Lack of long-term behavioral alterations after early postnatal treatment with tropisetron: Implications for developmental psychobiology Dragos Inta a, ⁎ ,1 , Miriam A. Vogt a,1 , Juan M. Lima-Ojeda a , Natascha Pfeiffer a , Miriam Schneider b , Peter Gass a a Department for Psychiatry and Psychotherapy, RG Animal Models in Psychiatry, Central Institute of Mental Health Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany b Department of Psychopharmacology, Central Institute of Mental Health Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany abstract article info Article history: Received 18 June 2010 Received in revised form 17 March 2011 Accepted 25 March 2011 Available online 31 March 2011 Keywords: 5-HT 3 receptors Schizophrenia Autism Anxiety Depression The early postnatal period represents a critical time window for brain development. Transient Cajal–Retzius cells in layer I of the cortex play an important role in cortical lamination by modulating neuronal migration and maturation. Recent data have demonstrated that the 5-HT 3 receptor antagonist and alpha7 nicotinic receptor partial agonist tropisetron, acting via 5-HT 3 receptors expressed on Cajal–Retzius cells, can disturb the formation of cortical columns at perinatal stages. This process is thought to be involved in several neuropsychiatric disorders. Here we investigated the possible long-term behavioral effects of exposure to tropisetron at early postnatal stages in mice. We found that the administration of 1 mg/kg, intraperitoneal (i.p.) tropisetron from postnatal days 2–12 (P2–P12) did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays. These results may be of relevance regarding the possible protracted deleterious neuropsychiatric effects of tropisetron during early life. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Serotonin (5-HT) is a critical regulator of several neurodevelop- mental processes such as neurogenesis, dendritogenesis, axon branch- ing and apoptosis (Gaspar et al., 2003). Both excessive and deficient serotonin levels during development are associated with structural and behavioral abnormalities in later life. An excess of serotonin in mice lacking the serotonin transporter leads to abnormally increased dendritic branching of neurons in the prefrontal cortex (Wellman et al., 2007) and disturbed organization of the somatosensory cortex (Persico et al., 2001). Embryonic depletion of serotonin by the reversible inhibitor of serotonin synthesis DL-P-chlorophenylalanine (PCPA) from Embryonic Days E12 to E17 alters the maturation of pyramidal neurons in the somatosensory cortex (Vitalis et al., 2007). Serotonin depletion restricted to the neonatal period induces mor- phological abnormalities of the cortex (Durig and Hornung, 2000) and alters behavioral responses to spatial change and novelty in the adult (Hohmann et al., 2007). Genetic deletion of the transcription factor Lmx1b, required for the differentiation of 5-HT neurons causes an almost complete absence of serotonin in the mouse brain and impairs the formation of hippocampus-dependent spatial memory, together with a phenotype of reduced anxiety (Dai et al., 2008). The action of serotonin on neurons is mediated by several sero- tonin receptors grouped into seven different families (5-HT 1–7 ). With the exception of ionotropic 5-HT 3 receptors, all other serotonin re- ceptors are metabotropic G-protein coupled receptors. The 5-HT 3 receptors are pentameric ligand-gated ion channels, composed of five subunits (5-HT 3A–E )(Jackson and Yakel, 1995), the two main subunits being 5-HT 3A (Maricq et al., 1991) and 5-HT 3B (Davies et al., 1999), of which only the former is expressed in the brain (Morales and Wang, 2002). A role for 5-HT 3 receptors during brain development is indicated by the fact that they are expressed at high levels in the embryonic brain both in immature GABAergic interneurons and in the proliferative ventricular zone (Tecott et al., 1995). Furthermore, during the early postnatal period and in the adult, 5-HT 3 receptors are continuously expressed by newborn neurons migrating from the subventricular zone (Inta et al., 2008). These receptors are also present in Cajal–Retzius cells in layer I of the developing neocortex (Chameau et al., 2009). Cajal–Retzius cells represent a transient population of neurons that play a key role in the organization of the neocortex in cortical columns, acting via its secreted glycoprotein reelin (Tissir and Goffinet, 2003). Disturbances of the columnar structure of the neocortex are proposed to be associated with autism and schizophrenia (Casanova et al., 2002). Cajal–Retzius cells receive a strong serotonergic input from the brainstem early in embryonic development (Janusonis et al., 2004). Recent data have demonstrated Pharmacology, Biochemistry and Behavior 99 (2011) 35–41 ⁎ Corresponding author at: Central Institute for Mental Health Mannheim (ZI), University of Heidelberg, Germany. Tel.: +49 621 1703/2933; fax: +49 621 1703/6205. E-mail address: Dragos.Inta@zi-mannheim.de (D. Inta). 1 These authors contributed equally to this work. 0091-3057/$ – see front matter © 2011 Elsevier Inc. 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