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)

Pretreatment (15 min) of male rats with gepirone given parenterally (10 mg/kg i.p.) or intracranially into the dorsal raphe nucleus (14 or 21 micrograms) blocks the rapidly reversible increase in brain tryptophan hydroxylase activity and 5-hydroxyindolamine acetic acid tissue levels seen in vitro after 1-h acute sound stress. Chronic gepirone treatment over 28 days (40 mg/day s.c.) prevents the stable enzyme activity increase induced by repeated sessions of sound stress, and the rapidly reversible increase always observed following sound stress. The gepirone metabolite, 1-(2-pyrimidinyl)-1-piperazine, is inactive in each of these experiments. Transient blood pressure elevations occur with each sound presentation, but no persistent hypertension is observed with repeated sound-stress exposures. Gepirone may block the sound stress-induced biochemical increases by its inhibition of serotonergic neuronal firing in the dorsal raphe nucleus that is mediated by its agonist action at the somatodendritic (5-HT1A) autoreceptors.
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PMID:Effect of gepirone on increases in tryptophan hydroxylase in response to sound stress. 137 31

The biochemical and behavioural effects of isamoltane, a beta-adrenoceptor and 5-HT1B receptor antagonist that has higher affinity for 5-HT1B receptors than for 5-HT1A receptors, on 5-HT neurotransmission in the rat brain were examined. In binding experiments isamoltane was found to be about five times more potent as a ligand for the 5-HT1B receptor than for the 5-HT1A receptor (Ki values 21 and 112 nmol/l, respectively). Isamoltane increased the K(+)-evoked overflow of 3H from 3H-5-HT loaded slices of rat occipital cortex at 0.1 mumol/l, consistent with inhibition of the terminal 5-HT autoreceptor. In vivo, isamoltane significantly increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus and hippocampus indicating an increased 5-HT turnover with a maximal effect at 3 mg/kg s.c. A higher dose produced a less pronounced effect. This effect did not seem to be due to the beta-adrenoceptor blocking action of isamoltane since the beta-adrenoceptor antagonists. (-)-alprenolol, betaxolol or ICI 118.551 had no significant effects on 5-HT turnover at 5 mg/kg s.c. Isamoltane at 3 mg/kg s.c. induced the wet-dog shake response which was blocked by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. In contrast, the same response induced by the 5-HT2 receptor agonist quipazine was not blocked by pretreatment with p-chlorophenylalanine. The wet-dog shakes evoked by isamoltane and quipazine were blocked by ritanserin, which indicates that 5-HT2 receptors are involved in their expression. These observations indicate that isamoltane, by inhibiting the terminal 5-HT autoreceptors, increased the synaptic concentration of 5-HT to a level that induced a behavioural response.
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PMID:Biochemical and behavioural effects of isamoltane, a beta-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain. 167 59

The selective 5-HT1A receptor agonist 8-OH-DPAT increased serum corticosterone concentration in rats in a dose-dependent manner. The synthetic corticoid dexamethasone lowered the serum corticosterone level and abolished its rise induced by 8-OH-DPAT. The corticosterone response to 8-OH-DPAT was also antagonized by spiperone, (+/-)- and (-)-pindolol and (+/-)-propranolol, all of which have been shown to have a high affinity for 5-HT1A receptors, though in most cases no complete blockade was found. A partial antagonism of the response was also observed after flumazenil, a benzodiazepine antagonist. On the other hand, the 5-HT1B receptor antagonist 21009, the 5-HT2 receptor antagonists ketanserin and pirenperone, the 5-HT3 receptor antagonist ICS 205-930, the alpha 2-adrenoceptor antagonists yohimbine and idazoxan, the beta-adrenoceptor blocker with no affinity to 5-HT1 receptors, atenolol, the dopaminergic antagonist pimozide, the histamine receptor blocker chloropyramine and the opiate receptor antagonist naloxone did not affect the hormonal response to 8-OH-DPAT. The 8-OH-DPAT-induced corticosterone secretion was not affected either in rats pretreated with p-chlorophenylalanine (PCPA, an inhibitor of tryptophan hydroxylase) or p-chloroamphetamine (PCA, a drug-inducing lesion of serotonergic nerve terminals). It is concluded that 8-OH-DPAT-induced increase in serum corticosterone concentration results from its action at a site different than the adrenal cortex and is mediated by postsynaptic 5-HT1A receptors, whereas other subtypes (5-HT1B, 5-HT2, 5-HT3) of 5-HT receptors do not participate in this response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of corticosterone secretion by the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the rat. 253 May 90

