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)

Although several serotonin (5-HT) receptor subtypes influence ethanol consumption, the motivational mechanisms underlying these changes remain unclear. The present experiments characterized the rewarding, aversive and stimulant effects of ethanol in combination with a specific 5-HT1A receptor antagonist (pindobind-5HT1A). In a place conditioning study, adult male Swiss-Webster mice received 6 parings of a distinctive tactile stimulus with either 2 g/kg ethanol, 2.5 mg/kg pindobind-5HT1A, or both drugs in combination. Ethanol-conditioned preference for the tactile cue was enhanced in mice also receiving pindobind-5HT1A, which did not produce cue preference in the absence of ethanol. In a taste conditioning study, Swiss-Webster mice received 4 trials consisting of access to a distinctive NaCl flavor followed by either 4 g/kg ethanol, 2.5 mg/kg pindobind-5HT1A, or both drugs. As expected, ethanol produced avoidance of the flavor. Pindobind-5HT1A did not reduce or enhance ethanol-conditioned flavor aversion. In a study characterizing locomotor activity, 2 g/kg ethanol produced stimulation, which was enhanced after 10 daily treatments. Locomotor sensitization was not altered by co-treatment with pindobind-5HT1A. Overall, the present results show specific effects of 5-HT1A blockade on ethanol reward.
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PMID:5-HT1A receptor blockade and the motivational profile of ethanol. 1207 58

The effects of 8-OHDPAT and UH-301 injection into the dorsal raphe nucleus (DRN) on fear behavior of the light-dark transitions test and regional brain monoamines (NA, DA, 5-HT) and their metabolites (MHPG, DOPAC, 5-HIAA) in the hypothalamus (HPT), midbrain central gray matter (MID), amygdala (AMY), hippocampus (HIP) and pons (PO) were examined. An injection of 8-OHDPAT (300 ng) as well UH-301 (300 ng) into the DRN evoked an increase in the number of head dipping from dark to the illuminated compartment of chamber, an increase of time of motionless in the dark compartment and decrease of time of locomotion activity in the illuminated compartment. HPLC analysis showed reduction of 5-HIAA/5-HT ratio in the HPT, HIP and PO, increase of MHPG/NA ratio in the HIP and PO, and increase of DA content in the HPT, AMY and HIP after 8-OHDPAT injection. But injection of UH-301 reduced 5-HT in the MID and increased in the AMY, reduced 5-HIAA content in the HIP and increased in the MID and decreased MHPG/NA ratio in the PO. These results indicate that both 5-HT1A receptor agonists, acting on the 5HT1A autoreceptors caused the anxiolytic effects, reduced fear behavior on the rat connected with infringement of dynamic balance between the serotonergic and catecholaminergics systems.
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PMID:Fear behavior and regional brain monoamines distribution after R(+)-8-OHDPAT and R(+)-UH-301 injections into the dorsal raphe nucleus in rats. 1220 Oct 34

Successful application of antisense oligonucleotides (ODNs) in cell biology and therapy will depend on the ease of design, efficiency of (intra)cellular delivery, ODN stability, and target specificity. Equally essential is a detailed understanding of the mechanism of antisense action. To address these issues, we employed phosphorothioate ODNs directed against specific regions of the mRNA of the serotonin 5HT1A receptor, governed by sequence and structure. We demonstrate that rather than various intracellular factors, the gene sequence per se primarily determines the antisense effect, since 5HT1a autoreceptors expressed in RN46A cells, postsynaptic receptors expressed in SN48 cells, and receptors overexpressed in LLP-K1 cells are all efficiently downregulated following ODN delivery via a cationic lipid delivery system. The data also reveal that the delivery system as such is a relevant parameter in ODN delivery. Antisense ODNs bound extensively to the RNA matrix in the cell nuclei, thereby interacting with target mRNA and causing its subsequent degradation. Antisense delivery effectively diminished the mRNA pool, thus resulting in downregulation of newly synthesized 5HT1A proteins, without the appearance of truncated protein fragments. In conjunction with the selected mRNA target sequences of the ODNs, the latter data indicated that effective degradation rather than a steric blockage of the mRNA impedes protein expression. The specificity of the antisense approach, as described in this study, is reflected by the effective functional downregulation of the 5-HT1A receptor.
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PMID:Antisense oligonucleotides reach mRNA targets via the RNA matrix: downregulation of the 5-HT1A receptor. 1464 54

