]AZ10419369 was prepared by N-methylation of (8-(1-piperazinyl)-5-methylchrom-2-en-4-one-2-(4-morpholinophenyl) carboxamide, using carbon-11 methyl triflate. Regional brain uptake patterns of [11C]AZ10419369 were characterized by PET measurements in two macaques and a preliminary study in two human subjects. In addition, AZ10419369 was prepared in tritium labeled form for in vitro autoradiography studies in macaque brain tissue sections. The radiochemical purity of [11C]AZ10419369 was >99% and specific radioactivity was >3600 Ci/mmol. After iv injection of [11C]AZ10419369, 3-4% was in brain after 7.5 min. The regional brain distribution of radioactivity was similar in humans and macaques showing the highest uptake of radioactivity in the occipital cortex and the basal ganglia, in accord with autoradiographic studies performed using [3H]AZ10419369. Uptake was moderate in the temporal and frontal cortical regions, lower in the thalamus and lowest in the cerebellum. In macaques pre-treated with the selective 5-HT1B Receptor antagonist, AR-A000002, binding was reduced in a dose-dependent manner, consistent with specific binding to 5-HT1B Receptors. These data support [11C]AZ10419369 as a suitable radioligand for labeling 5-HT1B Receptors in the primate brain. This radioligand may be useful in future studies evaluating drug-induced Receptor occupancy and measurement of brain 5-HT1B Receptor levels in patients with psychiatric disorders.
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Regional expression of 5-HT1B Receptor mRNA in the human brain.
Synapse (New York N.Y.), 2005Co-Authors: Katarina Varnas, Yasmin L. Hurd, Håkan HallAbstract:The regional mRNA expression pattern of 5-HT1B Receptors has been extensively characterized in the rodent and guinea pig brain, but a detailed mapping of the 5-HT1B Receptor mRNA expression in the human brain has not previously been performed. In the present study, the mRNA expression of 5-HT1B Receptors was analyzed using in situ hybridization histochemistry and whole hemisphere sections of the human postmortem brain. The mRNA expression was compared with the autoradiographic distribution of 5-HT1B Receptors. High levels of mRNA expression were found in the striatum, cortex, lateral geniculate nucleus, and raphe nuclei. The expression was higher in ventral than in dorsal striatal regions and was absent from the substantia nigra and pallidum, where high levels of 5-HT1B Receptors were found. A layer-specific expression pattern was observed in cortical regions. The results extend previous knowledge about the localization of the 5-HT1B Receptor in the human brain. This study provides evidence of a mismatch of the regional expression of 5-HT1B Receptor mRNA and the 5-HT1B Receptor distribution in human brain, similar to what has been demonstrated in other species. This is in line with the localization of this Receptor subtype in nerve terminals. The results give support to species differences in the cortical mRNA expression pattern of this Receptor subtype. Synapse 56:21–28, 2005. © 2005 Wiley-Liss, Inc.
Lars Edvinsson - One of the best experts on this subject based on the ideXlab platform.
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erk1 2 inhibition attenuates cerebral blood flow reduction and abolishes etb and 5 ht1b Receptor upregulation after subarachnoid hemorrhage in rat
Journal of Cerebral Blood Flow and Metabolism, 2006Co-Authors: Jacob Hansenschwartz, Cangbao Xu, Petter Vikman, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
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ERK1/2 Inhibition Attenuates Cerebral Blood Flow Reduction and Abolishes ETB and 5-HT1B Receptor Upregulation after Subarachnoid Hemorrhage in Rat:
Journal of Cerebral Blood Flow and Metabolism, 2005Co-Authors: Jacob Hansen-schwartz, Cangbao Xu, Petter Vikman, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
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triptan induced contractile 5 ht1b Receptor responses in human cerebral and coronary arteries relationship to clinical effect
Clinical Science, 2005Co-Authors: Lars Edvinsson, Erik Uddman, Angelica Wackenfors, Anthony P Davenport, Jenny Longmore, Malin MalmsjoAbstract:Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) Receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B Receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D Receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan = rizatriptan = sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B Receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B Receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels.
