Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Pyramidal neurons of the medial prefrontal cortex (mPFC) project to midbrain serotonergic neurons and control their activity. The stimulation of prefrontal 5-HT2A and AMPA receptors increases pyramidal and serotonergic cell firing, and 5-hydroxytryptamine (5-HT) release in mPFC. As the mPFC contains abundant alpha1-adrenoceptors whose activation increases the excitability of pyramidal neurons, we examined the effects of their stimulation on local 5-HT release, using microdialysis. The application of the alpha1-adrenoceptor agonist cirazoline by reverse dialysis increased the prefrontal 5-HT release in a concentration-dependent manner, an effect antagonized by coperfusion of TTX, prazosin (alpha1-adrenoceptor antagonist), BAY x 3702 (5-HT1A agonist), NBQX (AMPA/KA antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by MK-801 (NMDA antagonist). Cirazoline also enhanced the increase in 5-HT release induced by DOI (5-HT2A/2C agonist) and AMPA. In addition, M100907 (5-HT2A antagonist) but not SB-242084 (5-HT2C antagonist) reversed the cirazoline- and AMPA-induced 5-HT release. These results suggest that the stimulation of prefrontal alpha1-adrenoceptors activates pyramidal afferents to ascending serotonergic neurons. The effect of cirazoline was also reversed by coperfusion of classical (chlorpromazine, haloperidol) and atypical (clozapine, olanzapine) antipsychotics, which suggests that a functional antagonism of the alpha1-adrenoceptor-mediated activation of prefrontal neurons may partly underlie their therapeutic action.
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PMID:Stimulation of alpha1-adrenoceptors in the rat medial prefrontal cortex increases the local in vivo 5-hydroxytryptamine release: reversal by antipsychotic drugs. 1462 14

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [3H]serotonin ([3H]5-HT), superfused, and the electrically induced efflux of radioactivity was determined. The nonselective 5-HT receptor agonist 5-carboxamido-tryptamine (5-CT; 0.001 to 1 microM) inhibited the electrically stimulated [3H]5-HT overflow from raphe nuclei slices (IC50 of 3.34 +/- 0.37 nM). This effect of 5-CT on [3H]5-HT overflow was antagonized by the 5-HT7 receptor antagonist SB-258719 (10 microM) and the 5-HT(1B/1D) antagonist SB-216641 (1 microM), the IC50 values for 5-CT in the presence of SB-258719 and SB-216641 were 94.23 +/- 4.84 and 47.81 +/- 4.66 nM. The apparent pA2 values for SB-258719 and SB-216641 against 5-CT were 6.43 and 7.12, respectively. The inhibitory effect of 5-CT on [3H]5-HT overflow was weakly antagonized by 10 microM of WAY-100635, a 5-HT1A receptor antagonist (IC50 6.65 +/- 0.56 nM, apparent pA2 4.99). The antagonist effect of SB-258719 (10 microM) on 5-CT-evoked [3H]5-HT overflow inhibition was also determined in the presence of 1 microM SB-216641 or 1 microM SB-216641 and 10 microM WAY-100635, and additive interactions were found between the antagonists of 5-HT7 and 5-HT1 receptor subtypes. Addition of the Na+ channel blocker tetrodotoxin (1 microM) in the presence of SB-216641 (1 microM) and WAY-100635 (10 microM) attenuated the inhibitory effect of 5-CT on KCl-induced [3H]5-HT overflow. These findings indicate that 5-CT inhibits [3H]5-HT overflow from raphe nuclei slices of the rat by stimulation of 5-HT7 and 5-HT(1B/1D receptors, whereas the role of 5-HT1A receptors in this inhibition is less pronounced. They also suggest that 5-HT7 receptors are probably not located on serotonergic neurons and thus may serve as heteroreceptors in regulation of 5-HT release in the raphe nuclei. 5-CT (0.1 microM) also inhibited [3H]glutamate release, and SB-258719 (10 microLM) suspended this effect. We therefore speculated that the axon terminals of the glutamatergic cortico-raphe neurons may possess 5-HT7 receptors that inhibit glutamate release, which consequently leads to decreased activity of serotonergic neurons. The postulated glutamatergic-serotonergic interaction in the raphe nuclei was further evidenced by the finding that N-methyl-D-aspartate and AMPA enhanced [3H]5-HT release.
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PMID:A 5-HT7 heteroreceptor-mediated inhibition of [3H]serotonin release in raphe nuclei slices of the rat: evidence for a serotonergic-glutamatergic interaction. 1526 Jan 25

