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)

Experimental lesions using the retrogradely transported toxin, volkensin, have been used in conjunction with autoradiography to investigate the cellular localization of 5-HT1A, muscarinic M1 and nicotinic receptors. Selective destruction of neocortical pyramidal neurones forming the corticostriatal or corticocortical pathways was achieved by intrastriatal or intracortical injection of volkensin. Selective destruction of layer V corticostriatal neurones was accompanied by loss of binding in the cortex to 5-HT1A and muscarinic M1 receptors, and an upregulation of [3H] nicotine binding contralateral to the pyramidal cell loss. Destruction of corticocortical neurones was accompanied by loss of binding to muscarinic and nicotinic receptors. The presence of these cholinoceptors on corticocortical neurones was confirmed by recording carbachol-induced depolarizations from a novel cortical brain slice preparation. It is proposed that cholinoceptors represent a consistent marker for neocortical pyramidal cells, and as such are viable targets for the continuing development of therapies designed to ameliorate the cortical hypoactivity observed in Alzheimer's disease. Ligands for these receptors may also be suitable for positron emission tomography to assess pyramidal neurone numbers in suspected Alzheimer's disease.
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PMID:Acetylcholine receptor targets on cortical pyramidal neurones as targets for Alzheimer's therapy. 911 62

To study whether the changes in cortical noradrenergic and serotonergic mechanisms observed in patients with Alzheimer's disease are the consequence of reduced cortical cholinergic activity, a novel colinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the lower affinity nerve growth factor receptor with the cytotoxic protein saporin, 192IgG-saporin) was used to produce a specific and selective loss of cholinergic cells in rat basal forebrain nuclei. To correlate the responses to cholinergic immunolesion in cholinoceptive cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure adrenoceptors and 5-hydroxytryptamine (5-HT) receptor subtypes, and histochemistry to estimate acetylcholinesterase activity, were performed in adjacent brain sections. alpha 1-adrenoceptor and 5-HT1A receptor binding were not affected by cholinergic immunolesion in any of the cortical and hippocampal regions studied. However, cholinergic immunolesion resulted in significantly reduced alpha 2- and beta-adrenoceptor as well as 5-HT2A receptor binding in a number of cortical and hippocampal regions displaying a reduced activity of acetylcholinesterase, already detectable seven days after a single injection of 192IgG-saporin and persisting up to three months post lesion without any significant recovery. The data suggest that at least a subpopulation of alpha 2- and beta-adrenoceptor as well 5-HT2A receptor subtype is present on cortical and hippocampal cholinergic terminals originating in the basal forebrain. The lesion-induced receptor changes suggest that the alterations in cortical 5-HT2 receptor binding observed in patients with Alzheimer's disease might be secondary to cholinergic deficits.
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PMID:Basal forebrain cholinergic immunolesion by 192IgG-saporin: evidence for a presynaptic location of subpopulations of alpha 2- and beta-adrenergic as well as 5-HT2A receptors on cortical cholinergic terminals. 923 51

Experimental lesions and quantitative autoradiography were used to investigate the cellular distribution of neurotransmitter receptors in rats. Lesions were produced by intracortical injections of either volkensin or ricin. However, only the former is retrogradely transported and volkensin treatment causes significant loss of contralateral cortical pyramidal neurones. Binding of [3H]pirenzepine (muscarinic M1 receptors) and [3H]nicotine was reduced in contralateral cortex in volkensin compared with ricin and/or control (uninjected) animals. However, binding of [3H]8-hydroxy-2-(n-dipropylamino)tetralin (5-HT1A receptors), [3H]ketanserin (5-HT2A receptors), and [3H]1,3-dipropylcyclopentylxanthine (adenosine A1 receptors) was unchanged. The most likely explanation for these results is that M1 and nicotinic receptors are present in large numbers on those pyramidal neurones that are lost. 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 scanning techniques.
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PMID:Selective loss of cholinergic receptors following unilateral intracortical injection of volkensin. 929 15

