Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HText) in rat striatum to 780% of baseline whereas its systemic administration (1–10 mg/kg s.c.) reduced 5-HText. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HText. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED50: 790, 14.9, and 0.8 μg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT1A receptors as assessed by microdialysis and single-unit recordings (ED50 values for 8-OH-DPAT were 0.45 and 2.34 μg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT1A agonist that markedly desensitizes 5-HT1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.