Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2;-methoxyphenyl)-1-[2;-(N-2"-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.
J Cereb Blood Flow Metab 2002 Jun
PMID:Modeling [18 F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection. 1204 74

A kinetic modeling approach for the quantification of in vivo tracer studies with dynamic positron emission tomography (PET) is presented. The approach is based on a general compartmental description of the tracer's fate in vivo and determines a parsimonious model consistent with the measured data. The technique involves the determination of a sparse selection of kinetic basis functions from an overcomplete dictionary using the method of basis pursuit denoising. This enables the characterization of the systems impulse response function from which values of the systems macro parameters can be estimated. These parameter estimates can be obtained from a region of interest analysis or as parametric images from a voxel-based analysis. In addition, model order estimates are returned that correspond to the number of compartments in the estimated compartmental model. Validation studies evaluate the methods performance against two preexisting data led techniques, namely, graphical analysis and spectral analysis. Application of this technique to measured PET data is demonstrated using [11C]diprenorphine (opiate receptor) and [11C]WAY-100635 (5-HT1A receptor). Although the method is presented in the context of PET neuroreceptor binding studies, it has general applicability to the quantification of PET/SPECT radiotracer studies in neurology, oncology, and cardiology.
J Cereb Blood Flow Metab 2002 Dec
PMID:Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. 1246 88

The 5-HT1A ligands [ 18F]FPWAY and [ 18F]FCWAY are metabolized to [ 18F]fluorobenzoic acid (FB) and [ 18F]fluorocyclohexanecarboxylic acid (FC), respectively. To quantify the penetration of these acids into the brain, dynamic positron emission tomography studies were performed in rhesus monkeys with [ 18F]FB and [ 18F]FC. High-performance liquid chromatography analysis of arterial blood samples showed no metabolites for [ 18F]FB, whereas [ 18F]FC was rapidly metabolized to [ 18F]fluoride. A model with one tissue compartment and vascular radioactivity was used to analyze gray matter time-activity curves. For [ 18F]FC, an additional term was added to account for [ 18F]fluoride skull spillover into the brain; this term accounted for 70% to 90% of the measured radioactivity concentration at 90 minutes. For [ 18F]FB, mean gray matter parameters were as follows: K1, 10 +/- 3 micro L. min(-1). mL(-1); distribution volume, 0.052 +/- 0.006 (mL/mL). For [ 18F]FC, the values were as follows: K1, 15 +/- 4 micro L. min(-1). mL(-1); V, 0.29 +/- 0.06 mL/mL. The values were consistent with a physiologic model that included brain-to-blood pH difference and the plasma free fraction of the acid. Simulations based on [ 18F]FCWAY human data showed that [ 18F]FC uptake produces significant biases in estimates in regions with low specific binding. These results can be used to correct the tissue [ 18F]FCWAY time-activity data for brain uptake of [ 18F]FC using the measured [ 18F]FC input function.
J Cereb Blood Flow Metab 2003 Feb
PMID:Brain uptake of the acid metabolites of F-18-labeled WAY 100635 analogs. 1257 56

The prefrontal cortex plays a key role in the control of higher brain functions and is involved in the pathophysiology and treatment of schizophrenia. Here we report that approximately 60% of the neurons in rat and mouse prefrontal cortex express 5-HT(1A) and/or 5-HT2A receptor mRNAs, which are highly co-localized (approximately 80%). The electrical stimulation of the dorsal and median raphe nuclei elicited 5-HT1A-mediated inhibitions and 5-HT2A-mediated excitations in identified pyramidal neurons recorded extracellularly in rat medial prefrontal cortex (mPFC). Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons. Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists. This inhibitory effect was antagonized by WAY-100635 and the prior inactivation of 5-HT1A receptors in rats and was absent in mice lacking 5-HT1A receptors. These observations help to clarify the interactions between the mPFC and the raphe nuclei, two key areas in psychiatric illnesses and improve our understanding of the action of atypical antipsychotics, acting through these 5-HT receptors.
Cereb Cortex 2004 Mar
PMID:Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. 1475 68

