Neuropharmacology 47 (2004) 841–847 www.elsevier.com/locate/neuropharm Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT 1A receptor mRNA in prenatally stressed rats S. Morley-Fletcher a,d , M. Darnaude ´ry a , E. Mocaer b , N. Froger c , L. Lanfumey c , G. Laviola d , P. Casolini e , A.R. Zuena e , Lorenzo Marzano f , M. Hamon c , S. Maccari a, a Laboratory of Perinatal Stress JE2365, University of Lille 1, Bt. SN4.1, 59655, Villeneuve d’Ascq, France b IRIS, 6 Place des Ple ´iades, 92415 Courbevoie, France c INSERM U288, CHU Pitie ´-Salpe ˆtrie `re, 91 Bd de l’Ho ˆpital, 75634 Paris Cedex 13, France d Section of Behavioural Pathophysiology, Laboratory FOS, ISS, Rome, Italy e Department of Human Physiology and Pharmacology, University of Rome ‘‘La Sapienza’’, Rome, Italy f Department of Psychiatric Science and Psychological Medicine, University of Rome ‘‘La Sapienza’’, Rome, Italy Received 23 March 2004; received in revised form 4 June 2004; accepted 18 June 2004 Abstract Prenatal stress in the rat induces enhanced reactivity of the hypothalamus–pituitary–adrenal (HPA) axis, disturbances in a var- iety of circadian rhythms and increased anxiety-like behaviour. Such abnormalities parallel those found in human depressed patients. Prenatally stressed (PS) rats could represent, therefore, an interesting animal model for the evaluation of the efficacy of pharmacotherapeutic intervention in psychiatric disorders that has often been addressed using control animals. In the present study, PS and non-stressed rats were chronically treated with the tricyclic antidepressant imipramine (10 mg/kg i.p. for 21 days) and assessed in the forced swim test. Glucocorticoid receptor binding sites in the hippocampus were measured and 5-HT 1A recep- tor mRNA levels in the frontal cortex were also assessed. PS rats were characterised by increased immobility in the forced swim test, reduced hippocampal corticosteroid receptor binding and increased levels of cortical 5-HT 1A mRNA. All these parameters were significantly reversed by chronic imipramine treatment. Conversely, no significant effects were observed for non-stressed rats. All these effects are consistent with the expected pharmacotherapy of depression-like abnormalities in PS rats. These results fur- ther indicate that PS rats are a relevant animal model of depression. # 2004 Elsevier Ltd. All rights reserved. Keywords: Prenatal stress; Depression; Animal model; Forced swim test; Tricyclic antidepressant 1. Introduction Clinically, the effects of antidepressant drugs do not appear earlier than two or three weeks after the onset of treatment (Quitkin et al., 1996). Nevertheless, only a limited number of studies have employed chronic administration of antidepressants during a clinically relevant time in animals (Reul et al., 1993; Yau et al., 2002a,b). Also, the efficacy of pharmacotherapeutic intervention in psychiatric disorders has often been addressed using control animals, whereas, clinically, antidepressants affect neither the mood nor the behav- iour of non-depressed individuals (Gelfin et al., 1998; Wilson et al., 2002; Bonne et al., 1999). Therefore, data obtained in control rats have a limited relevance for understanding both the neurobiological abnormalities observed in depression and the beneficial effects of anti- depressant drugs. Many of the neurobiological abnormalities found in prenatally stressed (PS) rats parallel those found in human depressed patients. For instance, a long-lasting impairment of HPA axis feedback inhibition has been reported in PS rats (Maccari et al., 1995; Koehl et al., 1997, 1999; Vallee et al., 1997; Morley-Fletcher et al., 2003), associated with a life-span impairment of hippo- campal neurogenesis (Lemaire et al., 2000). Alterations  Corresponding author. Tel.: +33-320434083; fax: +33-320434602. E-mail address: stefania.maccari@univ-lille1.fr (S. Maccari). 0028-3908/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.06.011