title: Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters.
abstract: BACKGROUND
  Atypical antipsychotic drugs (AAPDs) such as olanzapine have a serious side effect profile including weight gain and metabolic dysfunction, and a number of studies have suggested a role for gender in the susceptibility to these effects. In recent times, the gut microbiota has been recognised as a major contributor to the regulation of body weight and metabolism. Thus, we investigated the effects of olanzapine on body weight, behaviour, gut microbiota and inflammatory and metabolic markers in both male and female rats.
  
  
  METHODS
  Male and female rats received olanzapine (2 or 4 mg/kg/day) or vehicle for 3 weeks. Body weight, food and water intake were monitored daily. The faecal microbial content was assessed by 454 pyrosequencing. Plasma cytokines (tumour necrosis alpha, interleukin 8 (IL-8), interleuin-6 and interleukin 1-beta (IL-1β)) as well as expression of genes including sterol-regulatory element binding protein-1c and CD68 were analysed.
  
  
  RESULTS
  Olanzapine induced significant body weight gain in the female rats only. Only female rats treated with olanzapine (2 mg/kg) had elevated plasma levels of IL-8 and IL-1β, while both males and females had olanzapine-induced increases in adiposity and evidence of macrophage infiltration into adipose tissue. Furthermore, an altered microbiota profile was observed following olanzapine treatment in both genders.
  
  
  CONCLUSIONS
  This study furthers the theory that gender may impact on the nature of, and susceptibility to, certain side effects of antipsychotics. In addition, we demonstrate, what is to our knowledge the first time, an altered microbiota associated with chronic olanzapine treatment.
authors.affiliation: Alimentary Pharmabiotic Centre, Laboratory of Neurogastroenterology, University College Cork, Cork, Ireland.
authors.forename: Kieran J
authors.initials: KJ
authors.lastname: Davey
authors.forename: Siobhain M
authors.initials: SM
authors.lastname: O'Mahony
authors.forename: Harriet
authors.initials: H
authors.lastname: Schellekens
authors.forename: Orla
authors.initials: O
authors.lastname: O'Sullivan
authors.forename: John
authors.initials: J
authors.lastname: Bienenstock
authors.forename: Paul D
authors.initials: PD
authors.lastname: Cotter
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001569:Benzodiazepines / Q000009:adverse effects* / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000097:blood*; D018836:Inflammation Mediators / Q000097:blood*; D020738:Leptin / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D054892:Metagenome / Q000187:drug effects*; D009687:Nuclear Proteins / Q000096:biosynthesis; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014150:Antipsychotic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001569:Benzodiazepines; D015415:Biomarkers; D054439:Ghrelin; D018836:Inflammation Mediators; D020738:Leptin; D009687:Nuclear Proteins; D000077152:Olanzapine; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C506001:Mlxipl protein, mouse