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Subarachnoid hemorrhage—induced upregulation of the 5-HT1B Receptor in cerebral arteries in rats
Journal of neurosurgery, 2003Co-Authors: Jacob Hansen-schwartz, Natalie Løvland Hoel, Niels-aage Svendgaard, Lars EdvinssonAbstract:Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced blood flow in the brain. Inspired by organ culture-induced changes in the Receptor phenotype of cerebral arteries, the authors investigated possible changes in the 5-hydroxytryptamine (HT) Receptor phenotype after experimental SAH. Methods. Experimental SAH was induced in rats by using an autologous prechiasmatic injection of arterial blood. Two days later, the middle cerebral artery (MCA), posterior communicating artery (PCoA), and basilar artery (BA) were harvested and examined functionally with the aid of a sensitive in vitro pharmacological method and molecularly by performing quantitative real-time reverse transcription-polymerase chain reaction (PCR). In the MCA and BA the 5-HT1B Receptor was upregulated, as determined through both functional and molecular analysis. In response to selective 5-HT1 Receptor agonists both the negative logarithm of the 50% effective concentration was increased (one log unit in the MCA and one half unit in the BA), as was the agonist's potency (increased by 50% in the MCA and doubled in the BA). In addition, the authors found an approximately fourfold increase in the number of copies of messenger RNA coding for the 5-HT1B Receptor as determined by quantitative real-time PCR. In the PCoA no upregulation of the 5-HT1B Receptor was observed. Conclusions. Changes in the Receptor phenotype in favor of contractile Receptors may well represent the end stage in a sequence of events leading from SAH to the actual development of cerebral vasospasm. Insight into the mechanism of upregulation may provide new targets for developing specific treatment against cerebral vasospasm. (Less)
Patricia J. Sollars - One of the best experts on this subject based on the ideXlab platform.
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Photic entrainment is altered in the 5-HT1B Receptor knockout mouse.
Journal of biological rhythms, 2006Co-Authors: Patricia J. Sollars, Malcolm D. Ogilvie, Anne M. Simpson, Gary E. PickardAbstract:The hypothalamic suprachiasmatic nucleus (SCN) is a circadian oscillator that receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain. Activation of presynaptic serotonin 1B (5-HT1B) Receptors on retinal terminals in the SCN inhibits retinohypothalamic neurotransmission and light-induced behavioral phase shifts. To assess the role of 5-HT1B Receptors in photic entrainment, 5-HT1B Receptor knockout (5-HT1B KO) and wild-type (WT) mice were maintained in non-24 h L:D cycles (T cycles). WT mice entrained to T = 21 h and T = 22 h cycles, whereas 5-HT1B KO animals did not. 5-HT1B KO animals did entrain to T = 23 h and T = 26 h cycles, although their phase angle of entrainment was altered compared to WT animals. 5-HT1B KO mice were significantly more phase delayed under T = 23 h conditions and significantly more phase advanced under T = 26 h conditions compared to WT mice. When 5-HT1B KO mice were housed in a T = 23 h short-day photoperiod (9.5L:13.5D), the delayed phase angle of entrainment was more pronounced. Light-induced phase shifts were reduced in 5-HT1B KO mice, consistent with their behavior in T cycles, suggesting an attenuated response to light. Based on previous work, this attenuated response to light might not have been predicted but can be explained by consideration of GABAergic mechanisms within the SCN. Phase-delayed circadian rhythms during the short days of winter are characteristic of patients suffering from seasonal affective disorder, and 5-HT has been implicated in its pathophysiology. The 5-HT1B KO mouse may be useful for investigating the altered entrainment evident during this serious mood disorder.
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5-HT1B Receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus.
Journal of neurophysiology, 2005Co-Authors: Jayne R. Bramley, Patricia J. Sollars, Gary E. Pickard, F. Edward DudekAbstract:The suprachiasmatic nucleus (SCN) receives a dense serotonergic innervation that modulates photic input to the SCN via serotonin 1B (5-HT1B) presynaptic Receptors on retinal glutamatergic terminals. However, the majority of 5-HT1B binding sites in the SCN are located on nonretinal terminals and most axonal terminals in the SCN are GABAergic. We therefore tested the hypothesis that 5-HT1B Receptors might also be located on SCN GABAergic terminals by examining the effects of the highly selective 5-HT1B Receptor agonist CP-93,129 on SCN miniature inhibitory postsynaptic currents (mIPSCs). Whole cell patch-clamp recordings of mIPSCs were obtained from rat and mouse SCN neurons in hypothalamic slices. Using CsCl-containing microelectrodes with QX314, we isolated mPSCs that were sensitive to the GABAA Receptor antagonist, bicuculline. Bath application of CP-93,129 (1 μM) decreased the frequency of mIPSCs by an average of 22% (n = 7) in rat SCN neurons and by an average of 30% (n = 8) in mouse SCN neurons with n...