5-HT1A type serotonin receptors influence the immunomodulating action of the selective preparations 8-OH-DPAT (5-HT1A receptor agonist) and WAY-100635 (5-HT1A receptor antagonist) in CBA mice. The activation of 5HT1A receptors with 8-OH-DPAT (1 mg/kg) decreased, while their blocking with WAY-100635 (1 mg/kg) increased the reaction intensity at the peak of response to immunization with ram erythrocytes. Preliminary blocking of the 5-HT1A receptors with WAY-100635 prevented the inhibiting action of 8-OH-DPAT.
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PMID:[Activation and blocking of 5-HT1A receptors influence on the immune response in CBA mice]. 1578 64

Serotonin (5-HT) has long been implicated in a number of neurodevelopmental processes including neuronal cell division, migration, neurite outgrowth, and synapse formation. However, relatively little is known about how these effects are mediated during normal brain development in vivo and the identity of the receptor subtypes involved in mediating these effects. In recent years, a number of pharmacological studies have suggested a role for the serotonin 1A (5HT1A) receptor subtype in mediating the developmental effects of 5-HT in the hippocampus. These studies, however, have been difficult to interpret due to lack of information regarding the expression and distribution of 5HT1A in the developing brain and hippocampus in particular. In the current study, specific anti-5-HT1A antibodies, developed in our laboratory [F.C. Zhou, T.D. Patel, D. Swartz, Y. Xu, M.R. Kelley, Production and characterization of an anti-serotonin 1A receptor antibody which detects functional 5-HT1A binding sites, Brain Res Mol Brain Res, 69 (1999) 186-201], were utilized to map the ontogeny and distribution of the 5HT1A receptor protein in the developing rat hippocampus through embryonic and early postnatal life. This is the first such study of 5-HT1A expression in the developing rat brain. Our findings revealed that expression of the 5HT1A receptor emerges during the initial stages of embryonic hippocampal development. Remarkably, most if not all hippocampal neurons begin to express 5HT1A shortly upon completion of their terminal mitosis. We found that 5HT1A is initially concentrated around the cell bodies and later becomes more sparsely distributed along the dendrites after the neurons have matured. In addition to postmitotic neurons, we have observed that S100 and GFAP positive glia transiently express 5HT1A during early postnatal development of the hippocampus. These findings demonstrate that the 5-HT1A receptor is positioned to mediate developmental effects of serotonin in the hippocampus. Furthermore, the temporal patterns of expression suggest a role for 5-HT1A in postmitotic events such as neuronal migration, neurite outgrowth, and phenotypic differentiation.
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PMID:Ontogeny of 5-HT1A receptor expression in the developing hippocampus. 1593 84

Selective serotonin reuptake inhibitors like paroxetine (Prx) often requires 4-6 weeks to achieve clinical benefits in depressed patients. Pindolol shortens this delay and it has been suggested that this effect is mediated by somatodendritic 5-hydroxytryptamine (5-HT) 1A autoreceptors. However clinical data on the beneficial effects of pindolol are conflicting. To study the effects of (+/-)-pindolol-paroxetine administration, we used genetical and pharmacological approaches in 5-HT1A knockout mice (5-HT1A-/-). Two assays, in vivo intracerebral microdialysis in awake mice and the forced swimming test (FST), were used to assess the antidepressant-like effects of this drug combination. Basal levels of extracellular serotonin, 5-HT ([5-HT]ext) in the frontal cortex (FCX) and the dorsal raphe nucleus (DRN) did not differ between the two strains of mice, suggesting a lack of tonic control of 5-HT1A autoreceptors on nerve terminal 5-HT release. Prx (1 and 4 mg/kg) dose-dependently increased cortical [5-HT]ext in both genotypes, but the effects were greater in mutants. The selective 5-HT1A receptor antagonist, WAY-100635 (0.5 mg/kg), or (+/-)-pindolol (5 and 10 mg/kg) potentiated the effects of Prx (4 mg/kg) on cortical [5-HT]ext in 5-HT1A+/+, but not in 5-HT1A-/- mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or (+/-)-pindolol (100 microM each). In the FST, Prx administration dose-dependently decreased the immobility time in both strains of mice, but the response was much greater in 5HT1A-/- mice. In contrast, (+/-)-pindolol blocked Prx-induced decreases in the immobility time while WAY-100635 had no effect in both genotypes. These findings using 5-HT1A-/- mice confirm that (+/-)-pindolol behaves as an antagonist of 5-HT1A autoreceptor in mice, but its blockade of paroxetine-induced antidepressant-like effects in the FST may be due to its binding to other neurotransmitter receptors.
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PMID:Blockade of 5-HT1A receptors by (+/-)-pindolol potentiates cortical 5-HT outflow, but not antidepressant-like activity of paroxetine: microdialysis and behavioral approaches in 5-HT1A receptor knockout mice. 1645 92

