Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats

• Published in: Behavioural brain research 2011-03, Vol.217 (2), p.337-346
• Main Authors: Weston-Green, Katrina, Huang, Xu-Feng, Deng, Chao
• Format: Article
• Language: English
• Subjects: Adiposity - drug effects; Analysis of Variance; Animal model; Animals; Antipsychotic; Behavior, Animal - drug effects; Behavioral psychophysiology; Benzodiazepines - administration & dosage; Benzodiazepines - blood; Biological and medical sciences; Cholecystokinin - metabolism; Dose; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating - drug effects; Exploratory Behavior - drug effects; Female; Fundamental and applied biological sciences. Psychology; Hormones - blood; Intra-Abdominal Fat - drug effects; Intra-Abdominal Fat - metabolism; Medical sciences; Metabolic Diseases - chemically induced; Metabolic side-effect; Neuropharmacology; Olanzapine; Peptide Fragments; Peptide YY - metabolism; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopharmacology; Rats; Rats, Sprague-Dawley; Self Administration - methods; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - blood; Statistics as Topic; Weight gain; Weight Gain - drug effects
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2010.10.039

▶ An animal model of olanzapine-induced obesity by oral self-administration (three times/day). ▶ Self-administration of olanzapine mixed with food, given at eight-hourly intervals may better mimic the clinic. ▶ Olanzapine increased ghrelin and CCK levels, and decreased insulin and locomotor activity. ▶ 0.5–2.0mg/kg (three times/day) olanzapine in the rat replicates aspects of human metabolic dysfunction. ▶ A low dosage of 0.25mg/kg (three times/day) olanzapine had no significant effect on body weight. Second generation antipsychotics are commonly prescribed for the treatment of schizophrenia, however some can induce metabolic dysfunction side-effects such as weight gain, obesity and diabetes. Clinical reports suggest olanzapine alters satiety signals, although findings appear conflicting. Previous animal model studies have utilised a range of olanzapine dosages, however the dosage that better mimics the human scenario of olanzapine-induced weight gain is unclear. Female Sprague–Dawley rats were treated orally, three times daily with olanzapine (0.25mg/kg, 0.5mg/kg, 1.0mg/kg, 2.0mg/kg), self-administered in a sweet cookie dough pellet at eight-hourly intervals) or vehicle (n=12/group) for 14-days. Olanzapine orally self-administered in multiple doses (eight-hourly intervals) may circumvent a drop in plasma drug concentration and ensure the maintenance of a consistently high olanzapine level in the rat. Olanzapine increased body weight (0.5mg/kg, 1.0mg/kg, 2.0mg/kg), food intake (2.0mg/kg) and feeding efficiency (0.5–2.0mg/kg), with no effect on water intake. Subcutaneous inguinal (1.0mg/kg, 2.0mg/kg) and intra-abdominal perirenal fat were increased (2.0mg/kg), but not interscapula brown adipose tissue. Olanzapine increased circulating ghrelin and cholecystokinin, but had no effect on peptide YY(3–36). Olanzapine decreased insulin (0.25–2.0mg/kg) and locomotor activity in the open field arena (0.5–2.0mg/kg). A low dosage of 0.25mg/kg olanzapine had no effect on most parameters measured. Olanzapine-induced weight gain is associated with hyperphagia, enhanced feeding efficiency and adiposity, decreased locomotor activity and altered satiety signaling. The animal model used in the present study of self-administered oral olanzapine treatment (t.i.d.) at a dosage range of 0.5–2.0mg/kg (but not 0.25mg/kg) mimics aspects of the clinic.