A Murine Model of Atypical Antipsychotic‐Induced Weight Gain and Metabolic Dysregulation

Roberto Coccurello1, Anna Moles1

1 Institute of Neuroscience, National Research Council (C.N.R.), Rome, Italy
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.33
DOI:  10.1002/0471142301.ns0933s52
Online Posting Date:  July, 2010
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Abstract

In comparison with conventional, first‐generation antipsychotics (e.g., haloperidol), the administration of atypical antipsychotics (AAPs) has been associated with a higher risk of metabolic derangements, including body weight increase, dysregulation of glucose homeostasis, fat accumulation, and even liability to develop type II diabetes. Since this is a serious clinical problem that may be further exacerbated in overweight schizophrenics, establishing animal models of AAP‐induced adverse effects may contribute to clarifying the mechanisms underlying these effects. Here we present three basic protocols by which this problem has been modeled. The three protocols differ in many aspects (routes of administration, extent of the chronic treatment, diets, and dosage regimen), and the pros and cons of each procedure are systematically detailed throughout. It should be noted that several factors (e.g., species, sex, duration, and class of AAPs) could restrict the feasibility of these models, as well as their correspondence to the clinical condition. Curr. Protoc. Neurosci. 52:9.33.1‐9.33.22. © 2010 by John Wiley & Sons, Inc.

Keywords: atypical antipsychotic; olanzapine; weight gain; metabolic dysregulation; food intake; high‐fat diet

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Chronic Olanzapine (OL) Oral Administration: Body Weight Gain, Food Intake, and Metabolic Dysregulation
  • Basic Protocol 2: Chronic Olanzapine (OL) Voluntary Ingestion: Body Weight Gain, Food Intake, and Metabolic Dysregulation
  • Basic Protocol 3: Chronic Olanzapine (OL) Administration Via Subcutaneous Implantation of Osmotic Mini‐Pumps in Mice: Body Weight Gain, Food Intake, and Metabolic Dysregulation
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Chronic Olanzapine (OL) Oral Administration: Body Weight Gain, Food Intake, and Metabolic Dysregulation

  Materials
  • Female outbred type CD‐1 mice (Charles River Italia), 5 to 8 weeks of age on arrival (weighing ∼28 to 30 g)
  • Standard food pellets for mice maintenance (e.g., Mucedola, ref. no. 4RF21)
  • 10% sucrose solution in distilled water for preparation of HS wet mash
  • Dry powdered food pellets
  • Olanzapine [LY170053, 2‐methyl‐4‐(4‐methyl‐1‐piperazinyl)‐10H‐thieno[2,3‐b][1,5] benzodiazepine; dissolving tablets (5 or 10 mg) commercially known as Zyprexa‐Velotab, by Eli Lilly and Company]
  • Sterile isotonic saline solution: 0.9% (w/v) NaCl
  • Testing room with tight‐controlled temperature and humidity and 12‐hr light/dark cycle (light on at 7:00 AM)
  • Food dispensers: these can be assembled by placing two plastic cylinders of different diameters (6 and 4 cm) but of the same height (4 cm) one inside the other and both mounted (i.e., glued) on a Plexiglas square‐shaped stand (6 × 6 cm; see Fig. )
  • Home cage of ∼26.7 × 20.7 × 14–cm scattered with sawdust bedding (e.g., Harlan‐Teklad) to serve as testing cage
  • Marking pen, picric acid, or nontoxic tattoo pigments to identify mice
  • Electric food processor, optional
  • Analytical balance to weigh animals and calculate food intake
  • Curved stainless steel feeding needles of about 3.8 cm in length and 20 to 22 gauge diameters (depending on mouse weight), equipped with a metal or silicon ball on the tip of 1.2 to 2.5 mm to prevent injuries (e.g., Kent Scientific, SouthPointe Surgical Supply, Fine Science Tools)
  • Locomotor activity recording equipment to collect activity scores across 24‐hr (e.g., ActiviScope system, NewBehavior AG)
NOTE: All protocols using live animals must first be reviewed and approved by an Institutional Animal Care and Use Committee (IACUC) and must follow the officially approved procedures for the care and use of laboratory animals.

Basic Protocol 2: Chronic Olanzapine (OL) Voluntary Ingestion: Body Weight Gain, Food Intake, and Metabolic Dysregulation

  • Sweetened (10% sucrose) distilled water
  • White lard, commercially available
  • Standard dry food pellets in powdered form
  • Vehicle of carboxymethyl cellulose sodium salt (0.5% to 1%) and 0.1% HCl
  • 1 N NaOH, optional
  • Electric food processor

Basic Protocol 3: Chronic Olanzapine (OL) Administration Via Subcutaneous Implantation of Osmotic Mini‐Pumps in Mice: Body Weight Gain, Food Intake, and Metabolic Dysregulation

  • Animal models (e.g., ob/ob mice or leptin‐resistant obese Zucker rats)
  • 1 M NaOH
  • 1% to 2% glacial acetic acid in distilled water
  • Isoflurane
  • Ketamine
  • Xylazine
  • Betadine solution
  • Isopropyl alcohol
  • Osmotic mini‐pumps (e.g., Alzet Durect Corporation)
  • 37°C sterile saline bath
  • Gas anesthesia system, optional
  • Surgical shaver
  • Straight blunt scissors
  • Hemostat
  • Microsurgery forceps
  • Scalpel handle and sterile blades
  • Suture silk or nylon and suture needles (or surgical staples)
  • Heating plate
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Figures

Videos

Literature Cited

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Key References
   Goudie et al., 2005. See above.
  This manuscript is one of the first successful attempts to model in rodents (female rats) the weight gain described in patients as a consequence of chronic olanzapine administration.
   Kapur et al., 2003. See above.
  This is a seminal study, which establishes for the first time a criterion for the comparison of clinically effective doses of AAP agents and the use of these compounds in preclinical models. An alternative route of administration is suggested and the accuracy of the measures showed made this manuscript very informative and interesting as well.
   Newcomer, 2005. See above.
  This an excellent review that evaluates the broad spectrum of adverse metabolic effects (weight gain, hyperglycemia, dyslipidemia, diabetes, and ketoacidosis) induced by the administration of atypical antipsychotics in psychotic patients. The comprehensive database analysis posits that both clozapine and olanzapine are associated with the greater risk of significant metabolic derangement. The review also raises important questions concerning the role played by preclinical studies in addressing the multifactorial mechanisms underlying this relevant clinical problem.
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