Pica in Rats as a Preclinical Model of Emesis

T. Gregg Davis1

1 Boehringer Ingelheim Pharmaceuticals Inc, Connecticut
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.53
DOI:  10.1002/cpns.12
Online Posting Date:  October, 2016
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

The ability to assess the potential for gastrointestinal adverse events in a preclinical setting is a challenge in the development of new drugs, as the vast majority of in vivo research is conducted in rodent species lacking a vomiting reflex. The use of higher species capable of emesis is often limited by cost, technical experience, and relevant efficacy models to define a therapeutic index. Additionally, investigators should be mindful of ethical considerations when using more sentient species when an alternative in lower species is available. This unit describes the use of pica behavior in rodents as an alternative for evaluating emetic potential in vivo. After an acclimation period, the incidence of rats engaging in pica following the administration of a test article can be used to generate a dose‐response curve of the pica behavior. When linked with an appropriate efficacy model, this allows compounds to be ranked based on therapeutic index. © 2016 by John Wiley & Sons, Inc.

Keywords: pica; emesis; rats; therapeutic index

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

Basic Protocol 1:

  Materials
  • Nontoxic modeling clay (e.g., Laguna self‐hardening clays)
  • Rats of interest (any strain or gender)
  • Test article
  • Appropriate vehicle for test article
  • Forced‐air oven, set to 70°C (e.g., VWR)
  • Cages with wire bottoms and removable food cup
  • Scale, to weigh pica substrate
  • Polystyrene weigh boats (14 × 14 × 2.5 cm)
  • Equipment suitable for test article delivery route (e.g., syringe and gavage feeding needle)
  • Computer with curve‐fitting software capable of logistic regression analysis (e.g., SAAS, XLfit)
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
  Davis, T.G., Peterson, J.J., Kou, J.‐P., Capper‐Spudich, E.A., Ball, D., Nials, A.T., Wiseman, J., Solanke, Y.E., Lucas, F.S., Williamson, R.A., Ferrari, L., Wren, P., Knowles, R.G., Barnette, M.S., and Podolin, P.L. 2009. The identification of a novel phosphodiesterase 4 inhibitor, 1‐Ethyl‐5‐{5‐[(4‐methyl‐1‐piperazinyl)methyl]‐1,3,4‐oxadiazol‐2‐yl}‐N‐(tetrahydro‐2H‐pyran‐4‐yl)‐1H‐pyrazolo[3,4‐b]pyridin‐4‐amine (EPPA‐1), with improved therapeutic index using pica feeding in rats as a measure of emetogenicity. J. Pharmacol. Exp. Ther. 330:922‐931. doi: 10.1124/jpet.109.152454.
  Mitchell, D., Wells, C., Hoch, N., Lind, K., Woods, S.C., and Mitchell, L.K. 1976. Poison induced pica in rats. Physiol. Behav. 17:691‐697. doi: 10.1016/0031‐9384(76)90171‐2.
  Rutter, A.R., Poffe, A., Cavallini, P., Davis, T.G., Schneck, J., Negri, M., Vicentini, E., Montanari, D., Arban, R., Gray, F.A., Davies, C.H., and Wren, P.B. 2014. GSK356278, a potent, selective, brain‐penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition‐enhancing effects without inducing side effects in preclinical species. J. Pharmacol. Exp. Ther. 350:153‐163. doi: 10.1124/jpet.114.214155.
  Takeda, N., Hasegawa, S., Morita, M., Horri, A., Uno, A., Yamatodani, A., and Matsunaga, T. 1995a. Neuropharmacological mechanisms of emesis. I. Effects of antiemetic drugs on motion‐ and apomorphine‐induced pica in rats. Methods Find Exp. Clin. Pharmacol. 17:589‐596.
  Takeda, N., Hasegawa, S., Morita, M., Horri, A., Uno, A., Yamatodani, A., and Matsunaga, T. 1995b. Neuropharmacological mechanisms of emesis. II. Effects of anti‐emetic drugs on cisplatin‐induced pica in rats. Methods Find Exp. Clin. Pharmacol. 17:647‐652.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library