A model for antipsychotic-induced obesity in the male rat.

INTRODUCTION: Weight gain is a common and severe side effect of antipsychotic drugs. A usual tool to study the side effects of psychotropic drugs is animal models. However, attempts to create an animal model of antipsychotic-induced weight gain were not successful so far. Female rodents are sensitive to the effects of antipsychotics, but not males. This does not match the human clinical situation. Antipsychotics have different pharmacokinetic properties in rats and humans, and rats and humans have different spontaneous diets. MATERIALS AND METHODS: In the present study, we tested the hypothesis that the insensitivity of male rats to the weight-promoting effects of antipsychotics could be related to the mode of administration of antipsychotics and to the animals' diet. Antipsychotics were mixed with the food, and rats were fed a diet resembling the human diet. Rats were treated with 0.01, 0.1, 0.5, and 2 mg/kg of olanzapine or with a control solution for 6 weeks. Their weight and food intake were recorded, and their body composition were analyzed. The effects on weight and food intake of olanzapine (1 mg/kg), haloperidol (1 mg/kg), and ziprasidone (10 mg/kg) were also compared in a 3-week treatment experiment. RESULTS: The results showed that 0.5 and 2 mg of olanzapine, but not lower doses, increase body weight and subcutaneous fat deposition. After the 3-week treatment, olanzapine-treated rats, but not haloperidol- or ziprasidone-treated rats, had significantly increased their weight. CONCLUSION: This study shows that a rat model of obesity induced by antipsychotics can be created under specific conditions of drug administration, diet, and dose.

Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermogenic alteration.

Body weight gain is a worrying side effect of many new antipsychotic drugs. The mechanisms by which antipsychotic drugs increase weight in humans are not known. Attempts to model the metabolic effects of antipsychotic drugs in the animal have not been successful. Female rats appear to be sensitive to the effects of antipsychotics, but male rats less, and this does not match the clinical situation in humans. In previous rodent studies, antipsychotics were always given by daily gavage or injections. Antipsychotics have different pharmacokinetics in rodents and humans, and in the present study, we tested the hypothesis that the insensitivity of male rats to the effects of antipsychotics could be related to their mode of administration. Thus, we administered antipsychotic drugs mixed with the food. Animals were treated during 6 weeks with haloperidol (1mg/kg), olanzapine (1mg/kg), ziprasidone (10mg/kg), or a control solution. Animals were allowed to self-select food among three macronutrients (carbohydrates, lipids and proteins). Food selection was measured throughout the study. At the end of the study, body composition was measured by dissection and weighing of the rat's main organs and tissues. Mitochondrial thermogenesis was measured in brown adipose tissue in olanzapine-treated animals. Circulating leptin, insulin, glucose, triglycerides, cholesterol, high-density lipoprotein (HDL) were also assayed at the end of the study. The results show that none of the antipsychotic treatments modified caloric intake, food selection or body weight. Olanzapine did not alter mitochondrial thermogenesis. However, haloperidol and olanzapine induced a significant increase in adiposity and circulating leptin. Ziprasidone produced a moderate fat accumulation. It is concluded that mixing antipsychotic treatments with the food provides a reliable animal model of antipsychotic-induced fat accumulation.

Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection.

New antipsychotic drugs often increase weight and produce metabolic disturbances in treated patients. However, the mechanisms by which neuroleptics induce these undesirable side effects in humans are not known. Studies have shown that antipsychotics can increase body weight in female but not in male rats. However, no studies investigated changes in macronutrient selection during chronic treatments with antipsychotics in male rats, and no studies investigated precisely body composition after such treatments. In the present work, we studied in male rats the effects of long-term administration of two neuroleptics: haloperidol, a classical neuroleptic which has a moderate effect on weight gain in humans, and olanzapine, an atypical neuroleptic which has a more important effect on weight gain. Treatments (both 1 mg/kg) were given orally for 6 weeks, and the animals were allowed to self-select food among carbohydrates, lipids and proteins. Food selection was measured throughout the study, and body composition was measured by dissection and weighing of the main organs and tissues. Circulating leptin, insulin and glucose were also assayed at the end of the study on blood collected at the time of carcass analysis. The results show that none of the neuroleptic treatments modified caloric intake, food selection, body weight, and body composition. Olanzapine produced a statistically non-significant increase in subcutaneous fat tissue. It is concluded that a 6-week olanzapine or haloperidol treatment in male rats under dietary macronutrient selection does not significantly affect energy regulation.