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

  • 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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Literature Cited

   Albaugh, V.L., Henry, C.R., Bello, N.T., Hajnal, A., Lynch, S.L., Halle, B., and Lynch, C.J. 2006. Hormonal and metabolic effects of olanzapine and clozapine related to body weight. Obesity 14:36‐51.
   Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Cappelleri, J.C., Infante, M.C., and Weiden, P.J. 1999. Antipsychotic‐induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry 156:1686‐1696.
   Bardin, L., Kleven, M.S., Barret‐Grévoz, C., Depoortère, R., and Newman‐Tancredi, A. 2006. Antipsychotic‐like vs. cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5‐HT1A agonist properties. Neuropsychopharmacology 31:1869‐1879.
   Bergman, R.N. and Ader, M. 2005. Atypical antipsychotics and glucose homeostasis. J. Clin. Psychiatry 66:504‐514.
   Bushe, C. and Holt, R. 2004. Prevalence of diabetes and impaired glucose tolerance in patients with schizophrenia. Br. J. Psychiatry Suppl. 47:67‐71.
   Casey, D.E. 2005. Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am. J. Med. 118:15‐22.
   Cheng, C.Y., Hong, C.J., and Tsai, S.J. 2005. Effects of subchronic clozapine administration on serum glucose, cholesterol and triglyceride levels, and body weight in male BALB/C mice. Life Sci. 76:2269‐2273.
   Chiu, J.A. and Franklin, R.B. 1996. Analysis and pharmacokinetics of olanzapine (LY170053) and two metabolites in rat plasma using reversed‐phase HPLC with electrochemical detection. J. Pharm. Biomed. Anal. 14:609‐615.
   Coccurello, R., Caprioli, A., Ghirardi, O., Conti, R., Ciani, B., Daniele, S., Bartolomucci, A., and Moles, A. 2006. Chronic administration of olanzapine induces metabolic and food intake alterations: A mouse model of the atypical antipsychotic‐associated adverse effects. Psychopharmacology 186:561‐571.
   Coccurello, R., Caprioli, A., Conti, R., Ghirardi, O., Borsini, F., Carminati, P., and Moles, A. 2008a. Olanzapine (LY170053, 2‐methyl‐4‐(4‐methyl‐1‐piperazinyl)‐10H‐thieno[2,3‐b][1,5] benzodiazepine), but not the novel atypical antipsychotic ST2472 (9‐piperazin‐1‐ylpyrrolo[2,1‐b][1,3]benzothiazepine), chronic administration induces weight gain, hyperphagia, and metabolic dysregulation in mice. J. Pharmacol. Exp. Ther. 326:905‐911.
   Coccurello, R., D'Amato, F.R., and Moles, A. 2008b. Chronic administration of olanzapine affects Behavioral Satiety Sequence and feeding behavior in female mice. Eat. Weight Disord. 13:55‐60.
   Coccurello, R., D'Amato, F.R., and Moles, A. 2009a. Chronic social stress, hedonism and vulnerability to obesity: Lessons from Rodents. Neurosci. Biobehav. Rev. 33:537‐550.
   Coccurello, R., Brina, D., Caprioli, A., Conti, R., Ghirardi, F., Schepis, F., and Moles, A. 2009b. 30 Days of continuous olanzapine infusion determines energy imbalance, glucose intolerance, insulin resistance, and dyslipidemia in mice. J. Clin. Psychopharmacol. 29:576‐583.
   Cooper, G.D., Pickavance, L.C., Wilding, J.P., Halford, J.C., and Goudie, A.J. 2005. A parametric analysis of olanzapine‐induced weight gain in female rats. Psychopharmacology 181:80‐89.
   Cooper, G.D., Harrold, J.A., Halford, J.C., and Goudie, A.J. 2008. Chronic clozapine treatment in female rats does not induce weight gain or metabolic abnormalities but enhances adiposity: Implications for animal models of antipsychotic‐induced weight gain. Prog. Neuropsychopharmacol. Biol. Psychiatry 32:428‐436.
   Cope, M.B., Nagy, T.R., Fernández, J.R., Geary, N., Casey, D.E., and Allison, D.B. 2005. Antipsychotic drug‐induced weight gain: Development of an animal model. Int. J. Obes. 29:607‐614.
   Dwyer, D.S. and Donohoe, D. 2003. Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol. Biochem. Behav. 75:255‐260.
   Farde, L., Nordstrom, A.L., Wiesel, F.A., Pauli, S., Halldin, C., and Sedvall, G. 1992. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch. Gen. Psychiatry 49:538‐544.
   Fell, M., Marshall, K., Williams, J., and Neill, J. 2004. Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats. J. Psychopharmacol. 18:149‐155.
   Goudie, A.J., Smith, J.A., and Halford, J.C. 2002. Characterization of olanzapine‐induced weight gain in rats. J. Psychopharmacol. 16:291‐296.
   Haupt, D.W. 2006. Differential metabolic effects of antipsychotic treatments. Eur. Neuropsychopharmacol. 16:S149‐S155.
   Kane, J.M. 1999. Pharmacologic treatment of schizophrenia. Biol. Psychiatry 46:1396‐408.
   Kapur, S. and Remington, G. 2001. Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu. Rev. Med. 52:503‐517.
   Kapur, S., Zipursky, R., Jones, C., Remington, G., and Houle, S., 2000. Relationship between dopamine D(2) occupancy, clinical response, and side effects: A double‐blind PET study of first‐episode schizophrenia. Am. J. Psychiatry 157:514‐520.
   Kapur, S., VanderSpek, S.C., Brownlee, B.A., and Nobrega, J.N. 2003. Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: A suggested solution based on in vivo occupancy. J. Pharmacol. Exp. Ther. 305:625‐631.
