Overview of the Use of Transgenic Animals in CNS Drug Discovery

Eric J. Nestler1, Berend Olivier1

1 PsychoGenics, Inc., Tarrytown, New York
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.20
DOI:  10.1002/0471141755.ph0520s07
Online Posting Date:  May, 2001
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Abstract

This overview highlights how transgenic mice, and related genetic manipulations, can contribute in important ways to the goal of developing novel treatments for neuropsychiatric disorders. A brief background of the field of drug discovery is covered and then new animal models of CNS disorders are discussed along with the topics of target validation, identification of novel targets, and functional genomics.

     
 
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Table of Contents

  • Drug Discovery in the Molecular Era
  • New Animal Models of CNS Disorders
  • Target Validation
  • Identification of Novel Targets
  • Conclusions
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

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Literature Cited

Literature Cited
   Barden, N. 1999. Regulation of corticosteroid receptor gene expression in depression and antidepressant action. J. Psychiatry Neurosci. 24:25‐39.
   Barkats, M., Bilang‐Bleuel, A., Buc‐Caron, M.H., Castel‐Barthe, M.N., Corti, O., Finiels, F., Horellou, P., Revah, F., Sabate, O., and Mallet, J. 1998. Adenovirus in the brain: Recent advances of gene therapy for neurodegenerative diseases. Prog. Neurobiol. 55:333‐341.
   Baron, U., Schnappinger, D., Helbl, V., Gossen, M., Hillen, W., and Bujard, H. 1999. Generation of conditional mutants in higher eukaryotes by switching between the expression of two genes. Proc. Natl. Acad. Sci. U.S.A. 96:1013‐1018.
   Bassett, A.S., Hodgkinson, K., Chow, E.W., Correia, S., Scutt, L.E., and Weksberg, R. 1998. 22q11 deletion syndrome in adults with schizophrenia. Am. J. Med. Genet. 81:328‐337.
   Blomer, U., Naldini, L., Kafri, T., Trono, D., Verma, I.M., and Gage, F.H. 1997. Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J. Virol. 71:6641‐6649.
   Boehme, S.A., Gaur, A., Crowe, P.D., Liu, X.J., Tamraz, S., Wong, T., Pahuja, A., Gaur, P.D., Ling, N., Vale, W., De Souza, E.B., and Conlon, P.J. 1997. Immunosuppressive phenotype of corticotropin‐releasing factor transgenic mice is reversed by adrenalectomy. Cell. Immunol. 176:103‐112.
   Brunner, D. and Hen, R. 1997. Insights into the neurobiology of impulsive behavior from serotonin receptor knockout mice. Ann.N.Y. Acad. Sci. 836:81‐105.
   Carlezon, W.A., Jr., Thome, J., Olson, V.G., Lane‐Ladd, S.B., Brodkin, E.S., Hiroi, N., Duman, R.S., Neve, R.L., and Nestler, E.J. 1998. Regulation of cocaine reward by CREB. Science. 282:2272‐2275.
   Chen, J.S., Kelz, M.B., Zeng, G.Q., Sakai, N., Steffen, C., Shockett, P.E., Picciotto, M., Duman, R.S., and Nestler, E.J. 1998. Transgenic animals with inducible, targeted gene expression in brain Mol. Pharmacol. 54:495‐503.
   Davies, S.W., Turmaine, M., Cozens, B.A., DiFiglia, M., Sharp, A.H., Ross, C.A., Scherzinger, E., Wanker, E.E., Mangiarini, L., and Bates, G.P. 1997. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 90:537‐548.
   Dunnett, S.B. and Bjorklund, A. 1999. Prospects for new restorative and neuroprotective treatments in Parkinson's disease. Nature. 399:A32‐A39.
   Gainetdinov, R.R., Jones, S.R., Fumagalli, F., Wightman, R.M., and Caron, M.G. 1998. Re‐evaluation of the role of the dopamine transporter in dopamine system homeostasis. Brain Res. Rev. 26:148‐153.
   Heisler, L.K., Chu, H.M., and Tecott, L.H. 1998. Epilepsy and obesity in serotonin 5‐HT2Creceptor mutant mice. Ann. N.Y.Acad. Sci. 861:74‐78.
   Kelz, M.B., Chen, J.S., Carlezon, W.A., Whisler, K., Gilden, L., Beckmann, A.M., Steffen, C., Zhang, Y., ‐, J., Marotti, L., and Self, S.W. 1999. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature. 401:272‐2476.
