Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study William Pitchot * , Jacques Wauthy, Jean-Jacques Legros, Marc Ansseau Psychiatric Unit, CHU Sart Tilman, B-4000 Lie `ge, Belgium Received 3 December 2002; received in revised form 1 July 2003; accepted 1 July 2003 Abstract Rationale: Flesinoxan is a highly potent and selective 5-HT1A agonist. In a recent study, in normal volunteers, flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Objectives: In order to better define the role of 5-HT receptor subtypes in response to flesinoxan, we assessed the influence of 5-HT1A and 5-HT2 antagonists on hormonal and temperature responses to flesinoxan. Methods: Hormonal and temperature responses were studied in 6 volunteers with or without pretreatment with pindolol (30 mg p.o.), a 5-HT1A antagonist, or ritanserin (10 mg p.o.), a selective 5-HT2 antagonist, using a double-blind crossover design. Results: Pindolol significantly antagonized ACTH, PRL, GH and temperature responses to flesinoxan and ritanserin exhibited similar activity on PRL and ACTH responses. Conclusions: These results show the role of 5-HT1A mechanisms in the PRL, ACTH, GH, and temperature responses to flesinoxan, and the role of 5-HT2 mechanisms in PRL and ACTH responses. Therefore, they confirm the interest of flesinoxan as a 5-HT neuroendocrine probe. D 2003 Elsevier B.V./ECNP. All rights reserved. Keywords: Flesinoxan; 5-HT1A receptor; Serotonin; Hypothermia; Prolactin; Growth hormone; Cortisol; Pindolol; Ritanserin 1. Introduction Flesinoxan is a potent and selective 5-HT1A full agonist (Olivier et al., 1991). In a recent study (Pitchot et al., 2002), we showed a robust effect of flesinoxan 1 mg on neuroen- docrine function and body temperature in a sample of male healthy volunteers. Indeed, the administration of flesinoxan induced a very significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature, which tended to confirm a previous study (Seletti et al., 1995). In 1995, Seletti et al. suggested the implication of 5- HT1A receptors in GH responses to flesinoxan by demon- strating a significant blocking effect of pindolol, a 5-HT1A antagonist, but not methysergide, a mixed 5-HT 1/2 antag- onist, in GH increase after administration of flesinoxan which was consistent with other antagonist studies using other 5-HT1A agents (Lesch, 1991; Anderson and Cowen, 1992). To a lesser extend, hypothermic response to flesi- noxan appeared also to be under the control of 5-HT1A function. In contrast, PRL, ACTH and cortisol responses to flesinoxan were not antagonized by pretreatment with pindolol. On the basis of their results, they suggested that GH and temperature responses to flesinoxan could be used as an indirect index of 5-HT1A receptor function in human. The purpose of the present study was to clarify better the selective serotonergic mechanisms implicated in hormonal and temperature responses to flesinoxan using various serotonergic antagonists. 2. Methods 2.1. Subjects Six healthy volunteers took part to the study. They were in good health, as demonstrated by history and clinical examination. They were free of depressive symptomatolo- gy, as demonstrated by scores less than 6 on the Beck, Carroll and Hamilton rating scale for depression. They 0924-977X/$ - see front matter D 2003 Elsevier B.V./ECNP. All rights reserved. doi:10.1016/S0924-977X(03)00108-1 * Corresponding author. Tel.: +32-4-366-79-60; fax: +32-4-366-72-83. E-mail address: wpitchot@chu.ulg.ac.be (W. Pitchot). www.elsevier.com/locate/euroneuro European Neuropsychopharmacology 14 (2004) 151 – 155