Ž . European Journal of Pharmacology 420 2001 103–112 www.elsevier.nlrlocaterejphar 5-HT receptor activation and antidepressant-like effects: F 13714 has 1A high efficacy and marked antidepressant potential Wouter Koek ) , Bernard Vacher, Cristina Cosi, Marie-Bernadette Assie, ´ Jean-Franc ¸ois Patoiseau, Petrus J. Pauwels, Francis C. Colpaert Centre de Recherche Pierre Fabre, 17 AÕe. Jean Moulin, 81106 Castres Cedex, France Received 4 January 2001; received in revised form 10 April 2001; accepted 24 April 2001 Abstract To examine further the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT receptors determines the 1A magnitude of their psychotropic activity, we studied the relationship between the maximal receptor activation produced by various Ž . 5-HT receptor ligands and their antidepressant-like effects i.e., decreased immobility in the forced swimming test in rats . Using three 1A different in vitro assays suitable to measure differences among high, intermediate, and low efficacy 5-HT receptor agonists, ligands 1A Ž w w Ž . were identified with intrinsic activities ranging from low-negative i.e., the inverse agonist N- 2- 4- 2-methoxyphenyl -1-pipera- x x Ž . Ž .. Ž Ž wŽ zinyl ethyl -N- 2-pyridinyl cyclohexane-carboxamide WAY 100635 to high-positive i.e., 3-chloro-4-fluorophenyl- 4-fluoro-4- 5- . x 4 Ž .. methyl-6-methylamino-pyridin-2-ylmethyl -amino -methyl -piperidin-1-yl-methanone F 13714 . In addition, novel compounds with intermediate intrinsic activity, like buspirone, but with high selectivity for 5-HT receptors, unlike buspirone, were identified. The 1A Ž . maximal effects of the 5-HT receptor ligands in the forced swimming test correlated positively r s0.91, P -0.005 with the rank 1A S order of their intrinsic activity at 5-HT receptors. This relationship constitutes evidence that the magnitude of the psychotropic activity 1A of 5-HT receptor ligands is a positive function of their intrinsic activity at the receptor, and suggests that F 13714, which had maximal 1A effects in the forced swimming test significantly larger than any of the other compounds examined here, did so because of its higher intrinsic activity at 5-HT receptors. q 2001 Elsevier Science B.V. All rights reserved. 1A w 35 x Ž . Keywords: 5-HT receptor; Intrinsic activity; S GTPgS binding; cAMP; Forced swimming test; Antidepressant; Rat 1A 1. Introduction The introduction of buspirone for the treatment of anxi- Ž ety, and also of depression see reviews by Tunnicliff et . al., 1991; Fulton and Brogden, 1997 , suggested a novel mechanism of anxiolytic and antidepressant drug action: direct activation of a 5-HT receptor subtype, the 5-HT 1A receptor. The clinical effectiveness of buspirone and its analogues, gepirone and ipsapirone, however, does not appear to be an improvement over that of other available Ž . treatments Deakin, 1993 . Their limited clinical efficacy has prompted the search for 5-HT receptor agonists with 1A enhanced activity in animal models of anxiety and depres- sion. Recent pre-clinical evidence suggests that the ability of Ž agonists to activate 5-HT receptors i.e., intrinsic activ- 1A . ity may be an important determinant of the magnitude of ) Corresponding author. Tel.: q 33-5-63-71-42-39; fax: q 33-5-63-71- 42-99. Ž . E-mail address: wouter.koek@pierre-fabre.com W. Koek . Ž . their psychotropic activity i.e., clinical effectiveness . In particular, the magnitude of the anxiolytic- and antidepres- sant-like effects of 5-HT receptor agonists appears to be 1A positively related to the magnitude of their intrinsic activ- Ž ity at the receptor Colpaert et al., 1992; De Vry, 1995, . 1996; Koek et al., 1998 . This relationship may explain why buspirone and its analogues, gepirone and ipsapirone, have limited clinical effects; these compounds activate the 5-HT receptor only weakly and are generally considered 1A to be partial 5-HT receptor agonists. 1A Previously, we reported a significant, positive correla- tion between the magnitude of the anxiolytic-like effects Ž i.e., maximal increase of punished responding in a conflict . procedure in pigeons and the intrinsic activity of 5-HT 1A Ž receptor agonists Spearman rank correlation r s 0.78, S . P - 0.005; Koek et al., 1998 . Although a similar positive relation was apparent between intrinsic activity and antide- Ž pressant-like effects i.e., inhibition of immobility in a . forced swimming test in rats , the number of compounds studied was too limited to examine this putative relation- ship in detail. 0014-2999r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 01 01011-1