5-HT1A receptor agonist effects of BMY-14802 on serotonin release in dorsal raphe and hippocampus.
BMY-14802 (BMS-181100; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol monohydrochloride) is a sigma receptor antagonist with potential antipsychotic activity. BMY-14802 also binds to 5-HT1A receptors and is able to inhibit the firing of dorsal raphe serotonergic neurons, suggesting that this compound has 5-HT1A receptor agonist properties in vivo. In the present study, we used in vivo microdialysis to study the effects of BMY-14802 on extracellular serotonin (5-hydroxytryptamine), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphe and ventral hippocampus in the awake rat. Systemic injections of 5-20 mg/kg BMY-14802 induced a simultaneous dose-dependent decrease in 5-HT and markedly increased the dopamine metabolite, HVA concentrations in dialysates from dorsal raphe and hippocampus. Extracellular concentrations of the 5-HT metabolite, 5-HIAA decreased only after 20 mg/kg BMY-14802. The 5-HT decreases in dorsal raphe and hippocampus produced by BMY-14802 were completely antagonized by pretreatment with 1.0 mg/kg of the specific 5-HT1A antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). These data indicate that BMY-14802 decreases dorsal raphe and hippocampal release of 5-HT by interaction with somatodendritic 5-HT1A receptors in the raphe nuclei and suggest that this compound is a potential anxiolytic.
Matos
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FF
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492, USA.
Korpinen
C
C
Yocca
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FD
D000818:Animals; D014151:Anti-Anxiety Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D006719:Homovanillic Acid