The 5HT1A receptor is one of at least 14 different receptors for serotonin which has a role in moderating several brain functions and may be involved in the aetiology of several psychiatric disorders. The C(-1019)G 5-HT1A promoter polymorphism was reported to be associated with major depression, depression-related personality traits and suicidal behavior in various samples. The G(-1019) allele carriers are prone to depressive personality traits and suicidal behavior, because serotonergic neurotransmission is reduced. The aim of this study is to replicate previous findings in a sample of 185 Alcohol-dependent individuals. Personality traits were evaluated using the NEO FFI and TCI. History of suicidal behavior was assessed by a standardized semistructured interview (SSAGA). No significant differences across C(-1019)G 5-HT1A genotype groups were found for TCI temperament and character traits and for NEO FFI personality scales. No association was detected between this genetic variant and history of suicide attempts. These results neither support a role of C(-1019)G 5-HT1A promoter polymorphism in the disposition of personality traits like harm avoidance or neuroticism, nor confirm previous research reporting an involvement of the G allele in suicidal behavior in alcoholics. Significant associations, however, were detected between Babor's Type B with number of suicide attempts in history, high neuroticism and harm avoidance scores in alcoholics.
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PMID:The C(-1019)G 5-HT1A promoter polymorphism and personality traits: no evidence for significant association in alcoholic patients. 1650 34

Observations in humans and animals have indicated that chronic, but not acute, antidepressant treatment (ADT) can desensitize 5-HT1A receptor-mediated responses, such as hypothermia. We hypothesized that 5-HT1A desensitization would be necessary for an antidepressant response (ADR) to occur. To test this hypothesis, we examined 5HT1A-agonist ipsapirone (IPS)-induced hypothermia in 28 depressed patients being treated with fixed doses of nortriptyline (75 mg) at 3-day and 3-week treatment points. Decreases in 24-item Hamilton scores (>12) were used to dichotomize the response data into ADR groups of 13 responders (ADR+) and 15 nonresponders (ADR-). A two-way repeated measures analysis of variance indicated significant temperature differences in the area under the curve between response groups across time from 3-day to 3-week intervals (df=1, 26, F=6.6, p<0.02). In comparison to 3 days treatment, at 3 weeks, the ADR+ patients showed blunted hypothermic responses to IPS. ADR- did not show this effect, implicating ADR+ patients to be less responsive to 5HT1A-receptor stimulation after 3 weeks treatment. Similar effects were not found for 5HT1A postsynaptically mediated ACTH and cortisol responses. These results indicate that to achieve ADR, serotonergic neurotransmission needs to be altered as reflected by the change in 5-HT1a receptor responsiveness documented herein.
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PMID:Temperature regulation in depression: functional 5HT1A receptor adaptation differentiates antidepressant response. 1664 36

Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.
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PMID:Serotonergic mechanisms in amyotrophic lateral sclerosis. 1686 Nov 47

The effects of the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) were investigated on food intake in non-deprived mice. 8-OH-DPAT (50-200 mg/kg) administered subcutaneously (s.c.) 5 min prior to presentation of food, produced a dose-related increase in cumulative food intake in C57BC6 mice. The hyperphagic effect of 8-OH-DPAT (100 mg/kg, s.c.) was abolished by concurrent treatment with the 5HT1A receptor antagonist N-[2-(4-2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridyl) cyclohexanecarboxamide (WAY100635; 0.3 mg/kg, s.c.). These data show that 8-OH-DPAT produces an increase in food consumption in non-deprived mice by a 5-HT1A receptor-mediated mechanism of action.
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PMID:The effects of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on food intake in non-deprived C57BL6 mice. 1730 Jul 78


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