Brodmann's area (BA) 5 of the human superior parietal cortex occupies a central anatomical position between the primary motor (BA 4), somatosensory (area 3b and BA 2), cingulate (area 23c), and superior parietal association cortex (BA 7). We studied the regional and laminar distributions of the binding sites of 12 different neurotransmitter receptors (glutamatergic: AMPA, kainate, NMDA; GABAergic: GABAA, GABAB; cholinergic: muscarinic M2, nicotinic; adrenergic: alpha1, alpha2; serotoninergic: 5-HT1A, 5-HT2; dopaminergic: D1) in human postmortem brains by means of quantitative receptor autoradiography, since the structural and functional aspects of human BA 5 are widely unknown, and previous observations have demonstrated characteristic differences in receptor distribution between motor and somatosensory areas. Binding site densities were measured in the cytoarchitectonically defined BA 5 and surrounding regions. Similarities and differences of receptor distribution between cortical areas were studied by cluster analysis of mean binding site densities averaged over all cortical layers, univariate and multivariate statistics, and by density profiles representing laminar receptor distribution patterns. Based on regional heterogeneities of binding site densities and of the cytoarchitecture within BA 5, we suggest a subdivision into three subareas: medial area 5M, lateral area 5L, and area 5Ci in the region around the cingulate sulcus. BA 5 is therefore a heterogeneous cortical region, comprising three subareas showing receptor expression patterns similar to the adjoining higher order somatosensory, multimodal parietal, or cingulate regions. These findings suggest that human BA 5 constitutes a higher order cortical area, clearly distinct from the primary somatosensory and motor cortex.
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PMID:Subdivisions of human parietal area 5 revealed by quantitative receptor autoradiography: a parietal region between motor, somatosensory, and cingulate cortical areas. 1580 98

Early experiences have long-term effects on brain function and behavior. However, the precise mechanisms involved still remain elusive. In an effort to address this issue, we employed the model of "early handling", which is known to affect the ability of the adult organism to respond to stressful stimuli, and determined its effects on hippocampal pCREB and BDNF 2, 4, and 8 h later. 8 h following "handling" on postnatal day 1, there was an increase in pCREB and BDNF positive cells in the hippocampus, a brain area which is a specific target of "handling". On the other hand, vehicle injection resulted in decreased pCREB and BDNF in both handled and non-handled animals 2 and 4 h later. The "handling"-induced increase of pCREB and BDNF was cancelled by inhibition of NMDA, AMPA/kainate, GABA-A, 5-HT1A or 5-HT2A/C receptors, as well as L-type voltage-gated Ca(2+) channels. It thus appears that "early handling" activates these neurotransmitter receptors, leading to increased intracellular Ca(2+), phosphorylation of the transcription factor CREB, and increased BDNF expression. BDNF can then exert its morphogenetic effects and thus "imprint" the effects of "handling" on the brain.
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PMID:Cellular mechanisms underlying an effect of "early handling" on pCREB and BDNF in the neonatal rat hippocampus. 1602 4

Regional distributions of ligand binding sites of 12 different neurotransmitter receptors (glutamatergic: AMPA, kainate, NMDA; GABAergic: GABA(A), GABA(B); cholinergic: muscarinic M2, nicotinic; adrenergic: alpha1, alpha2; serotonergic: 5-HT1A, 5-HT2; dopaminergic: D1) were studied in human postmortem brains by means of quantitative receptor autoradiography. Binding site densities were measured in the superior parietal lobule (SPL) (areas 5L, 5M, 5Ci, and different locations within Brodmann's area (BA) 7), somatosensory (BA 2), and visual cortical areas (BA 17, and different locations within BAs 18 and 19). Similarities of receptor distribution between cortical areas were analyzed by cluster analysis, uni- and multivariate statistics of mean receptor densities (averaged over all cortical layers), and profiles representing the laminar distribution patterns of receptors. A considerable heterogeneity of regional receptor densities and laminar patterns between the sites was found in the SPL and the visual cortex. The most prominent regional differences were found for M2 receptors. In the SPL, rostrocaudally oriented changes of receptor densities were more pronounced than those in mediolateral direction. The receptor distribution in the rostral SPL was more similar to that of the somatosensory cortex, whereas caudal SPL resembled the receptor patterns of the dorsolateral extrastriate visual areas. These results suggest a segregation of the different SPL areas based on receptor distribution features typical for somatosensory or visual areas, which fits to the dual functional role of this cortical region, i.e., the involvement of the human SPL in visuomotor and somatosensory motor transformations.
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PMID:Transmitter receptors reveal segregation of cortical areas in the human superior parietal cortex: relations to visual and somatosensory regions. 1605 41

