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 serotonergic neurons of the mammalian brain comprise one of the most expansive chemical systems known. The cell bodies are largely confined to the midline (raphe) region of the brain stem in two general clusters: a superior group that consists of the dorsal raphe nucleus (B-7 and B-6), median raphe nucleus (B-8 and B-5), caudal linear nucleus (rostral B-8), and supralemniscal nucleus (B-9), and an inferior group that consists of nucleus raphe obscurus (B-2), nucleus raphe pallidus (B-1), nucleus raphe magnus (B-3), ventral lateral medulla (B-1/B-3), and the area postrema. The axons from these cells project throughout the neuroaxis from the spinal cord to the olfactory bulb and from the cerebral cortex to the hypothalamus. The development of this giant system begins very early in gestation and is influenced by a variety of growth regulatory factors, including the astroglial protein S-100 beta. Evidence will be presented that the serotonergic system plays a major role in the maturation of the brain by interacting with the 5-HT1A receptors which are most dense during these early developmental periods. The 5-HT1A receptor is located on both neurons and astrocytes, and in the latter cells may serve to stimulate release of S-100 beta. The developmental role of 5-HT appears to become dormant as the brain matures, and during aging and Alzheimer's disease, 5-HT receptors are significantly depressed. However, specific damage to 5-HT fibers in the adult brain by 5,7-dihydroxytryptamine produces a sharp fall in the levels of 5-HT which seems to reactivate the developmental signals in the brain. Not only are the serotonergic fibers encouraged to sprout and expand their territory, but the stimulation of the astrocytic growth factor by a 5-HT1A agonist is reinstated. The ability to recall developmental processes in the adult brain by interrupting the 5-HT fibers may provide important tools for understanding and treating the aged brain.
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PMID:Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system. 175 58

Stimulation of astroglial 5-HT1A receptors causes astroglial cells to acquire a more mature morphology and to release a factor (or factors) which promotes growth of serotonergic neurons. By using an antibody-blocking approach, we have shown that at least one of the growth-promoting factors thus released is the astroglial-specific protein S-100. This may be a particularly important observation, in view of studies implicating S-100 in both Down's syndrome and Alzheimer's disease.
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PMID:Stimulation of astroglial 5-HT1A receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology. 224 32

A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.
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PMID:The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory. 295 85

Serotonin and dexamethasone act as differentiating agents during development. Reducing circulating adrenal steroids or central 5-HT levels via adrenalectomy (ADX) or the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA), respectively, has been shown to have de-differentiating effects in the adult brain. Morphometric analysis of 5-HT, S100 beta, MAP-2 and synaptophysin immunoreactivity (IR) was used to follow the molecular plasticity of several brain regions after lesioning of 5-HT nerve terminals by para-chloroamphetamine (PCA; 2 x 10 mg/kg s.c.), a serotonin neurotoxin. Two weeks after PCA treatment we observed reductions of 5-HT, S100 beta, and MAP-2 IR in parietal and temporal cortex, temporal pole, hippocampus and hypothalamus. The reductions in MAP-2 and synaptophysin-IR were reversed by 3 days of treatment with dexamethasone (10 mg/l drinking water) or ipsapirone, a 5-HT1A agonist (1 mg/kg s.c.). The loss of S100-IR was reversed only by the 5-HT1A agonist. These results indicate that both dexamethasone and serotonin have effects on adult neuronal plasticity but may work via different mechanisms. The implications of these findings to the loss of synaptophysin and MAP-2 staining in Alzheimer's disease are discussed.
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PMID:5-HT1A agonist and dexamethasone reversal of para-chloroamphetamine induced loss of MAP-2 and synaptophysin immunoreactivity in adult rat brain. 755 42