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5-HT1B Receptor Knockout Mice Exhibit an Enhanced Response to Constant Light:
Journal of biological rhythms, 2002Co-Authors: Patricia J. Sollars, Malcolm D. Ogilvie, Michael A. Rea, Gary E. PickardAbstract:Serotonin (5-HT) can act presynaptically at 5-HT1B Receptors on retinal terminals in the suprachiasmatic nucleus (SCN) to inhibit glutamate release, thereby modulating the effects of light on circadian behavior. 5-HT1B Receptor agonists (1) inhibit light-induced phase shifts of circadian activity rhythms, (2) attenuate light-induced Fos expression in the SCN, and (3) reduce the amplitude of optic nerve-evoked excitatory postsynaptic currents in SCN neurons in vitro. To determine whether functional disruption of the 5-HT1B presynaptic Receptors would result in an amplified response of the SCN to light, the period (τ) of the cir- cadian rhythm of wheel-running activity was estimated under several different conditions in 5-HT1B Receptor knockout (KO) mice and genetically matched wild- type animals. Under constant light (LL) conditions, the τ of 5-HT1B Receptor KO mice was significantly greater than the τ of wild-type mice. A quantitative analy- sis of the wheel-running activity revealed no differences between wild-type and KO mice in either total activity or the temporal distribution of activity under LL conditions, suggesting that the observed increase in τ was not a function of reduced activity. Under constant dark conditions, the period of the circadian rhythm of wheel-running activity of wild-type and 5-HT1B Receptor KO mice was similar. In addition, no differences were noted between wild-type and 5-HT1B Receptor KO mice in the rate of reentrainment t oa6h phase advance in the 12:12 light:dark cycle or in phase shifts in response to a 10 min light pulse presented at circadian time 16. The enhanced response of the SCN circadian clock of the 5- HT1B Receptor KO mice to LL conditions is consistent with the hypothesis that the endogenous activation of 5-HT1B presynaptic Receptors modulates circadian behavior by attenuating photic input to the SCN.
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5 ht1b Receptor mediated presynaptic inhibition of retinal input to the suprachiasmatic nucleus
The Journal of Neuroscience, 1999Co-Authors: Gary E. Pickard, Bret N Smith, Michael Belenky, Edward F Dudek, Patricia J. SollarsAbstract:The suprachiasmatic nucleus (SCN) receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain, and serotonin (5-HT) can modify the response of the SCN circadian oscillator to light. 5-HT1B Receptor-mediated presynaptic inhibition has been proposed as one mechanism by which 5-HT modifies retinal input to the SCN ([Pickard et al., 1996][1]). This hypothesis was tested by examining the subcellular localization of 5-HT1BReceptors in the mouse SCN using electron microscopic immunocytochemical analysis with 5-HT1B Receptor antibodies and whole-cell patch-clamp recordings from SCN neurons in hamster hypothalamic slices. 5-HT1B Receptor immunostaining was observed associated with the plasma membrane of retinal terminals in the SCN. 1-[3-(Trifluoromethyl)phenyl]-piperazine HCl (TFMPP), a 5-HT1B Receptor agonist, reduced in a dose-related manner the amplitude of glutamatergic EPSCs evoked by stimulating selectively the optic nerve. Selective 5-HT1A or 5-HT7Receptor antagonists did not block this effect. Moreover, in cells demonstrating an evoked EPSC in response to optic nerve stimulation, TFMPP had no effect on the amplitude of inward currents generated by local application of glutamate. The effect of TFMPP on light-induced phase shifts was also examined using 5-HT1B Receptor knock-out mice. TFMPP inhibited behavioral responses to light in wild-type mice but was ineffective in inhibiting light-induced phase shifts in 5-HT1B Receptor knock-out mice. The results indicate that 5-HT can reduce retinal input to the circadian system by acting at presynaptic 5-HT1B Receptors located on retinal axons in the SCN. [1]: #ref-54
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5-HT1B Receptor–Mediated Presynaptic Inhibition of Retinal Input to the Suprachiasmatic Nucleus