   Kistner, A., Gossen, M., Zimmermann, F., Jerecic, J., Ullmer, C., Lubbert, H., and Bujard, H. 1996. Doxycycline‐mediated quantitative and tissue‐specific control of gene expression in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 93:10933‐10938.
   Kozian, D.H. and Kirschbaum, B.J. 1999. Comparative gene‐expression analysis. Trends Biotechnol. 17:73‐78.
   Lawrence, M.S., Ho, D.Y., Sun, G.H., Steinberg, G.K., and Sapolsk, R.M. 1996. Overexpression of Bcl‐2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo. J. Neurosci. 16:486‐496.
   Ledent, C., Vaugeois, J.M., Schiffmann, S.N., Pedrazzini, T., El Yacoubi, M., Vanderhaeghen, J.J., Costentin, J., Heath, J.K., Vassart, G., and Parmentier, M. 1997. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature. 388:674‐678.
   Liang, P. and Pardee, A.B. 1994. Differential display of mRNA by PCR. In Current Protocols in Molecular Biology. F.A. Ausubel, R. Brent, R.E. Kingston, D.D. Moore, J.G. Seidman, J.A. Smith, K. Struhl, pp.15.8.1‐15.8.8. John Wiley & Sons, New York.
   Mansuy, I.M., Winder, D.G., Moallem, T.M., Osman, M., Mayford, M., Hawkins, R.D., and Kandel, E.R. 1998. Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron. 21:257‐265.
   Marsh, D.J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K.A., Fisher, S.L., Burn, P., and Palmiter, R.D. 1999. Response of melanocortin‐4 receptor‐deficient mice to anorectic and orexigenic peptides. Nature Genet. 21:119‐122.
   Mayford, M., Bach, M.E., Huang, Y.Y., Wang, L., Hawkins, R.D., Kandel, E.R. 1996. Control of memory formation through regulated expression of a CaMKII transgene. Science. 274:1678‐1683.
   Nestler, E.J. 1998. Antidepressant treatments in the 21st century. Biol. Psychiatry. 44:526‐533.
   Patel, M. and Sive, H. 1996. PCR‐based subtractive cDNA cloning. In Current Protocols in Molecular Biology. F.A. Ausubel, R. Brent, R.E. Kingston, D.D. Moore, J.G. Seidman, J.A. Smith and K. Struhl, pp.5.9.1‐5.9.20. John Wiley & Sons, New York.
   Ramboz, S., Oosting, R., Amara, D.A., Kung, H.F., Blier, P., Mendelsohn, P., Mann, J.J., Brunner, D., and Hen, R. 1998. Serotonin receptor 1A knockout: An animal model of anxiety‐related disorder. Proc. Natl. Acad. Sci. U.S.A. 95:14476‐14481.
   Rocha, B.A., Scearce‐Levie, K., Lucas, J., Hiroi, N., Castanon, N., Crabbe, J.C., Nestler, E.J., and Hen, R. 1998. Increased vulnerability to cocaine in mice lacking the serotonin 1B receptor. Nature. 393:175‐178.
   Smith, G.W., Aubry, J.M., Dellu, F., Contarino, A., Bilezikjian, L.M., Gold, L.H., Chen, R., Marchuk, Y., Hauser, C., Bentley, C.A. 1998. Corticotropin releasing factor receptor 1–deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron. 20:1093‐1102.
   Stein, L.D. 2000. Genetic analyses of DNA microarrays. In Current Protocols in Human Genetics N. Dracopoli, J.L. Haines, B.R. Korf, D.T. Moire, C.C. Morton, C.E. Seidman, J.G. Seidman and D.R. Smith, pp.11.1.1‐11.1.8. John Wiley & Sons, New York.
   Swift, R.G., Polymeropoulos, M.H., Torres, R., and Swift, M. 1998. Predisposition of Wolfram syndrome heterozygotes to psychiatric illness. Mol. Psychiatry. 3:86‐91.
   Takahashi, M., Terwilliger, R., Lane, C., Mezes, P.S., Conti, M., and Duman, R.S. 1999. Chronic antidepressant administration increases the expression of cAMP‐specific phosphodiesterase 4A and 4B isoforms. J. Neurosci. 19:610‐618.
   Wong, P.C., Borchelt, D.R., Lee, M.K., Pardo, C.A., Thinakaran, G., Martin, L.J., Sisodia, S.S., and Price, D.L. 1998. Familial amyotropic lateral sclerosis and Alzheimer's disease. Transgenic models. Adv.Exp. Med. Biol. 446:145‐159.
   Xu, M., Moratolla, R., Gold, L.H., Hiroi, N., Koob, G.F., Graybiel, A.M., and Tonegawa, S. 1994. Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine‐mediated behavioral responses. Cell 79:729‐7442.
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