Neurobehavioral and metabolic long-term consequences of neonatal maternal deprivation stress and adolescent olanzapine treatment in male and female rats Alvaro Llorente-Berzal a , Virginia Mela a , Erika Borcel a , Manuel Valero a , Meritxell López-Gallardo b , Maria-Paz Viveros a, * , Eva M. Marco a, ** a Departamento de Fisiología (Fisiología Animal II), Facultad de CC. Biológicas, Universidad Complutense de Madrid (UCM). C/Jose Antonio Novais, n  2, 28040 Madrid, Spain b Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain article info Article history: Received 2 December 2010 Received in revised form 9 July 2011 Accepted 19 July 2011 Keywords: Animal models Maternal deprivation Adolescence Antipsychotic CB1 cannabinoid receptor Sex differences abstract Early maternal deprivation (MD), 24 h of dam-litter separation on postnatal day (PND) 9, has been proposed as a suitable animal model to investigate some neuropsychiatric disorders with a base in neurodevelopment that also compromises metabolic and endocrine homeostasis. Atypical antipsychotics are frequently prescribed to children and adolescents as first-line treatment for several mental disorders despite the adverse metabolic effects frequently reported. However, persistent long-term effects after adolescent drug therapy have been scarcely investigated. In the present study we aimed to investigate the long-lasting metabolic and behavioral effects of MD in combination with the administration of an atypical antipsychotic, i.e. olanzapine, during adolescence. For that purpose, male and female Wistar rats not exposed (control group, Co) and exposed to the MD protocol were administered with oral olanzapine (Olan, 7.5 mg/kg/day) or vehicle (Vh, 1 mM acetic acid) in drinking water from PND 28 to PND 49. Body weight gain, glycaemia and plasma triglyceride (TG) levels were evaluated as relevant metabolic parameters. MD significantly diminished body weight gain, while Olan administration only induced a subtle decrease in body weight gain among female animals in the long-term. Olan discontinuation decreased plasma TG levels in adult rats, an effect that was coun- teracted by neonatal exposure to the MD protocol. Both MD and Olan treatment impaired cognitive function in the novel object recognition test, although no interaction between treatments was observed. Neither MD nor Olan administration affected psychotic-related symptoms evaluated in the prepulse inhibition task, although animals treated with Olan showed an increased reactivity to the first acoustic stimulus. MD diminished the corticosterone stress-induced response among females, and reduced the expression of CB1 receptors in the hippocampus of both male and female rats. Notably, Olan adminis- tration tended to counterbalance these two MD-induced effects (i.e. corticosterone response and CB1 receptor expression). Present findings provide evidence for the long-lasting effects of neonatal MD and Olan administration during adolescence, and suggest some sex-dependent interactions between these two protocols. Further research on the interactions between early life stress and antipsychotic drugs is urgently needed, and sex differences should be consistently considered both in animal models and in translation to human studies. This article is part of a Special Issue entitled ‘Schizophrenia’. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Early brain developmental abnormalities, often related to early traumatic experiences, have been extensively associated to a wide range of psychopathologies, including schizophrenia (Levine, 2005; Lewis and Levitt, 2002; Tyrka et al., 2008). Consequently, several animal models have been developed in an attempt to mimic some of the neurobehavioral impairments of early life stress (Marco et al., 2011). In particular, early maternal deprivation (MD), 24 h of dam-litter separation on postnatal day (PND) 9, has arisen as a suitable animal model to inves- tigate some neuropsychiatric disorders with a base in neuro- development (Ellenbroek et al., 2005; Marco et al., 2009; Viveros et al., 2009). At adulthood, maternally deprived animals showed * Corresponding author. Tel.: þ34 91 394 4993; fax: þ34 91 394 4935. ** Corresponding author. Tel.: þ34 91 394 4939; fax: þ34 91 394 4935. E-mail addresses: pazviver@bio.ucm.es (M.P. Viveros), emmarco@bio.ucm.es (E.M. Marco). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.07.031 Neuropharmacology 62 (2012) 1332e1341