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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of 7 day exposure to 2G fields on serotonergic modulation at two synapses on a hippocampal pathway were examined by recording dentate gyrus and CA1 pyramidal cell layer electrical activity. Serotonin decreased the amplitude of the population spike (synchronous action potentials in hundreds of neurons) in both the dentate gyrus and CA1 regions of rats exposed to 2G fields for 7 days. The inhibition, averaging 26 +/- 4% (mean +/- SEM) in the dentate gyrus and 80 +/- 5% in the CA1 region, was not significantly different from inhibitory responses observed in 1G controls. The 5-HT1A agonist 8-OH-DPAT mimicked this inhibition in the dentate and CA1 regions of 1G rats. 8-OH-DPAT responses were not affected by exposure to 2G fields. We conclude that the hippocampus contains surplus 5-HT receptors so that decreases in receptor density reported in receptor binding studies do not result in a decrease in modulatory capability. A model to account for the physiological pathway that relates gravitational field strength to 5-HT receptor density without changing the effectiveness of 5-HT neuromodulation is discussed.
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PMID:Effects of hypergravic fields on serotonergic neuromodulation in the rat hippocampus. 1154 65

We investigated the combined effect of 5-hydroxytryptamine (5-HT, serotonin) and calcium ionophore (A23187) on human platelet aggregation. Aggregation, monitored at 37 degrees C using a Dual-channel Lumi-aggregometer, was recorded for 5 min after challenge by a change in light transmission as a function of time. 5-HT (2-200 microM) alone did not cause platelet aggregation, but markedly potentiated A23187 (low dose) induced aggregation. Inhibitory concentration (IC50) values for a number of compounds were calculated as means +/- SEM from dose-response determinations. Synergism between 5-HT (2-5 microM) and A23187 (0.5-2 microM) was inhibited by 5-HT receptor blockers, methysergide (IC50 = 18 microM) and cyproheptadine (IC50 = 20 microM), and calcium channel blockers (verapamil and diltiazem, IC50 = 20 microM and 40 microM respectively). Interpretation of the effects of these blockers is complicated by their lack of specificity. Similarly, U73122, an inhibitor of phospholipase C (PLC), blocked the synergistic effect at an IC50 value of 9.2 microM. Wortmannin, a phosphatidylinositide 3-kinase (PI 3-K) inhibitor, also blocked the response (IC50 = 2.6 microM). However, neither genistein, a tyrosine-specific protein kinase inhibitor, nor chelerythrine, a protein kinase C inhibitor, affected aggregation at concentrations up to 10 microM. We conclude that the synergistic interaction between 5-HT and ionophore may be mediated by activation of PLC/Ca2+ and PI 3-kinase signalling pathways, but definitive proof will require other enzyme inhibitors with greater specificity.
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PMID:Second messengers in platelet aggregation evoked by serotonin and A23187, a calcium ionophore. 1172 80

The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis. Protein binding of lerisetron was measured in vitro by ultrafiltration. The unbound fraction was 14.4 +/- 1.4%. A nonlinear mixed effects ("population") bicompartmental pharmacokinetic analysis showed that volume of distribution and clearance (CL) were high for both forms of the drug, but CL was significantly smaller for TL [(mean +/- SEM) 0.014 +/- 0.03 L/min for UL versus 0.006 +/- 0.03 L/min for TL, p < 0.05)]. Large interindividual variabilities were observed for both forms. The response to lerisetron administration (inhibition of bradycardia) was evaluated at different doses (2, 3, 5, 6, and 10 microg/kg, iv) at times 2-180 min after dose administration and related to simulated concentrations. Inhibition was 100% 5 min after the 10-microg/kg dose and, 3 h later, it was still > 10%. Response to lerisetron was dose related in the range studied. Pharmacodynamic parameters were estimated by a sigmoid E(max) naive-pooled model. The parameters were also different between the two forms: EC(50) was 0.44 ng/mL (CV = 5.9%) for UL and 0.88 ng/mL (CV = 4.9%) for TL. We conclude that UL and TL pharmacokinetics were linear and that the differences in the kinetics and dynamics between the two forms suggest the presence of at least one metabolite.
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PMID:Pharmacokinetics and pharmacological effect of lerisetron, a new 5-HT3 antagonist, in rats. 1178 96