   Kessler, R.M., Ansari, M.S., Riccardi, P., Li, R., Jayathilake, K., Dawant, B., and Meltzer, H.Y. 2005. Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30:2283‐2289.
   Mattiuz, E., Franklin, R., Gillespie, T., Murphy, A., Bernstein, J., Chiu, A., Hotten, T., and Kassahun, K. 1997. Disposition and metabolism of olanzapine in mice, dogs, and rhesus monkeys. Drug Metab. Dispos. 25:573‐583.
   Monleon, S., D'Aquila, P., Parra, A., Simon, V.M., Brain, P.F., and Willner, P. 1995. Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine. Psychopharmacology 117:453‐457.
   Naiker, D.V., Catts, S.V., Catts, V.S., Bedi, K.S., and Bryan‐Lluka, L.J. 2006. Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D2‐receptor occupancy method in the rat. Eur. J. Pharmacol. 540:87‐90.
   Newcomer, J.W., Haupt, D.W., Fucetola, R., Melson, A.K., Schweiger, J.A., Cooper, B.P., and Selke, G. 2002. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch. Gen. Psychiatry 59:337‐345.
   Newcomer, J.W. 2005. Second‐generation (atypical) antipsychotics and metabolic effects: A comprehensive literature review. CNS Drugs 19:1‐93.
   Newcomer, J.W. 2007. Metabolic syndrome and mental illness. Am. J. Manag. Care 13:S170‐S177.
   Olsen, C.K., Brennum, L.T., and Kreilgaard, M. 2008. Using pharmacokinetic‐pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics. Eur. J. Pharmacol. 584:318‐327.
   Patil, B.M., Kulkarni, N.M., and Unger, B.S. 2006. Elevation of systolic blood pressure in an animal model of olanzapine induced weight gain. Eur. J. Pharmacol. 551:112‐115.
   Peet, M. 2004. Diet, diabetes and schizophrenia: review and hypothesis. Br. J. Psychiatry Suppl. 47:102‐105.
   Perez‐Costas, E., Guidetti, P., Melendez‐Ferro, M., Kelley, J.J., and Roberts, R.C. 2008. Neuroleptics and animal models: Feasibility of oral treatment monitored by plasma levels and receptor occupancy assays. J. Neural. Transm. 115:745‐753.
   Sondhi, S., Castellano, J.M., Chong, V.Z., Rogoza, R.M., Skoblenick, K.J., Dyck, B.A., Gabriele, J., Thomas, N., Ki, K., Pristupa, Z.B., Singh, A.N., MacCrimmon, D., Voruganti, P., Foster, J., and Mishra, R.K. 2006. cDNA array reveals increased expression of glucose dependent insulinotropic polypeptide following chronic clozapine treatment: Role in atypical antipsychotic drug‐induced adverse metabolic effects. Pharmacogenomics 6:131‐140.
   Stefanidis, A., Verty, A.N., Allen, A.M., Owens, N.C., Cowley, M.A., and Oldfield, B.J. 2009. The role of thermogenesis in antipsychotic drug‐induced weight gain. Obesity 17:16‐24.
   Strohmayer, A.J. and Smith, G.P. 1987. The meal pattern of genetically obese (ob/ob) mice. Appetite 8:111‐123.
   Surwit, R.S., Feinglos, M.N., Rodin, J., Sutherland, A., Petro, A.E., Opara, E.C., Kuhn, C.M., and Rebuffé‐Scrive, M. 1995. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44:645‐651.
   Tauscher, J., Jones, C., Remington, G., Zipursky, R.B., and Kapur, S., 2002. Significant dissociation of brain and plasma kinetics with antipsychotics. Mol. Psychiatry 7:317‐321.
   Taylor, D.M. and McAskill, R. 2000. Atypical antipsychotics and weight gain—A systematic review. Acta Psychiatr. Scand. 101:416‐432.
   Tulipano, G., Rizzetti, C., Bianchi, I., Fanzani, A., Spano, P., and Cocchi, D. 2007. Clozapine‐induced alteration of glucose homeostasis in the rat: The contribution of hypothalamic‐pituitary‐adrenal axis activation. Neuroendocrinology 85:61‐70.
   Turrone, P., Remington, G., Kapur, S., and Nobrega, J.N., 2005. Continuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats. Biol. Psychiatry 57:406‐411.
   van der Zwaal, E.M., Luijendijk, M.C., Adan, R.A., and la Fleur, SE. 2008. Olanzapine‐induced weight gain: Chronic infusion using osmotic minipumps does not result in stable plasma levels due to degradation of olanzapine in solution. Eur. J. Pharmacol. 585:130‐136.
   van Winkel, R., De Hert, M., Wampers, M., Van Eyck, D., Hanssens, L., Scheen, A., and Peuskens, J. 2008. Major changes in glucose metabolism, including new‐onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J. Clin. Psychiatry 69:472‐479.
   Wadenberg, M.L. and Hicks, P.B. 1999. The conditioned avoidance response test re‐evaluated: Is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci. Biobehav. Rev. 23:851‐862.
   Watson, P.M., Commins, S.P., Beiler, R.J., Hatcher, H.C., and Gettys, T.W. 2000. Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet‐induced obesity. Am. J. Physiol. Endocrinol. Metab. 279:356‐365.
   West, D.B., Waguespack, J., and McCollister, S. 1995. Dietary obesity in the mouse: Interaction of strain with diet composition. Am. J. Physiol. 268:658‐665.
   Zarate, J.M., Boksa, P., Baptista, T., and Joober, R. 2004. Effects of clozapine on behavioural and metabolic traits relevant for schizophrenia in two mouse strains. Psychopharmacology 171:162‐172.
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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