Non-endocrine corticotropin-releasing factor (CRF) is believed to be involved in mediating stress behaviors in rats. The present study investigated the role of CRF in mediating the activation of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, produced in response to sound stress. Bilateral injections of 0.5-3.0 micrograms of CRF directed towards the central nucleus of the amygdala increased tryptophan hydroxylase activity measured ex vivo when compared to vehicle-injected controls. This increase in enzyme activity, like that due to sound stress, was reversed in vitro by alkaline phosphatase. Intra-amygdala CRF (0.5 microgram) also enhanced the in vivo accumulation of 5-hydroxytryptophan (5-HTP) following the administration of m-hydroxylbenzylamine (NSD-1015, 200 mg/kg). The activation of tryptophan hydroxylase, produced by intra-amygdala CRF, was blocked by the CRF receptor antagonist alpha-helical CRF9-41 (10 micrograms). Additionally, the 5-HT1A agonist, gepirone, given either systemically (10 mg/kg) or intracerebrally into the region of the dorsal raphe (14 micrograms), blocked the tryptophan hydroxylase response to CRF. CRF did not increase tissue levels of 5-hydroxyindole acetic acid (5-HIAA) or the ratio of 5-HIAA to serotonin (5-HT) within the striatum of the same animals in which tryptophan hydroxylase activity was quantified, an effect produced by sound stress. Thus, while intra-amygdala CRF failed to mimic the sound stress response in its entirety, these data suggest that CRF is involved in mediating the activation of tryptophan hydroxylase produced by sound stress within the midbrain serotonin neurons.
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PMID:Evidence that corticotropin-releasing factor within the extended amygdala mediates the activation of tryptophan hydroxylase produced by sound stress in the rat. 750 8

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

Differentiation leads to specific morphological and biochemical characteristics. We examined whether epigenetic factors (e.g., glucocorticoids) are required to maintain neuronal differentiation in the adult brain. In the midbrain, adrenalectomy (ADX) (1-2 wk) reduced the size of tryptophan hydroxylase (WH)-immunoreactive (IR) neurons. ADX rats exposed to short-term (24-72-h) dexamethasone (ST-DEX) in the drinking saline (10 mg/l) showed an increase in WH protein, somal area and dendritic size of WH-IR neurons. In the hippocampus, ADX for 2-3 mo (long-term; LT) reduced Nissl staining, calbindin (CBD)-IR and 5-HT1A receptor mRNA in the granular cell layer, and the size of the molecular layer and its CBD-IR dendrites. Small vimentin (Vim)-IR glial cells emerged in the granular layer. ST-DEX after LT-ADX rapidly induced a recovery of 5-HT1A mRNA, Nissl labeling and CBD-IR in the granule cell layer. In the molecular layer, there was an increase in the area and in the number of CBD-IR dendrites. Furthermore, the Vim-IR glial cells were enlarged in size and branching. The rate of cell proliferation was studied in these animals. Immunostaining with antibodies against proliferating cell nuclear antigen (PCNA) and use of bromouridine argue against enhanced neurogenesis after ST-DEX in LT-ADX. We propose that glucocorticoids induce and maintain differentiation of serotonergic and CBD-IR neurons in the midbrain-hippocampal axis. A neuronotrophic role for the glial 5-HT1A receptor is suggested.
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PMID:Dexamethasone reverses adrenalectomy-induced neuronal de-differentiation in midbrain raphe-hippocampus axis. 782 75

(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma ligand, at doses above 3 mg/kg (s.c.) increased the ambulatory activity of rats, while the (-) isomer of 3-PPP with low affinity for sigma receptors, did not significantly modify the ambulatory activity at 10 and 30 mg/kg (s.c.). The ambulation-increasing effect of (+)-3-PPP was prevented by the sigma receptor antagonists BMY 14802 and rimcazole or the sigma/dopamine D2 antagonist haloperidol. The (+)-3-PPP effect was also attenuated by pretreatment with the monoamine depletor reserpine or the tyrosine hydroxylase inhibitor alpha-methyltyrosine, but was not affected by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. Moreover, the (+)-3-PPP effect was antagonized by the dopamine D2 antagonist sulpiride, whereas pretreatment with the 5-HT1A agonist 8-OH-DPAT and the alpha-adrenoceptor antagonist phenoxybenzamine did not exert any significant effect. These results indicate that sigma receptors are involved in the neuronal mechanism(s) of hyperambulation induced by (+)-3-PPP, and the sigma system may exert both a presynaptic action and a dopamine D2 receptor-mediated action to increase the central dopaminergic function.
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PMID:Pharmacological characteristics of hyperambulation induced by the sigma ligand (+)-3-PPP in rats. 791 83

