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)

Hyperammonemia is an important cause of cerebral dysfunction in liver failure. We used two well-established models to induce hyperammonemia in rats, injection of urease and injection of methionine sulfoximine (MSO). Urease gave a 10-fold increase in blood ammonia while MSO, a glutamine synthetase inhibitor, gave a 4-fold increase in blood ammonia with no increase in brain glutamine levels. We observed a 2-fold increase in 5-HT1A receptor (5-HT1A-R) expression ([3H] 8-OH-DPAT binding) in hippocampus, and little change elsewhere, including thalamus in both models, thus eliminating a role for increased glutamine in the receptor induction. In contrast, a 4 to 8-fold increase in 5-HT1A-R mRNA was observed both in hippocampus and thalamus, suggesting some post-transcriptional regulation. In the absence of glutamine, ammonium acetate treatment of a hippocampal cell line which had been engineered to stably express the 5-HT1A-R (HN2-5) gave a 1.5-fold increase in [3H] 8-OH-DPAT binding and a 4-fold increase in the mRNA levels for the 5-HT1A-R. We conclude that the cell line HN2-5 is a good model for studying some of the biochemical sequelae of hyperammonemia and that changes in brain function are not only at the metabolic level, as thought earlier, but can also occur at the transcriptional level.
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PMID:Hyperammonemia increases serotonin 1A receptor expression in both rat hippocampus and a transfected hippocampal cell line, HN2-5. 767 72

The functional significance of the conserved amino acids within transmembrane regions II and VII of the human 5-hydroxytryptamine (5-HT)1A receptor was analyzed by oligonucleotide-directed mutagenesis followed by transient expression of the mutated receptor genes in COS-1 cells. The substitution of a conserved asparagine at position 396 (transmembrane region VII) with either alanine, phenylalanine, or valine resulted in a receptor that did not bind the 5-HT1A agonist 8-hydroxy-2-(di-n-[3H]propylamino)tetralin. In contrast, replacement of Asn396 with glutamine did not affect agonist binding. In addition, serine residues at positions 391 and 393 (transmembrane domain VII) were changed to alanine. Changing the less conserved Ser391 to alanine had no effect on ligand binding. However, replacement of the conserved Ser393 with alanine reduced ligand binding by 86%. Replacement of a conserved aspartate at position 82 (transmembrane region II) with alanine also produced a receptor without detectable agonist binding. Protein immunoblotting detected receptor protein of approximately 51 kDa in both wild-type and mutant receptor-expressing cells, indicating that these mutations probably did not affect expression or processing of the protein. Importantly, the sequence of the human 5-HT1A receptor described in this paper differs from the published sequence [Nature (Lond.) 329:75-79 (1987)] in transmembrane region IV. The present sequence encodes a protein of 422 amino acids, instead of the 421-amino acid protein that has been described previously [Nature (Lond.) 329:75-79 (1987)], and has a change in the sequence in transmembrane region IV from ... RPRAL ... to ... RRAAA ..., which corresponds to the published sequence [J. Biol. Chem. 265:5825-5832 (1990)] of the rat 5-HT1A receptor. Moreover, conversion of the transmembrane region IV sequence of the present clone to that of the published sequence by site-directed mutagenesis abolished ligand binding to the receptor.
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PMID:Identification of residues important for ligand binding to the human 5-hydroxytryptamine1A serotonin receptor. 847 30

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.
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PMID:Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation. 1154 34

Neurochemical imaging is frequently applied to measure markers of pathological change so as to understand mechanisms that create symptoms of major depressive disorder. For example, indices of greater monoamine oxidase A(MAO-A) level, particularly in the prefrontal and anterior cingulate cortex, are associated with depressed mood states, and high-risk states for onset of major depressive episodes. MAO-A metabolises monoamines, and greater metabolism of monoamines occurs when MAO-A is elevated in brain. Lower extracellular serotonin is associated with greater pessimism in humans and chronic serotonin deficiency is associated with upregulation of 5-HT2A (serotonin2A) receptors in cortex. During major depressive episodes when pessimism is more severe, greater 5-HT2A BPND, an index of density occurs in prefrontal and anterior cingulate cortex. These results argue for a mechanism of lowering extracellular serotonin in the prefrontal and anterior cingulate cortex, consequent to elevated MAO-A level. The relationship between elevated 5-HTT BPND and greater pessimism during major depressive episodes suggests that greater 5-HTT density in the context of elevated MAO-A level further contributes to serotonin deficiency in these brain regions. A similar mechanism may explain the association between neuroimaging indices of greater dorsal striatal D2 density, DAT density and symptoms of motor retardation: Greater MAO-A level and relatively greater DAT density lower extracellular dopamine in the dorsal striatum, leading to motor retardation. Indices of greater 5-HT1A density, particularly in the cingulate cortex, have been associated with major depressive disorder, and well as anxiety disorders, suggesting that this abnormality is mechanistically related to presence of anxiety symptoms. To date, abnormalities of Glx a measure reflecting glutamate and glutamine levels have been most strongly associated with presence of major depressive episodes, with greater levels in occipital cortex, and reduced levels in prefrontal cortex. Ultimately, the future for neurochemical imaging is to better understand the mechanisms that predispose toward onset of MDE so as to create biologically informed, novel, methods of prevention, and superior, more symptom-targeted treatments.
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PMID:Neurochemical imaging and depressive behaviours. 2301 53