Serotonergic activity of HP 184: does spontaneous release have a role?
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 microM 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 micrograms/gram. We speculate that the spontaneous release effects of HP 184 may be responsible for the behavioral effects observed.
Smith
C P
CP
Neuroscience Therapeutic Domain, Hoechst Marion Roussel, Somerville, NJ 08876, USA.
Woods-Kettelberger
A T
AT
Corbett
R
R
Chesson
S M
SM
Bores
G M
GM
Petko
W W
WW
Roehr
J E
JE
Kongsamut
S
S
D006916:5-Hydroxytryptophan / Q000633:toxicity; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D001763:Blepharoptosis / Q000139:chemically induced / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004327:Drinking Behavior / Q000187:drug effects*; D004357:Drug Synergism; D005277:Fenfluramine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013747:Tetrabenazine
D006916:5-Hydroxytryptophan; D001679:Biogenic Amines; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid; D007211:Indoles; D009638:Norepinephrine; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013747:Tetrabenazine; C101289:nerispirdine