Serotonin reuptake inhibitors (SSRI), such as venalafaxine and paroxetine, are used in the treatment of generalized anxiety disorder (GAD). Patients with GAD frequently have comorbid psychiatric disorders, such as depression. SSRIs are effective in the treatment of a variety of anxiety disorders and depression. Citalopram, a newer SSRI used in the treatment of depression, has not been studied for GAD. This is the first report of the use of citalopram, the most selective SSRI, for the treatment of GAD in a retrospective case observation study. Thirteen patients diagnosed with GAD were treated with citalopram at an academic outpatient clinic. The main outcome measures were the Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impressions of Severity (CGI-S; at baseline) and Improvement (CGI-I). The mean age of the patients was 38 years. The mean dose of citalopram at endpoint was 33 mg/day (range 10-60 mg/day). After 12 weeks of treatment with citalopram, all 13 patients experienced full or partial improvement in GAD and depressive symptoms leading to meaningful improvement in social and occupational functioning. Mean baseline HAM-A scores (mean+/-SEM) decreased from 22.2+/-1.3 to 6.2+/-0.9 after citalopram treatment. The mean CGI-I score was 1.8+/-0.2 with 11 of the 13 patients responding (CGI-I of 1 or 2). These data suggest that citalopram may be an effective treatment for GAD. Several patients who had failed previous treatment with other SSRIs responded to citalopram, suggesting that a second SSRI, such as citalopram, may be beneficial in this population. A larger placebo-controlled study of citalopram is warranted in GAD.
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PMID:Treatment of generalized anxiety disorder with citalopram. 1198 50

Negative energy balance inhibits reproduction by restraining GnRH secretion. Leptin is a permissive metabolic signal for reproduction, but GnRH neurons do not appear to express leptin receptors, suggesting that interneurons transmit leptin signals to these cells. Serotonin (5HT) has satiety effects similar to those of leptin and alters LH release, and serotonergic neurons, which have been shown to express leptin receptors, terminate on GnRH neurons. We hypothesized that serotonergic neurons convey leptin signals to the reproductive neuroendocrine axis. To test this, mice were fasted for 48 h beginning on Diestrous Day 1. While fasting, mice received saline or leptin every 12 h or the 5HT-selective reuptake-inhibitor fluoxetine once at the start of the fast. Estrous cycles of fasted mice were longer (mean +/- SEM, 10.2 +/- 0.5 days; P < 0.0001) than those of fed mice (4.5 +/- 0.2 days). As previously reported, leptin prevented fasting-induced cycle lengthening (4.6 +/- 0.7 days). Fluoxetine also rescued estrous cycles in fasted mice (4.7 +/- 0.6 days), suggesting that 5HT and leptin have similar positive effects on reproduction. Coadministration of the 5HT 1/2/7 receptor-antagonist metergoline blocked rescue of cycle length by fluoxetine and by leptin. Treating leptin-deficient ob/ob and leptin receptor-deficient db/db mice with fluoxetine did not normalize body weight or rescue fertility, perhaps due to altered serotonergic tone in these animals. Together, these data demonstrate a permissive role for serotonergic systems in the metabolic control of reproduction and are consistent with the hypothesis that serotonergic neurons convey leptin signals to GnRH neurons.
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PMID:Serotonergic activation rescues reproductive function in fasted mice: does serotonin mediate the metabolic effects of leptin on reproduction? 1202 Oct 50