Alterations in the function of the neurotransmitter serotonin (5-HT) have been implicated in several neurobehavioral disorders, including depression, anxiety as well as a well-known disorder of aging, Alzheimer's disease. Age-dependent changes in the serotonergic system include a loss of 5-HT-containing fibers in brain areas which contain high levels of 5-HT1A receptors. Other changes with aging include decreased 5-HT levels, increases in monoamine oxidase (the major 5-HT degrading enzyme), and decreases in the density of 5-HT receptors. While age-related declines in the number of 5-HT1B and 5-HT2 receptors have been reported, little information is available describing the region-specific effects of aging on the functional dynamics of equilibrium binding at 5-HT receptors, including the 5-HT1A receptor subtype. For example, there are limited data showing a decrease in the maximal binding capacity (Bmax) of 5-HT1A receptors in the aging cortex of humans. However, changes in affinity (Kd) for this receptor subtype as a function of age and brain region have not been fully investigated. Other reports have failed to indicate age-related modifications in human and rat brain tissue 5-HT1A binding parameters. In contrast, electrophysiological studies suggest that the physiological function of the 5-HT1A receptor population is altered with aging. Therefore, to elucidate region-specific 5-HT1A receptor binding characteristics in aging rats, we have utilized a neurotoxic agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to irreversibly inactivate 5-HT1A receptors. In this way, subsequent age-related changes that occur in 5-HT1A receptor binding characteristics may be investigated. EEDQ is an alkylating agent which irreversibly inactivates serotonergic receptors which are coupled to G proteins. This compound is appropriate for examining the binding profile of several 5-HT receptors, including the 5-HT1A receptor. The 5-HT1A binding site is among the most sensitive of the serotonergic receptor subtypes to inactivation by EEDQ and is also negatively coupled to adenylate cyclase via interaction with a Gi protein. Thus, EEDQ administration is a useful neurotoxicant to examine the relationship between aging and binding characteristics of 5-HT1A receptors. In addition, using EEDQ to inactivate 5-HT1A binding sites, we can further investigate the extent to which receptor binding characteristics (Bmax and Kd) return to baseline levels (i.e., recover) in an age- and brain region-dependent manner following a neurotoxic insult. That is, the age- and region-dependent recovery of 5-HT1A receptors may be monitored in a time-dependent manner to determine receptor turnover parameters, including receptor synthesis and degradation rate constants, and half-life values. Following receptor inactivation by EEDQ, 5-HT1A receptors repopulate (i.e., return to baseline levels) with time and exhibit region-specific turnover rates. Therefore, EEDQ administration is an effective pharmacological tool to investigate region-specific differences in 5-HT1A receptor turnover characteristics. Likewise, by utilizing this neurotoxicant the cellular mechanisms by which pharmacological agents interact with central 5-HT receptors and produce their effects in the aging brain can be addressed. We will illustrate the application of the neurotoxicant EEDQ to irreversibly inactivate 5-HT1A receptors. Following EEDQ administration, region-specific changes in 5-HT1A binding characteristics, including receptor density and drug affinity, and kinetics of receptor recovery will be demonstrated by Scatchard analyses and calculations of the recovery of these receptor populations illustrated. Based on the presence of high densities of 5-HT1A receptors in the hippocampus and frontal cortex, these brain regions will be studied for comparisons of both age- and region-specific alterations in receptor binding characteristics.
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PMID:N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) administration for studies of 5-HT1A receptor binding site inactivation and turnover. 938 17

Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-me thylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors. Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidinyl benzilate vs that of [3H]-Oxotremorine-M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5-HT1 and 5-HT2 receptor subtypes. Carbachol and xanomeline stimulated basal [35S]-GTPgammaS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline-induced stimulation of [35S]-GTPgammaS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 microM and was inhibited by the selective 5-HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5-HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors. In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca2+ concentration in cells expressing h5-HT2A, h5-HT2B and h5-HT2c receptors with potencies similar to its affinity at these receptors. These studies indicate that xanomeline is a potent agonist at 5-HT1A and 5-HT1B receptors and an antagonist at 5-HT2 receptor subtypes.
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PMID:Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. 988 68

Multiple 5-hydroxytryptamine (5-HT) receptors have been identified (5-HT1A/1B/1D/1E/1F, 5-HT2A/2B/2C, 5-HT3A/3B, 5-HT4A/4B, 5-HT5A/5B, 5-HT6 and 5-HT7A/7B/7C/7D) and extensive evidence suggests that 5-HT receptors have a role in learning and memory. Indeed, available evidence strongly supports physiological, pathophysiological and therapeutic roles of 5-HT systems in cognitive processes, although the evidence seems incomplete. Indeed, there has been a clear tendency to use pre-learning administration most frequently, whereas post-learning and pre-retention administration protocols have been utilized in only a few studies, and probably this trend has led to missed relevant information. For instance, when pre- vs post-training administration of 5-HT1A agonist, 5-HT2 antagonists and 5-HT4 agonists have been compared contrasting findings were reported in aversive and appetitive learning tasks. Emerging evidence also indicates that 5-HT1A and 5-HT4 receptor agonists, as well as, 5-HT1A antagonists, 5-HT2 antagonists, 5-HT3 antagonists and 5-HT uptake inhibitors may have therapeutic utility in the treatment of Alzheimer's disease and amnesia. Inasmuch as the activation or blockade of diverse 5-HT receptors is able to modulate cognitive processes, and 5-HT uptake inhibition could have therapeutic applications in the treatment of cognitive disorders, it seems evident that the role of 5-HT in learning and memory is more complex than a simple imbalance. Consequently, the notion that activation of the 5-HT systems impairs performance, whereas reduced serotonergic function may facilitate learning, must be reconsidered.
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PMID:Physiological, pathophysiological and therapeutic roles of 5-HT systems in learning and memory. 988 42