Experimental lesions and quantitative autoradiography were used to investigate the cellular localisation of receptors. Lesions were produced by intrastriatal injections of either volkensin or ricin, only the former is retrogradely transported. Volkensin treatment caused significant losses in Fr1/Fr2 of neocortex in the number of infragranular pyramidal neurones and binding to deep cortical layers of both [3H]pirenzepine (muscarinic cholinergic m1 receptors) and [3H]kainate (kainate sensitive glutamate receptors). In common with previous findings, which also showed sparing of interneurones, supragranular pyramidal neurones were not reduced in number and the binding to deep cortical layers of [3H]8-hydroxy-2-(n-dipropylamino)tetralin (serotonin 1A receptors) was reduced. Significant increases in [3H]prazosin binding to both total alpha adrenoceptors and the alpha 1b subtype were observed in superficial layers. Adrenoceptors were not decreased in any layer. The binding of [3H] GABA to GABAA receptors was not affected at all. Muscarinic receptors and pyramidal neurones were also reduced in deep cortical layers of Par1/Par2 in common with serotonin 1A (5-HT1A) receptors and total alpha receptors were significantly decreased in the middle layers. Overall m1 and kainate receptors were less affected than 5-HT1A receptors. The results are discussed in terms of the biology of cortical pyramidal neurones, drugs for Alzheimer's disease and novel ligands for improving human brain in vivo scanning techniques.
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PMID:Localisation of muscarinic (m1) and other neurotransmitter receptors on corticofugal-projecting pyramidal neurones. 814 48

Pyramidal neurones of the neocortex have been implicated in a number of neuropsychiatric diseases, such as Alzheimer's disease. Markers that may identify these cells have been investigated using a novel technique. A subpopulation of corticifugal neocortical pyramidal neurones was destroyed by the unilateral striatal injection of volkensin, a toxin that undergoes retrograde suicide transport from the site of injection. Striatal volkensin injections produced significant reductions in the number of large pyramidal neurones of the infragranular cortical layer. The selectivity of the lesion was demonstrated by the preservation of cells containing glutamic acid decarboxylase mRNA, which are considered to be cortical interneurones. Ricin, another toxic lectin, but effective as a suicide transport agent exclusively in the PNS, produced local striatal damage but no cortical cell loss. In autoradiographic binding studies of animals treated with volkensin, binding in deep neocortical layers of [3H]8-hydroxy-2-(n-dipropylamino) tetralin ([3H]8-OH-DPAT) to 5-HT1A but not of [3H]ketanserin to 5-HT2 receptors was significantly reduced. The N-methyl-D-aspartate receptor complex was investigated using the novel glycine site antagonist [3H]L-689,560, and the muscarinic M1 receptor using [3H]pirenzepine. Significant reductions in binding of [3H]L-689,560 and [3H]pirenzepine were observed in the deep neocortical layers of the animals that had been injected with volkensin. The rank order of the ligands as effective markers for this subpopulation of pyramidal neurones was [3H]8-OH-DPAT >> [3H]pirenzepine > [3H]L-689,560 >> [3H]ketanserin. These findings are thought to have advanced the understanding of the biology of pyramidal neurones. Implications for in vivo imaging treatment of neuropsychiatric conditions such as Alzheimer's disease are discussed.
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PMID:Neurotransmitter receptors of rat cortical pyramidal neurones: implications for in vivo imaging and therapy. 839 Oct 81

Psychopharmacotherapy of the elderly must take into account the effects of age-related changes in the structure and function of the brain and various organs. In general, older people are more sensitive than young people to both the therapeutic and toxic effects of psychotropic medications, necessitating lower doses and longer dosage intervals. This holds true for the treatment of 5 major types of psychiatric illness (depression, bipolar disorder, anxiety, psychotic disorders and dementia). The tricyclic antidepressants, although efficacious, inexpensive, and backed by 30 years of experience, are less well tolerated by the elderly than are newer antidepressants such as the selective serotonin uptake inhibitors. Problems with monoamine oxidase (MAO) inhibitors, including orthostatic hypotension and restrictions in diet and other medication use, have been overcome by the advent of reversible selective inhibitors of MAO-A, but the efficacy of these in the elderly has yet to be proven in clinical trials. Lithium remains the mainstay for the treatment of bipolar disorder. However, careful dosing and monitoring of plasma lithium concentrations are required in the elderly due to changes in pharmacokinetics and pharmacodynamics which make older patients very sensitive to the toxic effects of this medication. Similarly, age-related changes in the pharmacokinetics and pharmacodynamics of the benzodiazepines, the most frequently prescribed medications for anxiety in the elderly, result in recommendations for lower doses and preferential use of those agents metabolised by conjugation (e.g. oxazepam). Buspirone, a partial serotonin 5-HT1A-agonist which is better tolerated than benzodiazepines in the elderly, may be used as an alternative. The elderly are extremely sensitive to extrapyramidal adverse effects which the typical antipsychotics (neuroleptics) exhibit to varying extents. The selection of a suitable agent for the treatment of a psychotic disorder should be based upon the adverse effect profile of the drug and the specific symptoms and situation of the patient. The newer atypical antipsychotics, clozapine and risperidone, have yet to be well-studied in the elderly. Dementia, exemplified by Alzheimer's disease, is almost exclusively an illness of the elderly. Only one medication, tacrine, has been approved for its treatment, based on extensive basic research and positive results of several clinical trials. Its long-term benefits have yet to be determined and it has several adverse effects, including a tendency to increase liver enzymes to the extent that the medication has to be discontinued.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Recent advances in geriatric psychopharmacology. 853 49