It has been suggested that antagonists at serotonin 5-HT1A receptors may exert a procognitive effect by facilitating glutamatergic neurotransmission. Here we further explored this issue by looking for the ability of a 5-HT1A antagonist to prevent the learning deficit induced by AMPA receptor blockade in two behavioural procedures in rats, and for concomitant molecular changes presumably involved in memory formation in the hippocampus. Pretraining administration of the competitive AMPA receptor antagonist, NBQX, produced a dose-related retention impairment in a passive avoidance task 24h later, and also impaired retention in a novel object recognition test when an intertrial interval of 3h was selected. Pretreatment with the selective 5-HT1A receptor antagonist, WAY-100635, prevented the learning deficit induced by NBQX in the two behavioural procedures. In biochemical studies performed on rat hippocampus after the retention tests, we found that learning increased the membrane levels of AMPA receptor GluR1 and GluR2/3 subunits, as well as the phosphorylated forms of GluR1, effects that were abolished by NBQX administration before the training session. Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression. Moreover, administration of WAY-100635 before object recognition training improved recognition memory 24h later and potentiated the learning-associated increase in AMPA receptor subunits. The results support the proposed utility of 5-HT1A antagonists in the treatment of cognitive disorders.
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PMID:Opposing effects of AMPA and 5-HT1A receptor blockade on passive avoidance and object recognition performance: correlation with AMPA receptor subunit expression in rat hippocampus. 1662 Aug 83

The laminar distributions of 16 neurotransmitter receptor binding sites were analysed in visual cortical areas V1-V3 by quantitative in vitro receptor autoradiography. For each receptor (glutamatergic: AMPA, kainate, NMDA; cholinergic: M1, M2, M3, nicotinic; GABAergic: GABAA, GABAB, benzodiazepine binding-sites; adrenergic: alpha1, alpha2; serotoninergic: 5-HT1A, 5-HT2; dopaminergic: D1; Adenosine: A1), density profiles extracted perpendicular to the cortical surface were compared to cyto- and myeloarchitectonic profiles sampled at corresponding cortical sites. When testing for differences in laminar distribution patterns, all receptor-density profiles differed significantly from the cyto- and myeloarchitectonic ones. These results indicate that receptor distribution is an independent feature of the cortical architecture not predictable by densities of cell bodies or myelinated fibres. Receptor co-distribution was studied by cluster analyses, revealing several groups of receptors, which showed similar laminar distribution patterns across all analysed areas (V1-V3). Other receptors were co-distributed in extrastriate but not primary visual cortex. Finally, some receptors were not co-distributed with any of the analysed other ones. A comparison of the laminar patterns of receptor binding sites in the human visual cortex with those reported for non-human primates and other mammals showed that the laminar distributions of cholinergic and glutamatergic receptors seem largely preserved, while serotoninergic and adrenergic receptors appear to be more variable between different species.
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PMID:Laminar distribution and co-distribution of neurotransmitter receptors in early human visual cortex. 1782 18

