Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine.
BACKGROUND
Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia.


OBJECTIVE
In a putative model of antipsychotic drug-induced weight gain, we investigated the effects of sub-chronic olanzapine on body weight, meal patterns, the expression of genes encoding for hypothalamic feeding-related neuropeptides and the contribution of hyperphagia to olanzapine-induced weight gain in rats.


METHODS
In experiment 1, female rats received either olanzapine (1 mg/kg, p.o.) or vehicle, twice daily for 7 days, while meal patterns were recorded. At the end of the treatment regimen, we measured the levels of hypothalamic messenger RNAs (mRNAs) encoding neuropeptide-Y (NPY), hypocretin/orexin (HCRT), melanin concentrating hormone and pro-opiomelanocortin. NPY and HCRT mRNA levels were also assessed in a separate cohort of female rats treated acutely with olanzapine (1 mg/kg, p.o.). In experiment 2, we investigated the effect of a pair-feeding paradigm on sub-chronic (1 mg/kg, p.o.) olanzapine-induced weight gain.


RESULTS
In experiment 1, sub-chronic olanzapine increased body weight, food intake and meal size. Hypothalamic neuropeptide mRNA levels were unchanged after both acute and sub-chronic olanzapine treatment. In experiment 2, the restriction of food intake to the level of vehicle-treated controls abolished the sub-chronic olanzapine-induced increase in body weight.


CONCLUSIONS
Hyperphagia mediated by drug-induced impairments in satiety (as evidenced by increased meal size) is a key requirement for olanzapine-induced weight gain in this paradigm. However, olanzapine-induced hyperphagia and weight gain may not be mediated via alterations in the expression of the feeding-related hypothalamic neuropeptides examined in this study.
Davoodi
Nima
N
Department of Psychology, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
Kalinichev
Mikhail
M
Korneev
Sergei A
SA
Clifton
Peter G
PG
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects*; D004435:Eating / Q000502:physiology / Q000523:psychology*; D005260:Female; D006963:Hyperphagia / Q000139:chemically induced*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D009478:Neuropeptide Y / Q000096:biosynthesis; D009479:Neuropeptides / Q000502:physiology; D000077152:Olanzapine; D000068797:Orexins; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects*
D014150:Antipsychotic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D012333:RNA, Messenger; D001569:Benzodiazepines; D011333:Pro-Opiomelanocortin; D000077152:Olanzapine