Glutamatergic hypofunction occurs in Alzheimer's disease (AD). MK801, a noncompetitive blocker of glutamate N-methyl-D-aspartate receptors, was used to disrupt the cognitive performance of rats trained on a delayed nonmatching to sample radial maze task. Drugs which act by blocking serotonin (5-HT) receptors were evaluated for their ability to reduce the cognitive impairment produced by MK801. Specifically, WAY-100635, a selective 5-HT1A receptor antagonist, buspirone, a 5-HT1A partial agonist, ritanserin, a 5-HT2 antagonist, and ondansetron, a 5-HT3 antagonist, were assessed. In addition, the muscarinic agonist arecoline was evaluated for its potential cognitive benefit in this model. It was found that WAY-100635 significantly reduced the cognitive impairment induced by MK801. Treatment with single doses of ritanserin, ondansetron, or arecoline in combination with MK801 did not result in a cognitive impairment, indicating that these drugs attenuated the MK801 impairment. The combination of buspirone and MK801 resulted in an inability of the animals to complete the task. These results suggest that interactions between 5-HT and glutamate may mediate the beneficial effects of reducing cognitive impairment and that 5-HT antagonists, especially selective 5-HT1A antagonists, may be useful in treating AD. Further, it is indicated that the MK801 model of cognitive impairment may add to the armamentarium of tools available to predict treatment efficacy in AD.
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PMID:5HT antagonists attenuate MK801-impaired radial arm maze performance in rats. 1019 5

Central glutamate neurotransmission is modulated by an upregulatory cholinergic influence and an inhibitory serotonergic influence. In Alzheimer's disease, cognitive decline is associated with loss of both glutamatergic and cholinergic neurones (Francis et al., 1992, Progress in Neurobiology 39, 517-545). While therapeutic strategies for alleviating this cognitive decline have concentrated on restoring cholinergic tone, we suggest that 5-HT1A antagonists also have the potential to alleviate the cognitive symptoms of Alzheimer's disease. Previous studies have shown that dizocilpine (MK-801), a glutamatergic antagonist acting at the NMDA receptor, produces learning impairments in the common marmoset, a non-human primate. Specifically, it impairs the acquisition of shape discrimination and visuospatial conditional tasks, at doses that do not affect locomotor behaviour or coordination (Harder et al., 1998, Society for Neuroscience Abstracts 23(1), 219). In the present study we investigated the effects of WAY 100 635, a 5-HT1A antagonist, on the cognitive deficits induced by dizocilpine. The number of trials required to learn each type of task under combined treatment with dizocilpine and WAY 100 635 was significantly lower than under dizocilpine treatment alone, and did not differ significantly from the number of trials required under saline, demonstrating that the cognitive effects of glutamatergic blockade can be overcome by treatment with a 5-HT1A antagonist.
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PMID:The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys. 1072 75

The 5-hydroxytryptamine1a (5-HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. The selective 5-HT1a receptor antagonist WAY-100635 (0.3 mg/kg) was itself without effect on accuracy, but was effective in reversing effects of 8-OH-DPAT (on both accuracy and DT). Within problems (i.e., over the 40-60 trials of a single discrimination), performance was reduced by treatment with 8-OH-DPAT at all stages of learning. We conclude that this effect is mediated through the 5-HT1a receptor site (rather than through some other serotonergic receptor site or non-specific mechanism) as it was reversible by treatment with WAY-100635. Although it could still arise from behaviourally non-specific effects, the performance deficit finds its best account in terms of the psychological processes necessary to visual learning. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.
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PMID:Rapid visual learning in the rat: effects at the 5-HT1a receptor subtype. 1100 20

The effects of EGb 761 on the CNS underlie one of its major therapeutic indications; i.e., individuals suffering from deteriorating cerebral mechanisms related to age-associated impairments of memory, attention and other cognitive functions. EGb 761 is currently used as symptomatic treatment for cerebral insufficiency that occurs during normal ageing or which may be due to degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory disturbances. Depressive symptoms of patients with Alzheimer's disease (AD) and aged non-Alzheimer patients may also respond to treatment with EGb 761 since this extract has an "anti-stress" effect. Basic and clinical studies, conducted both in vitro and in vivo, support these beneficial neuroprotective effects of EGb 761. EGb 761 has several major actions; it enhances cognition, improves blood rheology and tissue metabolism, and opposes the detrimental effects of ischaemia. Several mechanisms of action are useful in explaining how EGb 761 benefits patients with AD and other age-related, neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and free radical-scavenging activities, it reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A and muscarinic receptors, protects against ischaemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity, and counteracts the cognitive deficits that follow stress or traumatic brain injury. Identified chemical constituents of EGb 761 have been associated with certain actions. Both flavonoid and ginkgolide constituents are involved in the free radical-scavenging and antioxidant effects of EGb 761 which decrease tissue levels of reactive oxygen species (ROS) and inhibit membrane lipid peroxidation. Regarding EGb 761-induced regulation of cerebral glucose utilization, bilobalide increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels, a result that is supported by the finding that bilobalide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase. With regard to its "anti-stress" effect, EGb 761 acts via its ginkgolide constituents to decrease the expression of the peripheral benzodiazepine receptor (PBR) of the adrenal cortex.
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PMID:Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. 1147 35


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