Experimental study of 5-hydroxytryptamine 1A receptor agonist to improve the voiding dysfunction in diabetic rats / 中华泌尿外科杂志

Objective To investigate the effect of 5-hydroxytryptamine 1A (5-HT1A) receptor agonists to improve micturition function in rats with diabetes mellitus (DM).Methods Fourteen female SD rats with the weight of 250 to 275 g were used.Seven rats were in the DM model group with intraperitoneal injection streptozotocin (STZ,65 mg/kg).Rats in the control group and DM group were anesthetized with urethane (1.3 g/kg) 8 weeks later.A polyethylene (PE)-50 catheter were placed in the left jugular vein for intravenous drug administration.A PE-90 catheter was inserted into the bladder,with the other end connected to a syringe pump for continuous infusion of saline and a pressure transducer for intravesical pressure monitor.Dose-response curves for 8-OH-DPAT were followed by WAY-100635 test.The capacity,residual volume,micturition volume,and EUS-EMG were measured.Results Compared to normal control,DM rats had a higher bladder capacity,residual volume,and a lower voiding efficiency.With increasing dose of 8-OH-DPAT (0.003-1.000 mg/kg,i.v.),the micturition volume increased from (2.15±0.49) ml to (2.85±0.21) ml,the residual volume decreased from (3.40±0.74)ml to (1.82±0.48) ml and voiding efficiency changed from (39.0±9.3)％ to (61.6±6.9)％.Control rats showed little change in cystometic variable.During the micturition,there was a dose-dependent increased phasic EUS activity correlated with the improved voiding efficiency.WAY-100635 (0.300 mg/kg,i.v.) reversed the 8-OH-DPAT-induced changes.Conclusions Both the bladder voiding efficiency and the periodic EUS activity decrease in DM rats.5-HT1A receptor agonist could promote periodic EUS activity and improve voiding efficiency.

Serotonin (5-HT) Receptor Subtypes Mediate Regulation of Neuromodulin Secretion in Rat Hypothalamic Neurons

Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol -1,4,5- triphosphate / calcium (InsP3/Ca2+) signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and neuromodulin secretion in rat hypothalamic neurons. Specific mRNA transcripts for 5-HT1A, 5-HT2C and 5-HT4 were identified in rat hypothalamic neurons. These experiments were supported by combined techniques such as cAMP and a Ca2+ assays in order to elucidate the associated receptors and signaling pathways. The cAMP production and neuromodulin release were profoundly inhibited during the activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor stimulated InsP3 production and caused Ca2+ release from the sarcoplasmic reticulum. Selective activation of the Gs-coupled 5-HT4 receptor also stimulated cAMP production, and caused an increase in neuromodulin secretion. These findings demonstrate the ability of 5-HT receptor subtypes expressed in neurons to induce neuromodulin production. This leads to the activation of single or multiple G-proteins which regulate the InsP3/Ca2+/PLC-gamma and adenyl cyclase / cAMP signaling pathways.

5-HT1A receptor agonist 8-OH-DPAT improves motor complications in Parkinson' s disease / 中华神经科杂志

Objective To investigate cellular and behavioural effects of 5-HT1A receptor agonist 8- OH-DPAT in a rat model of levodopa-induced motor complications.Methods The hemi-parkinsonian rat model was produced by stereotaxically injecting 6-OHDA to right medial forebrain bundle(MFB).Two sets of experiments were performed.First,rats were intrapefitoneally treated with levodopa 50 mg/kg plus benserazide 12.5 mg/kg twice a day for 22 days.On day 23,rats intraperitoneally received either 8-OH- DPAT(1 mg/kg)or 8-OH-DPAT plus WAY-100635(0.1 mg/kg)or dissolvent with each levodopa dose as controls.In the second set,rats were intraperitoneally treated either with levodopa(50 mg/kg)plus 8-OH- DPAT(1 mg/kg)or levodopa 50 mg/kg plus dissolvent,administered twice daily for 22 consecutive days. Rotational duration and frequency of off period were estimated.After sacrificed,subcellualr distribution of GluR1 and GluR1Ser845 phosphorylation was observed by Western blot.Results 8-OH-DPAT,reversing the shortened rotational duration induced by levodopa,prolonged the rotational duration by 27.8%?6.1% and reduced the frequency of failures to levodopa by 7.2%?1.7%.Co-administration of WAY-100635,a 5-HT1A receptor antagonist,with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications, indicating that the observed 8-OH-DPAT responses were probably mediated via the 5-HT1A autoreceptor. Moreover,8-OH-DPAT could regulate subcellular distribution of GluR1 and reduce hyperphosphorylation of GluR1 Ser845 by 22.1%?3.5%,which was closely associated with levodopa-induced motor complications. Conclusions These results suggest that pharmaceuticals stimulating 5-HT1A receptors could be useful in the treatment and prevention of the motor complications in parkinsonian patients.