title: Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain.
abstract: OBJECTIVE
  Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity.
  
  
  RESULTS
  Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD(65), enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [(3)H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD(65) mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine.
  
  
  CONCLUSIONS
  Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.
authors.affiliation: Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Katrina
authors.initials: K
authors.lastname: Weston-Green
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001483:Base Sequence; D001569:Benzodiazepines / Q000009:adverse effects*; D002186:Cannabinoids / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000187:drug effects; D008954:Models, Biological; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D000077152:Olanzapine; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D002186:Cannabinoids; D009478:Neuropeptide Y; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D011333:Pro-Opiomelanocortin; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D000077152:Olanzapine