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999Co-Authors: Gary E. Pickard, Michael A. Rea, Bret N Smith, Michael Belenky, F. Edward Dudek, Patricia J. SollarsAbstract:The suprachiasmatic nucleus (SCN) receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain, and serotonin (5-HT) can modify the response of the SCN circadian oscillator to light. 5-HT1B Receptor-mediated presynaptic inhibition has been proposed as one mechanism by which 5-HT modifies retinal input to the SCN (Pickard et al., 1996). This hypothesis was tested by examining the subcellular localization of 5-HT1B Receptors in the mouse SCN using electron microscopic immunocytochemical analysis with 5-HT1B Receptor antibodies and whole-cell patch-clamp recordings from SCN neurons in hamster hypothalamic slices. 5-HT1B Receptor immunostaining was observed associated with the plasma membrane of retinal terminals in the SCN. 1-[3-(Trifluoromethyl)phenyl]-piperazine HCl (TFMPP), a 5-HT1B Receptor agonist, reduced in a dose-related manner the amplitude of glutamatergic EPSCs evoked by stimulating selectively the optic nerve. Selective 5-HT1A or 5-HT7 Receptor antagonists did not block this effect. Moreover, in cells demonstrating an evoked EPSC in response to optic nerve stimulation, TFMPP had no effect on the amplitude of inward currents generated by local application of glutamate. The effect of TFMPP on light-induced phase shifts was also examined using 5-HT1B Receptor knock-out mice. TFMPP inhibited behavioral responses to light in wild-type mice but was ineffective in inhibiting light-induced phase shifts in 5-HT1B Receptor knock-out mice. The results indicate that 5-HT can reduce retinal input to the circadian system by acting at presynaptic 5-HT1B Receptors located on retinal axons in the SCN.
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a randomized placebo controlled pet study of ketamine s effect on serotonin 1b Receptor binding in patients with ssri resistant depression
Translational Psychiatry, 2020Co-Authors: Mikael Tiger, Emma R. Veldman, Per Svenningsson, Christer Halldin, Carl Johan Ekman, J M LundbergAbstract:The glutamate N-methyl-d-aspartate Receptor antagonist ketamine has a rapid antidepressant effect. Despite large research efforts, ketamine’s mechanism of action in major depressive disorder (MDD) has still not been determined. In rodents, the antidepressant properties of ketamine were found to be dependent on both the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the serotonin (5-HT)1B Receptor. Low 5-HT1B Receptor binding in limbic brain regions is a replicated finding in MDD. In non-human primates, AMPA-dependent increase in 5-HT1B Receptor binding in the ventral striatum (VST) has been demonstrated after ketamine infusion. Thirty selective serotonin reuptake inhibitor-resistant MDD patients were recruited via advertisement and randomized to double-blind monotherapy with 0.5 mg/kg ketamine or placebo infusion. The patients were examined with the 5-HT1B Receptor selective radioligand [11C]AZ10419369 and positron emission tomography (PET) before and 24–72 h after treatment. 5-HT1B Receptor binding did not significantly alter in patients treated with ketamine compared with placebo. An increase in 5-HT1B Receptor binding with 16.7 % (p = 0.036) was found in the hippocampus after one ketamine treatment. 5-HT1B Receptor binding in VST at baseline correlated with MDD symptom ratings (r = −0.426, p = 0.019) and with reduction of depressive symptoms with ketamine (r = −0.644, p = 0.002). In conclusion, reduction of depressive symptoms in MDD patients after ketamine treatment is correlated inversely with baseline 5-HT1B Receptor binding in VST. Further studies examining the role of 5-HT1B Receptors in the antidepressant mechanism of action of ketamine should be conducted, homing in on the 5-HT1B Receptor as an MDD treatment response marker.
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5-HT1B Receptor imaging and cognition: a positron emission tomography study in control subjects and Parkinson's disease patients.
