Effects of ethanol on hippocampal neurogenesis depend on the conditioned appetitive response Carolina Tesone-Coelho 1a,b Patricia Varela 1a , João C. Escosteguy-Neto 1 , Clarissa F. Cavarsan 1 , Luiz E. Mello 1 & Jair G. Santos-Junior 1,2 Laboratorio de Neurobiologia, Group of Neuronal Plasticity and Psychiatric Disorders, Universidade Federal de São Paulo, São Paulo, Brazil 1 and Departmento de Ciências Fisiologicas, Faculdade de Ciências Médicas de São Paulo, R. Cesário Motta Jr, São Paulo, Brazil 2 ABSTRACT Neurogenesis in the subgranular layer of the dentate gyrus (DG) has been suggested to underlie some forms of associative learning. The present study was undertaken to determine whether there was also a role of neurogenesis in the ethanol (EtOH)-induced conditioned place preference (CPP). Outbreed Swiss mice were conditioned with EtOH (2.0 g/kg) in one compartment of a non-biased place preference chamber and saline in the other compartment. This procedure produced three groups of mice: some developed a conditioned preference (EtOH_Cpp), others developed a conditioned avoidance (EtOH_Cpa) and still others demonstrated indifference to the context previously paired with ethanol (EtOH_Ind). BrdU (40 mg/kg, i.p.) was administered 4 hours after each session comprising the conditioning phase. When measured 24 hours following the CPP test, there was no effect of EtOH on doublecortin (DCX) expression or Fluoro Jade B staining. However, there were decreases in the number of BrdU+ and Ki-67+ cells in the EtOH_Cpa and EtOH_Ind groups, but not in the EtOH_Cpp group. Most of BrdU+ cells were co-labeled with DCX. Similarly, in another experiment, in that the perfusion was done 28 days after CPP test, most BrdU+ cells were co-localized with NeuN. These results suggest that conditioned appetitive response is able to maintain normal levels of neurogenesis in DG and might counteract ethanol-produced decreased cell proliferation/survival rate. Keywords Addiction, alcohol, cell proliferation, conditioned place preference, hippocampus, neuronal degeneration. Correspondence to: Jair G. Santos-Junior, R. Cesário Motta Jr, 61, 01221-020, 12 Andar, São Paulo, Brazil. E-mail: guilherme.stos.jr@gmail.com INTRODUCTION Behavioral responses to ethanol (EtOH) are very irregu- lar. Some subjects might have euphoric states after ethanol intake, while in other people, ethanol may produce aversive effects. Clinical study reports that indi- viduals that do not have dysphoric states during ethanol intoxication are more susceptible to have problems related to drug use, such as ethanol abuse and addiction (Schramm-Sapyta et al. 2008).Therefore, investigation of the neurobiological mechanisms involved in the indi- vidual variability is crucial, given that the appetitive effect of drugs play a pivotal role in the maintenance and esca- lation of drug intake (Bartels et al. 2007; Barrett et al. 2008). In pre-clinical studies, the appetitive effects of drugs of abuse have been studied using the conditioned place pref- erence (CPP) paradigm. This paradigm measures the con- ditioned reinforcing properties of drugs by determining the ability of environmental cues associated with the drug experience to become conditioned reinforces (Tzschentke 2007). Repeated exposure to many drugs of abuse produces a CPP and this effect has been attributed to drug-induced plasticity in brain mechanisms underly- ing learning and memory (Blaiss & Janak 2006; Tzschentke 2007). The hippocampus (HPC) has long been recognized as an important site of memory processing (Myers & Gluck 1994; Langston et al. 2010) and some researchers have suggested that neuroplasticity in HPC systems may a These authors participated equally to this study. b Present address: Université de Strasbourg, Faculté de Psychologie. 12 Rue Goethe, 67000 Strasbourg, France. PRECLINICAL STUDY Addiction Biology doi:10.1111/j.1369-1600.2011.00434.x © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction Addiction Biology