5-HT1A RECEPTOR AGONIST EFFECTS OF BMY-14802 ON SEROTONIN RELEASE IN DORSAL RAPHE AND HIPPOCAMPUS

BMY-14802 (BMS-181100; orophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperaz ine butanol monohydrochloride) is a sigma receptor antagonist with pot ential antipsychotic activity. BMY-14802 also binds to 5-HT1A receptor s and is able to inhibit the firing of dorsal raphe serotonergic neuro ns, suggesting that this compound has 5-HT1A receptor agonist properti es in vivo. In the present study, we used in vivo microdialysis to stu dy the effects of BMY-14802 on extracellular serotonin (5-hydroxytrypt amine), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid ( HVA) in the dorsal raphe and ventral hippocampus in the awake rat. Sys temic injections of 5-20 mg/kg BMY-14802 induced a simultaneous dose-d ependent decrease in 5-HT and markedly increased the dopamine metaboli te, HVA concentrations in dialysates from dorsal raphe and hippocampus . Extracellular concentrations of the 5-HT metabolite, 5-HIAA decrease d only after 20 mg/kg BMY-14802. The 5-HT decreases in dorsal raphe an d hipyocampus produced by BMY-14802 were completely antagonized by pre treatment with 1.0 mg/kg of the specific 5-HT1A antagonist, WAY-100635 ethoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxa mide trihydrochloride). These data indicate that BMY-14802 decreases d orsal raphe and hippocampal release of 5-HT by interaction with somato dendritic 5-HT1A receptors in the raphe nuclei and suggest that this c ompound is a potential anxiolytic.