Serotonergic 5-HT1A and 5-HT2A receptors are abundantly expressed in prefrontal cortex (PFC) and are targets of atypical antipsychotic drugs. They mediate, respectively, inhibitory and excitatory actions of 5-HT. The transcripts for both receptors are largely (approximately 80%) colocalized in rat and mouse PFC, yet their quantitative distribution in pyramidal and GABAergic interneurons is unknown. We used double in situ hybridization histochemistry to estimate the proportion of pyramidal and GABAergic neurons expressing these receptor transcripts in rat PFC. The number of GABAergic interneurons (expressing GAD mRNA) was a 22% of glutamatergic neurons (expressing vGluT1 mRNA, considered as putative pyramidal neurons). 5-HT2A receptor mRNA was present in a large percentage of pyramidal neurons (from 55% in prelimbic cortex to 88% in tenia tecta), except in layer VI, where it was localized only in 30% of those neurons. 5-HT2A receptor mRNA was present in approximately 25% of GAD-containing cells except in layer VI (10%). Likewise, approximately 60% of glutamatergic cells contained the 5-HT1A receptor transcript. We also found that approximately 25% of GAD-expressing cells contained the 5-HT1A receptor mRNA. These data help to clarify the role of 5-HT in prefrontal circuits and shed new light to the cellular elements involved in the action of atypical antipsychotics.
Cereb Cortex 2004 Oct
PMID:Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. 1511 44

Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors. Here we report that the physiological stimulation of the raphe nuclei excites local, putatively GABAergic neurons in the prelimbic and cingulate areas of the rat PFC in vivo. These excitations had a latency of 36 +/- 4 ms and a duration of 69 +/- 9 ms and were blocked by the i.v. administration of the 5-HT3 receptor antagonists ondansetron and tropisetron. The latency and duration were shorter than those elicited through 5-HT2A receptors in pyramidal neurons of the same areas. Double in situ hybridization histochemistry showed the presence of GABAergic neurons expressing 5-HT3 receptor mRNA in PFC. These cells were more abundant in the cingulate, prelimbic and infralimbic areas, particularly in superficial layers. The percentages of GAD mRNA-positive neurons expressing 5-HT3 receptor mRNA in prelimbic cortex were 40, 18, 6 and 8% in layers I, II-III, V and VI, respectively, a distribution complementary to that of cells expressing 5-HT2A receptors. Overall, these results support an important role of 5-HT in the control of the excitability of apical dendrites of pyramidal neurons in the medial PFC through the activation of 5-HT3 receptors in GABAergic interneurons.
Cereb Cortex 2004 Dec
PMID:In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors. 1516 6

The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]altanserin are discussed.
J Cereb Blood Flow Metab 2004 Sep
PMID:[18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge. 1535 24

Using positron emission tomography (PET) and microdialysis, the present study showed that neuronal damages after transient focal ischemia was partly induced by hyperactivation of the cyclic adenosine 3',5'-monophosphate (cAMP) second messenger system through modulations of dopamine D, and serotonin 5-HT1A receptors in the living brains of cynomolgus monkeys. Occlusion of the right middle cerebral artery for 3 hours suppressed CBF in the striatum, and reperfusion induced hyperperfusion in the neocortex and striatum of the occluded side. Six hours after reperfusion, the activity of the cAMP second messenger system assayed with [11C]rolipram was significantly facilitated in the neocortex and striatum where CBF was lowered more than 40% of normal during occlusion ("ischemic" area). Seven days later, impaired dopamine D1 and 5-HT1A receptor binding, measured with [11C]SCH23390 and [carbonyl-11C]WAY-100635, respectively, was observed in the ischemic area. Microdialysis analysis revealed that the striatal dopamine level provided a transient and marked increased during occlusion and after reperfusion, whereas the cortical serotonin level transiently increased only after reperfusion, and was at an undetectable level thereafter. Administration of rolipram (0.1 and 1 mg/kg, intravenously) during occlusion facilitated reduction of dopamine D1 binding, whereas rolipram administration 6 hours after reperfusion induced a further decrease in 5-HT1A receptor binding. These results suggest that the activation of cAMP second messenger system modulated by dopamine D1 and 5-HT1A receptors could be involved in the neuronal degeneration after transient cerebral ischemic insult.
J Cereb Blood Flow Metab 2004 Aug
PMID:Transient focal ischemia affects the cAMP second messenger system and coupled dopamine D1 and 5-HT1A receptors in the living monkey brain: a positron emission tomography study using microdialysis. 1536 20