Serotonergic neurons located at the base of the mammalian brain innervate practically every region of the brain and the spinal cord. These neurons exhibit spontaneous electrical discharges in a rhythmical way. Their firing frequency is modulated by serotonin autoreceptors which also regulate intracellular cAMP levels. We have investigated how elevated levels of cAMP alter the development and the functional properties of serotonergic neurons in culture. To study the influence of cAMP on the expression of genes underlying serotonergic activity, a quantitative RT-PCR approach using internal standards was developed. Cultures of embryonic rat brain serotonergic neurons were continuously treated with cAMP analogues. Increased cAMP levels had three effects. First, the neuronal morphology was changed towards that typical for mature serotonergic neurons. Second, the expression of tryptophan hydroxylase, the rate-limiting enzyme in serotonin production, was increased in dibutyryl-cAMP treated cultures. Third, the expression of the inhibitory autoreceptor (5-HT1A) was down-regulated. These results suggest the existence of a mechanism by which the neurons react to synaptic input regulating intracellular cAMP levels. Increased cAMP concentrations affect the development and cause a prolonged activation of serotonergic transmission. Since 5-HT1A receptors inhibit cAMP formation, their down-regulation argues against a negative feedback control in this system, consistent with observations in vivo.
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PMID:Long-term regulation of serotonergic activity in the rat brain via activation of protein kinase A. 838 55

The RN46A cell line was derived from embryonic day 13 rat medullary raphe cells by infection with a retrovirus encoding the temperature-sensitive mutant of SV40 large T antigen (tsT-ag). The RN46A cell line is neuronally restricted and constitutively differentiates following a shift to nonpermissive temperature. Differentiated RN46A cells express low levels of tryptophan hydroxylase (TPH) but no detectable levels of serotonin (5-HT). Treatment of cultures with the adrenocorticotropic hormone peptide ACTH4-10 up-regulates the expression of TPH immunoreactivity in differentiated RN46A cells, but 5-HT synthesis requires initial treatment with ACTH4-10, followed by partial membrane depolarizing conditions. Up-regulation of TPH by ACTH4-10 is apparently due to activation of adenylate cyclase, whereas the increased 5-HT synthesis with membrane depolarization can be blocked with the voltage-sensitive Ca(2+)-channel blockers nifedipine and omega-conotoxin. ACTH4-10 treatment also markedly up-regulates the expression of the 5-HT reuptake transporter, as do dibutyryl cyclic AMP and forskolin; chronic membrane depolarization has no effect on 5-HT reuptake. The expression of the high-affinity 5-HT1A receptor is increased threefold by ACTH4-10 treatment during differentiation and fivefold by differentiation under partial membrane depolarizing conditions. Combining ACTH4-10 treatment and membrane depolarization does not increase expression of the 5-HT1A receptor further. 5-HT release is constitutive in ACTH-treated RN46A cells and linked to spontaneous synaptic vesicle fusion in RN46A cells. Considered with previous results, these data indicate that multiple effectors, ACTH, brain-derived neurotrophic factor, and membrane depolarization, have both distinct and overlapping effects that regulate specific elements of the serotonergic neuronal phenotype during differentiation and maturation.
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PMID:Adrenocorticotropic hormone activation of adenylate cyclase in raphe neurons: multiple regulatory pathways control serotonergic neuronal differentiation. 859 7

Recent studies have shown that arthritis-susceptible Lewis female rats display a marked hypoactivity of the hypothalamo-pituitary-adrenal (HPA) axis and decreased concentrations of hippocampal serotonin receptors (5-HT1A), when compared with arthritis-resistant Fischer 344 female rats. Although previous studies have suggested that these inter-strain differences may extend to several behaviours, the hypothesis that Fischer 344 and Lewis differ in their anxiety and locomotor scores when placed in novel environments has been only scarcely tested. The present study has thus analysed the behaviours of male Fischer 344 and Lewis rats placed successively in activity cages, in an open field (low and high aversive conditions), and in two animal models of anxiety (the elevated plus-maze, the black/white box). Moreover, because the present study was conducted with male rats, we have also checked whether the HPA axis- and 5-HT1A receptor-related differences previously described between female Fischer 344 and Lewis rats extended to males. Under basal conditions: (i) activity of the HPA axis; and (ii) hippocampal 5-HT1A receptor binding and activity of tryptophan hydroxylase (the rate-limiting enzyme in 5-HT biosynthesis) were decreased in Lewis rats, compared with Fischer 344 rats. In addition, the response of the HPA axis to a mild stress (10 min in a novel environment) was lower in Lewis rats than in Fischer 344. When placed in activity cages, Lewis rats displayed a lower locomotor activity, compared with Fischer 344 rats. In the open-field, Lewis rats cross a lower number of inner squares and groomed less than Fischer 344 rats. In the elevated plus-maze and in the black/white box, Fischer 344 and Lewis rats exhibited similar 'anxious' profiles as none of the rats visited the open arms (elevated plus-maze) and the white compartment (black/white box). This study, which extends earlier neurochemical and neuroendocrine findings in females, suggests that both strains display high levels of anxiety but markedly differ in their locomotor activities. Whether the latter strain difference is due to alterations in the HPA axis and/or the central serotonergic systems is an issue that remains to be explored.
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PMID:Male Fischer 344 and Lewis rats display differences in locomotor reactivity, but not in anxiety-related behaviours: relationship with the hippocampal serotonergic system. 865 5


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