Abstract
Recombinant inbred (RI) mouse strains were developed primarily as a tool to detect and provisionally map major gene loci—those with effects large enough to cause a bimodal distribution in the trait of interest. This implied that progress toward gene mapping was possible only for gene loci accounting for at least half of the genetic variance. More recently, QTL (quantitative trait loci) approaches have been advanced that do not require bimodal distributions and are thus applicable to a much wider range of phenotypes. They offer the prospect of meaningful progress toward detecting and mapping minor as well as major gene loci affecting any trait of interest, provided there is a significant degree of genetic determination among the RI strains. This paper presents a review of RI gene mapping efforts concerning phenotypes related to drug abuse and presents new data for studies now in progress for nitrous oxide and acute ethanol withdrawal intensity. These two studies exemplify several strengths and limitations of the RI QTL approach.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Akers, T. K., and Belknap, J. K. (1988). Handling-induced convulsions as a sensitive index of hyperexcitability associated with the high pressure nervous syndrome (HPNS).Biomed. S. Sci. Instrument. 24:225–230.
Bailey, D. W. (1981). Recombinant inbred strains and bilineal congenic strains. In Foster, H. L., Small, J. D., and Fox, J. G. (eds.),The Mouse in Biomedical Research, Vol. I, Academic Press, New York, pp. 223–239.
Belknap, J. K. (1992). Empirical estimates of Bonferroni corrections for use in chromosome mapping studies with BXD recombinant inbred strains.Behav. Genet. 22:677–684.
Belknap, J. K., and Crabbe, J. C. (1992). Chromosome mapping of gene loci affecting morphine and amphetamine responses in BXD recombinant inbred mice. In Kalivas, P., and Samson, H., (eds.),The Neurobiology of Alcohol and Drug Addiction, Ann. N.Y. Acad. Sci.654:311–323.
Belknap, J. K., and O'Toole, L. A. (1991). Studies of genetic differences in response to opioid drugs. In Crabbe, J. C., and Harris, R. A. (eds.),The Genetic Basis of Alcohol and Drug Actions, Plenum, New York, pp. 225–252.
Belknap, J. K., Laursen, S. E., and Crabbe, J. C. (1987). Ethanol and nitrous oxide produce withdrawal-induced convulsions by similar mechanisms.Life Sci. 41:2033–2041.
Broadhurst, P. L. (1978).Drugs and the Inheritance of Behavior, Plenum Press, New York.
Crabbe, J. C., and Phillips, T. J. (1993). Selective breeding for alcohol withdrawal severity.Behav. Genet. 23:169–175.
Crabbe, J. C., Kosobud, A., Young, E. R., and Janowsky, J. S. (1983). Polygenic and single-gene determination of responses to ethanol in BXD/Ty recombinant inbred mouse strains.Neurobehav. Toxicol. Teratol. 5:181–187.
Crabbe, J. C., Phillips, T. J., Kosobud, A., and Belknap, J. K. (1990). Estimation of genetic correlation: Interpretation of experiments using selectively bred and inbred animals.Alcohol. Clin. Exp. Res. 14:141–151.
Crabbe, J. C., Merrill, C. D., and Belknap, J. K. (1991). Acute dependence on depressant drugs is determined by common genes in mice.J. Pharmacol. Exp. Ther. 257:663–667.
Davisson, M. T., and Roderick, T. H. (1989). Linkage map. In Lyon, M. F., and Rearle, A. G. (eds.),Genetic Variants and Strains of the Laboratory Mouse, 2nd ed., Oxford University Press, Oxford, pp. 416–428.
DeFries, J. C., Wilson, J. R., Erwin, V. G., and Peterson, D. R. (1989). LS x SS recombinant inbred strains of mice: Initial characterization.Alcohol. Clin. Exp. Res. 13:196–200.
Dietrich, W., Katz, H., Lincoln, S. E., Shin, H.-S., Friedman, J., Dracopoli, N. C., and Lander, E. S. (1992). A genetic map of the mouse suitable for typing intraspecific crosses.Genetics 131:423–447.
Eger, E. I., II (ed) (1985).Nitrous Oxide, Elsevier, New York.
Erwin, V. G., and Jones, B. C. (1993). Genetic correlations among ethanol-related behaviors and neurotensin receptors in SS x LS recombinant inbred strains of mice.Behav. Genet. 23:189–194.
Falconer, D. S. (1989).Introduction to Quantitative Genetics, Longman, New York.
Frankel, W. N., Stoye, J. P., Taylor, B. A., and Coffin, J. M. (1990). A linkage map of endogenous murine leukemia proviruses.Genetics 124:221–236.
Frishknecht, H. R., Siegfried, B., and Waser, P. G. (1988). Opioids and behavior: genetic aspects.Experientia 44:473–481.
Goldman, D., Lister, R. G., and Crabbe, J. C. (1987). Mapping of a putative genetic locus determining ethanol intake in the mouse.Brain Res. 420:220–226.
Gora-Maslak, G., McClearn, G. E., Crabbe, J. C., Phillips, T. J., Belknap, J. K., and Plomin, R. (1991). Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology.Psychopharmacology 104:413–424.
Halsey, M. J. (1982). Effects of high pressure on the central nervous system.Physiol. Rev. 62:1341–1377.
