LY310762 has a higher affinity for the guinea pig 5-HT1D receptor than for the 5-HT1B receptor. LY310762 potentiates the potassium-induced [3H]5-HT outflow from guinea pig cortical slices with an EC50 of 30 nM. The maximum potentiation of the potassium-induced outflow which is obtained with LY310762 is about 40%. [1] LY310762 blocks the decreased EPSC amplitude induced by Sumatriptan. [2]
In Vivo
Systemic administration of LY310762 (10 mg/kg i.p.) produces a further significant enhancement in the 5-HT response to fluoxetine (20 mg/kg i.p.) when compared to animals receiving a control vehicle injection. In fluoxetine treated animals, levels of 5-HT increases from 312±43% to a maximum of 683% after LY310762. In control animals, levels of 5-HT remains unchanged (250%). LY310762 administered alone also significantly increases basal levels of 5-HT above vehicle controls, reaching a maximum of 258% compared to the pre-injection control. [1]
Clinical Trials
Features
Combination Therapy
Description
Systemic administration of LY310762 (10 mg/kg i.p.) produces a further significant enhancement in the 5-HT response to fluoxetine (20 mg/kg i.p.) when compared to animals receiving a control vehicle injection. In fluoxetine treated animals, levels of 5-HT increases from 312% to a maximum of 683% after LY310762. In control animals, levels of 5-HT remains unchanged (250%). [1]In addition, Sumatriptan fails to decrease glutamatergic EPSCs in the presence of both LY310762 and GR55562 (95.2% of the LY310762 and GR55562 condition). [2]
Male Dunkin Hartley Guinea Pigs (350-400 g) are killed by asphyxiation with CO2 and their brains rapidly removed. Cortical slices (350 × 350 μm) are prepared, washed once in basal buffer (10 mM HEPES, 133 mM NaCl, 4.8 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4, 1.5 mM CaCl2, 11.1 mM glucose, 10 μM pargyline pH 7.4) and incubated in basal buffer at 25 mg/mL wet weight with [3H]5-HT (50 nM) for 30 minutes at 37 °C. The slices are washed three times in basal buffer and transferred to baskets (10 mm i.d. polypropylene tubes with 150 μm nylon mesh bases) at approximately 5 mg wet weight per basket. The baskets are used to transfer the tissue between the washing and release buffers. In order to obtain stable baseline release, the slices are incubated for 11 minutes in basal buffer (0.5 mL), transferred for 4 minutes to a second tube containing basal buffer (0.5 mL) and then, for a further 4 minutes, to basal buffer (0.5 mL) or to a buffer in which NaCl has been substituted with KCl, on an equimolar basis, to give a KCl concentration of 30 mM (release sample). All buffers used in the 11 minutes and the two 4 minutes incubations contained 1 μM paroxetine. Following the incubations, the tissue is digested with Soluene-350 (0.7 mL) and the baskets rinsed with propan-2-ol (0.7 mL). The tritium label in the tissue samples and in the buffers from the three incubation periods is estimated by liquid scintillation spectroscopy. LY310762 being tested is present throughout the three incubation periods and is tested in six replicates. The basal release is measured in four replicates and the control release in eight replicates. The tritium label in the release sample is expressed as the percentage of the total tritium in the tissue at the time the sample is collected (% fractional release). Stimulated release is calculated as the % fractional release produced by the high potassium buffer minus that of basal release. The percentage increase in release produced by LY310762 is calculated as the increase over the control stimulated release, where the control release is 100%. For individual experiments the mean of the replicate data is calculated. The results are the means and standard errors of at least three separate experiments.
刺激性 (Xi)