1. ¹Department of Neurochemistry, Institut d'Investigacions Biomèdiques de Barcelona, CSIC (IDIBAPS), Barcelona, Spain
2. ²Research & Development, Vita-Invest S.A. (Grupo Vita), Barcelona, Spain

Correspondence: Dr F Artigas, Department of Neurochemistry, Institut d'Investigacions Biomèdiques de Barcelona, CSIC (IDIBAPS), Rosselló 161, 08036 Barcelona, Spain. Tel: +3493 363 8315; Fax: +3493 363 8301; E-mail: fapnqi@iibb.csic.es

³Present address: Laboratorios Dr Esteve, 08041 Barcelona, Spain.

Received 4 June 2002; Revised 2 August 2002; Accepted 7 August 2002.

Abstract

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-HT_1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT_ext) in rat striatum to 780% of baseline whereas its systemic administration (1–10 mg/kg s.c.) reduced 5-HT_ext. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT_ext. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED₅₀: 790, 14.9, and 0.8 g/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT_1A receptors as assessed by microdialysis and single-unit recordings (ED₅₀ values for 8-OH-DPAT were 0.45 and 2.34 g/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-HT_1A agonist that markedly desensitizes 5-HT_1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.