Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats.
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.
School of Health Sciences, University of Wollongong, Wollongong, 2522, NSW, Australia.
Katrina
K
Weston-Green
Xu-Feng
XF
Huang
Chao
C
Deng
D050154:Adiposity / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000097:blood; D002766:Cholecystokinin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006728:Hormones / Q000097:blood; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D008659:Metabolic Diseases / Q000139:chemically induced*; D000077152:Olanzapine; D010446:Peptide Fragments; D019894:Peptide YY / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration / Q000379:methods; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000097:blood; D013223:Statistics as Topic; D015430:Weight Gain / Q000187:drug effects
D001569:Benzodiazepines; D002766:Cholecystokinin; D006728:Hormones; D000077152:Olanzapine; D010446:Peptide Fragments; D019894:Peptide YY; D017367:Selective Serotonin Reuptake Inhibitors; C061785:peptide YY (3-36)