Animal studies indicate that the anxiolytic properties of the antipsychotic agent cyamemazine may result from blockade of serotonin 5-HT(2C) receptors and to a lesser extent from blockade of serotonin 5-HT(3) receptors. Here, we used human recombinant receptors to determine the relative affinity of cyamemazine for serotonin and dopamine receptor subtypes. In addition, cyamemazine was tested in other brain receptor types and subtypes which are considered to mediate central nervous systems effects of drugs. Hence, cyamemazine affinity was determined in human recombinant receptors expressed in CHO cells (hD(2), hD(3), and hD(4.4) receptors, h5-HT(1A), h5-HT(2A), h5-HT(2C), and h5-HT(7), and hM(1), hM(2), hM(3), hM(4), and hM(5) receptors), L-cells (hD(1) receptor), and HEK-293 cells (h5-HT(3) receptors) or natively present in N1E-115 cells (5-HT(3) receptors) or in rat cerebral cortex (non-specific alpha(1)- and alpha(2)-adrenoceptors, GABA(A) and GABA(B) receptors, H(3) histamine receptors), and guinea-pig cerebellum (H(1) central and H(2) histamine receptors) membranes. Similarly to atypical antipsychotics, cyamemazine exhibited high affinity for: (i) h5-HT(2A) receptors (K(i)=1.5+/-0.7 nM, mean+/-SEM, N=3) and this was four times higher than for hD(2) receptors (K(i)=5.8+/-0.8 nM), (ii) h5-HT(2C) receptors (K(i)=11.8+/-2.2nM), and (iii) 5-HT(7) receptors (K(i)=22 nM). Conversely, cyamemazine exhibited very low affinity for h5-HT(3) receptors (K(i)=2.9+/-0.4 microM). In conclusion, similarly to atypical antipsychotic agents, cyamemazine, possesses high affinity for h5-HT(2A), h5-HT(2C), and h5-HT(7) receptors, a feature which can explain its low propensity to cause extrapyramidal adverse reactions in clinical practice. The high affinity for h5-HT(2C) receptors, but not for h5-HT(3) receptors, can account for the anxiolytic activity of cyamemazine in human subjects.
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PMID:Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes. 1252 36

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean +/- SEM, pg/20 microl, was 3.0 +/- 0.4 for LDS, 3.8 +/- 0.3 for HDS and 6.4 +/- 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (+/-)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500%) as compared with LDS (248%) or RDS (243%) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900% in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line.
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PMID:A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function. 1256 29

Local metabolic changes are suggested to be involved in muscle pain development in humans. Nineteen women with chronic work-related trapezius myalgia (TM) and 20 healthy female controls (CON) were studied during baseline rest, 20 min repetitive low-force exercise, and 120 min recovery. Interstitial serotonin (5-HT), glutamate, lactate, pyruvate, and blood flow were determined by microdialysis in the trapezius muscle. Baseline pressure pain threshold (PPT) was lower (143+/-18 (TM) vs. 269+/-17 (CON)kPa) (mean+/-SEM), pain intensity (visual analogue scale, VAS) higher (33+/-5 vs. 2+/-1mm), muscle 5-HT higher (22.9+/-6.7 vs. 3.8+/-1.3 nmol/l), and glutamate higher (47+/-3 vs. 36+/-4 micromol/l) in TM than in CON (all P<0.05), whereas muscle blood flow was similar in groups. Furthermore, muscle pyruvate was higher (180+/-15 vs. 135+/-12 micromol/l) and lactate higher (4.4+/-0.3 vs. 3.1+/-0.3 mmol/l) in TM than in CON (P<0.001). In response to exercise, VAS and glutamate increased in both TM and CON (all P<0.05). In TM only, lactate and pyruvate increased significantly (P<0.02), whereas blood flow increased to similar levels in both groups. During the initial 20 min recovery period, blood flow remained increased in TM (P<0.005) whereas it decreased to baseline levels in CON. In conclusion, patients with chronic work-related TM have increased levels of muscle 5-HT and glutamate that were correlated to pain intensity (r=0.55, P<0.001) and PPT (r=-0.47, P<0.001), respectively. In addition, TM was associated with increased anaerobic metabolism, whereas a normal rise in blood flow was seen with exercise. These findings indicate that peripheral nociceptive processes are active in work-related TM.
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PMID:Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: microdialysis in rest and during exercise. 1556 88