In Alzheimer's disease (AD), there are marked deficits in the function of both the cholinergic and serotonergic systems. We and others have shown altered muscarinic M1 receptor/G-protein coupling in the superior frontal cortex (Brodmann areas 8 and 9) from AD patients. In the present study, we investigated whether similar receptor/G-protein alterations would occur at the 5-HT1A receptor in the same brain area. Using [3H]8-OH-DPAT as a radioligand, two binding sites with high and low affinity were found. The high affinity site (Kd = 1 nM), which is consistent with the classical 5-HT1A receptor, was not affected in AD either in the absence or presence of the non-hydrolyzable guanine nucleotide analog, GppNHp (100 microM). On the other hand, although there was no change in the affinity of [3H]8-OH-DPAT at the low affinity site (Kd = 8-10 nM), agonist binding was less sensitive to inhibition by GppNHp in AD (-29%) compared to age-matched controls (-51%). Based on these findings, alterations in receptor/G-protein coupling of both cholinergic and serotonergic receptors may be one explanation why neurotransmitter replacement drug therapies have been unsuccessful thus far in the treatment of AD.
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PMID:Altered G-protein coupling of a frontal cortical low affinity [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin serotonergic binding site in Alzheimer's disease. 878 28

Age-dependent differences in the ability of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to irreversibly inactivate 5-HT1A receptors were investigated in female Fischer 344 rats (ages 3 and 22 months). In the hippocampus, frontal cortex and amygdala, EEDQ reduced 5-HT1A receptor density (33-70%) and drug affinity (2.3-6.2 fold) as determined by Scatchard analyses using [3H]8-hydroxy-2-(di-N-propylamino)tetralin. In the frontal cortex, the reduction in Bmax values was significantly greater in 3 months vs. 22 months groups. These region-specific and age-dependent alterations in 5-HT1A receptors may be of pathophysiological significance in age-related cognitive decline and Alzheimer's disease.
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PMID:Age-related assessment of central 5-HT1A receptors following irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). 886 8

Fornix transection in the marmoset produces a specific pattern of cognitive deficits, notably a lack of ability to recall visuospatial tasks learnt preoperatively, and a deficit in acquiring new visuospatial tasks following transection. Previous work has shown that this learning impairment can be ameliorated by cholinergic agonists, suggesting that it occurs as a consequence of destroying the cholinergic projection from the vertical limb of the diagonal band to the hippocampus which runs through the fornix. We have now shown that this deficit in new learning can be significantly alleviated by the 5-HT1A antagonist, WAY 100635. This result supports the suggestion that 5-HT1A projections are inhibitory on the same target cells for which cholinergic projections are excitatory, and that loss of function in the target cells caused by loss of excitatory tone can be compensated by blockade of inhibitory tone. Since cholinergic loss in the hippocampus (and neocortex) occurs in association with cognitive decline in Alzheimer's disease, these results suggest that 5-HT1A antagonists may have a role in the treatment of some of the cognitive symptoms of dementia.
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PMID:The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset. 891 3


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