Serotonergic activity of HP 184: Does spontaneous release have a role? |
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Authors: | Craig P Smith Ann T Woods-Kettelberger Roy Corbett Susan M Chesson Gina M Bores Wayne W Petko Joachim E Roehr Sathapana Kongsamut |
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Institution: | (1) Hoechst Marion Roussel, Neuroscience Therapeutic Domain, Route 202-206, 08876 Somerville, NJ |
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Abstract: | Examination of HP 184, N-n-propyl)-N-(3-fluoro-4-pyridinyl)-1H-3-methylindodel-1-amine hydrochloride], in a variety of tests
for serotonergic activity revealed some unique properties of this compound. We report here that 100 μM HP 184 enhanced spontaneous
release of 3H]serotonin (5-HT) from rat hippocampal slices. This release was independent of the uptake carrier. In vivo assays confirmed
that HP 184 (20 mg/kg, i.p.) lacked significant interactions at the norepinephrine (NE) or 5-HT uptake carrier itself. Notably,
HP 184 (15 mg/kg, i.p.) reduced drinking behavior in schedule-induced polydipsic (SIP) rats. We previously reported that some
selective 5-HT reuptake inhibitors decrease SIP 30–40% after a 14–21 day treatment. In the current study, HP 184 decreased
SIP beginning with the first treatment, and this reduction (30%) was maintained for 28 days. We further investigated HP 184
and serotonin metabolite levels. One hour after i.p. administration of 30 mg/kg HP 184, the ratio of whole brain 5-hydroxyindolacetic
acid (5-HIAA) to 5-HT was increased, suggesting serotonergic activation. Under these conditions, the brain: plasma ratio of
HP 184 was approximately 2∶1, with brain concentrations of 1.6 μg/gram. We speculate that the spontaneous release effects
of HP 184 may be responsible for the behavioral effects observed. |
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Keywords: | Schedule-induced polydipsia serotonin reuptake inhibitor HP 184 [3H]serotonin release |
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