Brain 5-HT neurotransmission has been described to be down-regulated in depressed people, and also suspected to be changed in overtraining state, the consequence of long-term physical overloading and stress in athletes. We studied brain serotonin (5-HT) transporter binding i.e., 5-HT reuptake with the specific radioligand (123-I-labelled 2beta-carbomethoxy-3beta[4-iodopenyl]-nortropane, Nor-beta-CIT), and with single photon emission tomography (SPET) in severely overtrained athletes and their controls at the baseline and after a one-year recovery period. Twelve overtrained (6 women and 6 men, mean age 27 yrs, range 16 - 39 yrs) and 11 healthy (6 women, 5 men, 26 yrs, 20 - 39 yrs) athletes were examined. Overtrained athletes 1) had suffered from an unexplained decrement in physical performance and fatigue for several weeks to many months and continued to have the same symptoms even after a recovery time of weeks to months, 2) had been examined to be otherwise healthy, and 3) had a suitable training history for overtraining. Nor-beta-CIT SPET was acquired 5 min, and 3, 6, and 24 h after the injection of the radioligand. 5-HT reuptake in ml/ml in midbrain (raphe nuclei) was calculated as (midbrain - cerebellum)/cerebellum. According to two-way analysis of variance, no changes inside the groups or group differences in 5-HT reuptake were found. Male athletes had significantly higher 5-HT reuptake than female athletes at the baseline (p = 0.034). The overtrained athletes were moderately depressed, while their scores in standardized Hamilton and Montgomery-Asberg Depression Rating Scales were 16 +/- 2 (mean +/- SEM, range 8 - 29) and 17 +/- 2 (7 - 28), respectively. In the CA, the scores were 6 +/- 1 (range 2 - 18) and 6 +/- 2 (1 - 19), respectively. 5-HT reuptake did not correlate with the depression scores either in the whole group or in the OA. The finding of the present study does not support the idea of long-term changes in 5-HT neurotransmission in overtraining state, in this case serotonin reuptake in midbrain, the regulating area of brain serotonin neurotransmission. Furthermore, depression of overtrained athletes may be its own variant having no correlation with 5-HT reuptake in midbrain. Sex may have effect on chronic stress response at the brain level in athletes, which may be a confusing factor in the overtraining studies, and has to be taken into consideration in the future.
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PMID:Brain serotonin reuptake did not change during one year in overtrained athletes. 1658 30

Serotonin antagonists show impressive analgesic efficacy in rheumatoid arthritis, osteoarthritis (OA) or fibromyalgia; however, this effect is not well understood. We examined the mechanism of serotonin-induced inflammation and its antagonists in OA. Serotonin receptor subtypes and COX-2 were analysed by RT-PCR from synovial tissue. Serum-free cultures were stimulated with 10 muM serotonin and/or the antagonists ketanserin (5-HT(2A)), tropisetron (5-HT(3)) and parecoxib (COX-2). Prostaglandin E(2) (PGE(2)), tumour necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and leukotriene B4 (LTB4) were measured by an immunoassay in the supernatants. RT-PCR results showed mRNA for 5-HT(2A) and 5-HT(3) receptors, and COX-2. PGE(2) in the supernatants increased by 261.2% +/- 56.7 (mean +/- SEM; P = 0.007) in response to serotonin. TNF-alpha, IL-1beta and LTB4 levels did not change. Ketanserin, tropisetron and parecoxib suppressed PGE(2). The serotonin-induced PGE(2) overexpression appeared thus to be mediated by 5-HT(2A) and 5-HT(3) receptors. This activation might involve COX-2. The findings may explain the potent benefit of 5-HT(3) antagonists.
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PMID:Serotonin mediates PGE2 overexpression through 5-HT2A and 5-HT3 receptor subtypes in serum-free tissue culture of macrophage-like synovial cells. 1836 10


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