Metabolic and behavioral effects of chronic olanzapine treatment and cafeteria diet in rats Alexandre P. Muller a , Ana H. Tort a , Jussa ˆ nia Gnoatto a , Julia D. Moreira a , Elsa R. Vinade ´ a , Marcos L. Perry a , Diogo O. Souza a , Diogo R. Lara b and Luis V. Portela a Olanzapine and highly palatable diets can alter metabolism and brain function. We investigated the interaction of chronic treatment (4 months) with olanzapine and a cafeteria diet on metabolic parameters, memory tasks (spatial and aversive), the elevated plus maze and locomotor activity induced by d-amphetamine. Male Wistar rats were separated into the following groups: standard diet vehicle, standard diet and olanzapine, cafeteria diet and vehicle and cafeteria diet and olanzapine. Olanzapine was administered in the drinking water (approximately 1.5 mg/kg/day), and after 3 days of treatment, the rats exhibited an expected anxiolytic effect and reduced amphetamine-induced hyperlocomotion. After 4 months of treatment, cafeteria diet and vehicle rats exhibited an increased body weight and heavier fat pads compared with the standard diet groups. Olanzapine increased only the epididymal and mesenteric fat pads. The cafeteria diet and olanzapine group showed greater glucose intolerance compared with all other groups. The cafeteria diet altered the effects of chronic olanzapine on the performance in the water maze and inhibitory avoidance tasks. Chronic olanzapine treatment failed to affect amphetamine-induced locomotion and to produce anxiolytic effects in the elevated plus maze task, regardless of the diet. Our results suggest that chronic olanzapine caused an increase in fat pads, which is putatively involved in the etiology of many metabolic diseases. Rats on the cafeteria diet were overweight and exhibited glucose intolerance. We did not observe these effects with olanzapine treatment with the standard diet. Moreover, the chronic treatment regimen caused tolerance to the antipsychotic and anxiolytic effects of olanzapine and seemed to potentiate some of the metabolic effects of the cafeteria diet. The cafeteria diet also modified the effects of chronic treatment with olanzapine on cognitive tasks, which may represent an undesirable effect of poor diets in psychiatric patients. Behavioural Pharmacology 00:000–000  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2010, 00:000–000 Keywords: highly palatable diet, insulin resistance, intra-abdominal obesity, locomotor activity, memory, olanzapine, rat a Departamento de Bioquı ´mica, ICBS, UFRGS, Programa de Po ´ s Graduac ¸a ˜ o em Cie ˆ ncias Biolo ´ gicas-Bioquı ´mica, Rua Ramiro Barcelos and b Departamento de Biologia Celular e Molecular, Faculdade de Biocie ˆ ncias, Pontifı ´cia Universidade Cato ´ lica do Rio Grande do Sul, Avenida Ipiranga, CEP, Porto Alegre, RS, Brazil Correspondence to Luis Valmor Portela, PhD, Departmento de Bioquı ´mica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600 anexo, Porto Alegre CEP 90035-003, RS, Brazil E-mail: roskaportela@gmail.com Received 21 September 2009 Accepted as revised 10 May 2010 Introduction The atypical antipsychotic olanzapine is associated with a robust therapeutic response in schizophrenia and mania (Lieberman et al., 2005), and with insulin resistance, weight gain and enhanced abdominal obesity and adiposity (Allison et al., 1999; Newcomer, 2005). In rodents, olanzapine can disrupt the performance of animals in spatial memory tasks designed to assess specific components of cognition that are affected in schizophrenia (Terry et al., 2002, 2008; Didriksen et al., 2006); however, olanzapine is able to reverse drug-induced cognitive dysfunction (Egashira et al., 2008). In addition, acute treatment with olanzapine reverses amphetamine (AMPH)-induced locomotion and induces an anxiolytic effect in rodents (Frye and Seliga, 2003; Samaha et al., 2007; Mead et al., 2008). Weight gain, especially when manifested by intra- abdominal obesity, is a significant long-term health issue associated with impaired metabolism (Newcomer, 2005, 2007). Data from human studies indicate that olanzapine is able to induce weight gain and cause metabolic altera- tions, such as changes in glucose metabolism, insulin resis- tance and metabolic syndrome (Casey, 2005; Lieberman et al., 2005; Haupt, 2006; Minet-Ringuet et al., 2006). Many authors have attempted to model such effects induced by olanzapine in a range of animal species, including rats (Minet-Ringuet et al., 2006; Cooper et al., 2007). These studies have been controversial, because animal models differ in the atypical antipsychotic used, strain, diet composition and duration of treatment. More- over, major discrepancies regarding weight gain are related to sex. Atypical antipsychotics, such as olanzapine, induced weight gain and metabolic changes much more readily in female rats with a standard diet (Cooper et al., 2005; Kirk et al., 2009). However, male rats treated with olanzapine (6 weeks, 0.5 and 2 mg/kg) and fed with a standard laboratory diet resembling the western diet presented an obese phenotype (Minet-Ringuet et al., Original article 1 0955-8810  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32833e7f2a CE: Lavanya ED: Asra Op: Ragu FBP: LWW_FBP_200465