SEROTONERGIC ACTIVITY OF HP-184 - DOES SPONTANEOUS RELEASE HAVE A ROLE

Examination of HP 184, N-(3-fluoro-4-pyridinyl)-1H-3-methlindodel-1-am ine hydrochloride], in a variety of tests for serotonergic activity re vealed some unique properties of this compound. We report here that 10 0 mu M HP 184 enhanced spontaneous release of [H-3]serotonin (5-HT) fr om 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 car rier itself. Notably, HP 184 (15 mg/kg, i.p.) reduced drinking behavio r in schedule-induced polydipsic (SIP) rats. We previously reported th at some selective 5-HT reuptake inhibitors decrease SIP 30-40% after a 14-21 day treatment. In the current study, HP 184 decreased SIP begin ning 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 rat io of whole brain 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was incre ased, suggesting serotonergic activation. Under these conditions, the brain:plasma ratio of HP 184 was approximately 2:1, with brain concent rations of 1.6 mu g/gram. We speculate that the spontaneous release ef fects of HP 184 may be responsible for the behavioral effects observed .