Systemic administration of selective 5-HT1A agonists, such as 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT), stimulates the electrical activity of ventral tegmental area (VTA) dopamine neurons by a mechanism which remains unknown. We have examined if this activation is dependent on glutamatergic, serotonergic and GABAergic neurotransmission and if 5-HT1A receptors located within the VTA or within the prefrontal cortex (PFC) could contribute. In vivo electrophysiological recordings were obtained from VTA dopamine neurons from anesthetized rats. The i.v. administration of the 5-HT1A agonist 8-OHDPAT induced a strong stimulation of burst and firing activity of dopamine neurons. This activation remained unchanged in rats pre-treated with the 5-HT depleting agent parachlorophenylalanine. However, pre-administration of the GABAB receptor antagonist phaclophen, but not of the GABAA antagonist picrotoxin, significantly reduced the 8-OHDPAT-induced activation. The N-methyl-d-aspartate (NMDA) antagonist MK 801 (dizocilpine), but not the AMPA/kainate antagonist [1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl)quinoxalin-1-yl] methyl-phosphonate (ZK 200775), partially prevented or reversed the effects of 8-OHDPAT. However, only the combined pre-administration of the two glutamate antagonists did completely prevent the activatory response to 8-OHDPAT and even converted the effect of 8-OHDPAT into an inhibition, in half of the dopamine neurons tested. Inactivation of the local 5-HT1A receptors by the microinfusion within the VTA of the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100,635), or of pertussis toxin, reduced the ability of 8-OHDPAT to stimulate the firing of dopamine neurons but not their burst activity. On the other hand, burst activation elicited by 8-OHDPAT was strongly reduced following the inactivation of prefrontal 5-HT1A receptors achieved by the microinfusion of WAY 100,635 within the PFC. These results show that activation of midbrain dopamine neurons by the systemic administration of 5-HT1A agonists does involve the inactivation of a tonic GABAergic tone, involving mainly the GABAB receptors, probably leading to the stimulation of a glutamatergic excitatory drive from the PFC to the VTA and an increase in glutamate release. This will excite dopamine neurons, preferentially through NMDA receptors. Furthermore, our results suggest that some 5-HT1A receptors located within the VTA may also participate in this activation.
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PMID:Involvement of glutamate neurotransmission and N-methyl-d-aspartate receptor in the activation of midbrain dopamine neurons by 5-HT1A receptor agonists: an electrophysiological study in the rat. 1880 15

The antiphospholipid syndrome (APS) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts. In experimental APS (eAPS), a mouse model of APS, behavioral abnormalities develop in the absence of vessel occlusion or infarcts. Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits, we checked for lymphocytic infiltration, activation of glia and macrophages, as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior. Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3, CD4, CD8 and forkhead box P3 (Foxp3), respectively. GFAP, Iba1 and CD68-immunohistochemistry was performed, to check for activation of astrocytes, microglia and macrophages. Ligand binding densities of NMDA, AMPA, GABAA and 5-HT1A receptors were analyzed by in vitro receptor autoradiography. No significant inflammatory reaction occurred in eAPS mice. There was neither activation of astrocytes or microglia nor accumulation of macrophages. Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged. However, ligand binding densities of the modulatory serotonergic 5-HT1A receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed.
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PMID:Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic 5-HT1A receptors. 2288 59

Experimental antiphospholipid syndrome (eAPS) in Balb/c mice causes neuropsychiatric abnormalities including hyperactivity, increased explorative behavior and cognitive deficits. Recently, we have demonstrated that these behavioral changes were linked to an upregulation of serotonergic 5-HT1A receptor binding densities in cortical and hippocampal regions while excitatory and inhibitory neurotransmitter receptors remain largely unchanged. To examine whether the observed behavioral features depend on a critical antibody concentration, mice with only moderately enhanced antiphospholipid antibodies (aPL), about 50-80% of high levels, were analyzed and compared to controls. The staircase test was used to test animals for hyperactivity and explorative behavior. The brains were analyzed for tissue integrity and inflammation. Ligand binding densities of NMDA, AMPA, GABAA, 5-HT1A, M1 and M2 muscarinic acetylcholine receptors, respectively, were analyzed by in vitro receptor autoradiography and compared to brains of mice from our previous study with high levels of aPL. Mice with only moderately enhanced aPL did not develop significant behavioral changes. Brain parenchyma remained intact and neither inflammation nor glial activation was detectable. However, there was a significant decrease of NMDA receptor binding densities in the motor cortex as well as an increase in M1 binding densities in cortical and hippocampal regions, whereas the other receptors analyzed were not altered. Lack of neuropsychiatric symptoms may be due to modulations of receptors resulting in normal behavior. In conclusion, our results support the hypothesis that high levels of aPL are required for the manifestation of neuropsychiatric involvement while at lower antibody levels compensatory mechanisms may preserve normal behavior.
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PMID:Altered receptor binding densities in experimental antiphospholipid syndrome despite only moderately enhanced autoantibody levels and absence of behavioral features. 2433 89


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