Repinotan is a highly potent 5-HT1A receptor agonist with strong neuroprotective efficacy in animal models of middle cerebral artery occlusion and traumatic brain injury. In this study, we characterized the time window for neuroprotective effects of repinotan in animal models. In the permanent middle cerebral artery occlusion model, repinotan showed neuroprotective efficacy when administered as a triple bolus injection (0.3-100 microg/kg) or an intravenous infusion (0.3-100 microg/kg per hour). A 73% reduction in infarct volume was observed with a 3 microg/kg intravenous bolus, and a 65% reduction was observed with a 3 and 10 microg/kg per hour intravenous infusion. When delayed until 5 hours after occlusion, repinotan (10 microg/kg per hour) reduced infarct volume by 43%. In the transient middle cerebral artery occlusion model, repinotan (10 microg/kg per hour) administered immediately after occlusion reduced infarct volume by 97%, and a delay to 5 hours reduced infarct volume by 81%. In the acute subdural hematoma model, repinotan (3 and 10 microg/kg per hour) reduced infarct volume by 65%. In this model, repinotan (3 microg/kg per hour) administered 5 hours after occlusion reduced infarct volume by 54%. The favorable neuroprotective efficacy, broad dose-response curve, and prolonged therapeutic window observed in all models strongly suggest that repinotan is a promising candidate for treating acute ischemic stroke in humans.
J Cereb Blood Flow Metab 2005 Apr
PMID:Neuroprotective efficacy of repinotan HCl, a 5-HT1A receptor agonist, in animal models of stroke and traumatic brain injury. 1567 37

[Carbonyl-(11)C]WAY-100635 has been used extensively in positron emission tomography (PET) imaging of serotonin 1A receptors (5-HT1A) in vivo in the human brain. Specific binding to receptors is usually estimated using compartmental modeling with arterial plasma input function. The use of reference tissue input (cerebellum) enables quantification without the need of arterial blood sampling, but the accuracy of this method is highly dependent on the validity of the reference region in terms of both specific and nonspecific binding. In this paper, we report exceptionally high uptake of [carbonyl-(11)C]WAY-100635 in the gray matter of cerebellum in one healthy male subject, which was reproducible in repeated PET scanning and most likely represents specific binding to 5-HT1A receptors in cerebellar gray matter. Serotonin 1A receptors are transiently expressed in the human cerebellum during early childhood and usually level off until adolescence but may persist in some individuals. As a methodological implication, the results of this study with regard to test-retest characteristics of [carbonyl-(11)C]WAY-100635 measurements in healthy volunteers using both arterial plasma and reference tissue input functions support the use of cerebellar white matter as reference region, to avoid the potential bias originating from binding of [carbonyl-(11)C]WAY-100635 to 5-HT1A receptors in cerebellar gray matter.
J Cereb Blood Flow Metab 2007 Jan
PMID:Measurement of serotonin 5-HT1A receptor binding using positron emission tomography and [carbonyl-(11)C]WAY-100635-considerations on the validity of cerebellum as a reference region. 1668 58


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