Synapse (New York N.Y.), 2015Co-Authors: Andrea Varrone, Per Svenningsson, Christer Halldin, Petter Marklund, Helena Fatouros-bergman, Anton Forsberg, Lars-göran Nilsson, Lars FardeAbstract:Introduction The serotonin 5-HT1B Receptor subtype is involved in the modulation of serotonin release and is a target of interest for neuroReceptor imaging. Previous studies have shown that the serotonin system is affected in Parkinson's disease (PD). Cognitive function, frequently impaired in PD, has been linked to the serotonin system. The aim of this study was to examine whether 5-HT1B Receptor availability in the brain of healthy subjects and PD patients is associated with measures of cognitive function. Methods Twelve control subjects and ten PD patients with normal mini-mental state examination scores were included in this study. Cognitive function was evaluated by assessment of semantic, episodic, and working memory, as well as fluency and visual attention. Creative ability, a measure of divergent thinking, was examined with the alternative uses of objects task. PET measurements were performed with the 5-HT1B Receptor-radioligand [11C]AZ10419369 using the HRRT system. Results PD patients showed statistically significant lower measures of semantic and episodic memory, as well as creative ability, compared with control subjects. Statistically significant positive correlations were found in control subjects between creative ability and average 5-HT1B Receptor availability in grey matter, and in PD patients between scores of Beck Depression Inventory-II and creative ability. Conclusion Though creativity has been conventionally linked to dopamine function, our findings in control subjects suggest a link between 5-HT1B Receptor availability and creative ability. In PD patients, creative ability was significantly associated with depressive symptoms but not with 5-HT1B Receptor availability. This finding deserves further investigation in future studies. Synapse 69:365–374, 2015. © 2015 Wiley Periodicals, Inc.
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A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B Receptors underlying the antidepressant action of ketamine: a PET study with macaques
Translational Psychiatry, 2014Co-Authors: H Yamanaka, Christer Halldin, C Yokoyama, H Mizuma, S Kurai, S J Finnema, H OnoeAbstract:Ketamine is a unique anesthetic reagent known to produce various psychotic symptoms. Ketamine has recently been reported to elicit a long-lasting antidepressant effect in patients with major depression. Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism has not been fully elucidated. To understand the involvement of the brain serotonergic system in the actions of ketamine, we performed a positron emission tomography (PET) study on non-human primates. Four rhesus monkeys underwent PET studies with two serotonin (5-HT)-related PET radioligands, [^11C]AZ10419369 and [^11C]DASB, which are highly selective for the 5-HT1B Receptor and serotonin transporter (SERT), respectively. Voxel-based analysis using standardized brain images revealed that ketamine administration significantly increased 5-HT1B Receptor binding in the nucleus accumbens and ventral pallidum, whereas it significantly reduced SERT binding in these brain regions. Fenfluramine, a 5-HT releaser, significantly decreased 5-HT1B Receptor binding, but no additional effect was observed when it was administered with ketamine. Furthermore, pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), a potent antagonist of the glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) Receptor, blocked the action of ketamine on the 5-HT1B Receptor but not SERT binding. This indicates the involvement of AMPA Receptor activation in ketamine-induced alterations of 5-HT1B Receptor binding. Because NBQX is known to block the antidepressant effect of ketamine in rodents, alterations in the serotonergic neurotransmission, particularly upregulation of postsynaptic 5-HT1B Receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine.
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a pet study with 11c az10419369 to determine brain 5 ht1b Receptor occupancy of zolmitriptan in healthy male volunteers
Cephalalgia, 2013Co-Authors: Katarina Varnas, Aurelija Jucaitė, Dennis J Mccarthy, Per Stenkrona, Magdalena Nord, Christer Halldin, Lars Farde, Stephen KanesAbstract:AIM: To investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B Receptors in human subjects after administration of the antimigraine drug zolmitriptan. METHODS: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment. RESULTS: After administration of 10 mg zolmitriptan, mean Receptor occupancy was 4-5%. No consistent changes in 5-HT1B Receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential ( BP ND) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline. CONCLUSION: This is the first demonstration of CNS 5-HT1B Receptor occupancy of a triptan. The findings are consistent with the low Receptor occupancy previously reported in PET studies with agonists at other G protein coupled Receptors.
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Dose-dependent binding of AZD3783 to brain 5-HT1B Receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369.
Psychopharmacology, 2011Co-Authors: Katarina Varnas, M. Edward Pierson, Dennis J Mccarthy, Svante Nyberg, Per Karlsson, Matts Kågedal, Zsolt Cselényi, Alan Xiao, Minli Zhang, Christer HalldinAbstract:Rationale The serotonin 5-HT1B Receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT1B Receptor occupancy with drug candidates targeting this Receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT1B Receptor antagonist with potential antidepressant properties.