Harper, P. M., Winter, B. H., Johnson, D. D., Koblin, D. D., and Eger, E. I. II (1980). Withdrawal convulsions in mice following nitrous oxide.Anesth. Agalg. 59:19–21.
Hent, W. A. (1985).Alcohol and Biological Membranes, Guilford Press, New York.
Jeste, D. V., Stoff, D. M., Rawlings, R., and Wyatt, R. J. (1984). Pharmacogenetics of phenylethylamine: Determination of heritability and genetic transmission of locomotor effects in recombinant inbred strains of mice.Psychopharmacology. 84:537–540.
Johnson, T. E., DeFries, J. C., and Markel, P. (1992). Mapping quantitative trait loci for behavioral traits in the mouse.Behav. Genet. 22:635–653.
Koblin, D. D., Deady, J. E., Dong, D. E., and Eger, E. I., II (1980). Mice tolerant to nitrous oxide are also tolerant to alcohol.J. Pharmacol. Exp. Ther. 213:309–312.
Koblin, D. D., Deady, J. E., and Eger, E. I., II (1982). Potencies of inhaled anesthetics and alcohol in mice selectively bred for resistance and susceptibility to nitrous oxide anesthesia.Anesthesiology 56:18–24.
Koblin, D. D., Lurz, F. W., O'Connor, B., Nelson, N. T., Eger, E. I. II, and Bainton, C. R. (1984). Potencies of barbiturates in mice selectively bred for resistance or susceptibility to nitrous oxide anesthesia.Anesth. Analg. 63:35–39.
Kosobud, A., and Crabbe, J. C. (1986). Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures.J. Pharmacol. Exp. Ther. 238:170–177.
Lander, E. S., and Botstein, D. (1989). Mapping mendelian factors underlying quantitative traits using RFLP linkage maps.Genetics 121:185–199.
McCall, R. D., and Frierson, D. (1981). Evidence that two loci predominantly determine the difference in susceptibility to the high pressure neurological syndrome type I seizure in mice.Genetics 99:285–307.
McClearn, G. E., (1991). The tools of pharmacogenetics. In Crabbe, J. C., and Harris, R. A. (eds.),The Genetic Basis of Alcohol and Drug Actions, Plenum, New York, pp. 1–24.
Miller, R. G. Jr. (1981).Simultaneous Statistical Inference, McGraw-Hill, New York.
Neumann, P. E., and Seyfried, T. N. (1990). Mapping of two genes that influence susceptibility to audiogenic seizures in crosses of C57BL/6J and DBA/2J mice.Behav. Genet. 20:307–323.
Neumann, P. E., and Collins, R. L. (1991). Genetic dissetion of susceptibility to audiogenic seizures in inbred mice.Proc. Natl. Acad. Sci. USA 88:5408–5412.
Oliverio, A., and Eleftheriou, B. E. (1976). Motor activity and alcohol: A genetic investigation in the mouse.Physiol. Behav. 16:577–581.
Oliverio, A., Eleftheriou, B. E., and Bailey, D. W. (1973). Exploratory activity; Genetic analysis of its modification by scopolamine and amphetamine.Physiol. Behav. 10:893–901.
Phillips, T. J., and Crabbe, J. C. (1991). Behavioral studies of genetic differences in alcohol action. In Harris, R. A., and Crabbe, J. C. (eds.),The Genetic Basis of Alcohol and Drug Actions, Plenum, New York, pp. 25–104.
Phillips, T. J., Belknap, J. K., and Crabbe, J. C. (1991). Use of voluntary morphine consumption in recombinant inbred strains to access vulnerability to drug abuse at the genetic level.J. Addict. Dis. 10:73–87.
Plomin, R., and McClearn, G. E. (1993). Quantitative trait loci (QTL) analyses and alcohol-related behaviors.Behav. Genet. 23:195–209.
Plomin, R., McClearn, G. E., and Gora-Maslak, C. (1991). Use of recombinant inbred strains to detect quantitative trait loci associated with behavior.Behav. Genet. 23:99–116.
Price, H., and Dripps, R. D. (1970). General anesthetics. In Goodman, L. S., and Gilman, A. (eds.),The Pharmacological Basis of Therapeutics, 4th ed., MacMillan, New York.
Rice, W. R. (1989). Analyzing tables of statistical tests.Evolution 43:223–225.
Rise, M. L., Frankel, W. N., Coffin, J. M., and Seyfried, T. N. (1991). Genes for epilepsy mapped in the mouse.Science 253:669–673.
Ruprecht, J., Dworacek, B., Ducardus, R., Schmitz, P., and Dzoljik, M. (1983). The involvement of the central cholinergic and endorphinergic systems in the nitrous oxide withdrawal syndrome in mice.Anesthesiologist.58:524–526.
Seale, T. W. (1991). Genetic differences in response to cocaine and stimulant drugs. In Harris, R. A., and Crabbe, J. C. (eds.)The Genetic Basis of Alcohol and Drug Actions, Plenum, New York, pp. 279–322.
Seale, T. W., Carney, J. M., Johnson, P., and Rennert, O. M. (1985). Inheritance of amphetamine-induced thermoregulatory responses in inbred mice.Pharmacol. Biochem. Behav. 23:373–377.
Shuster, L. (1984). Genetic determinants of responses to drugs of abuse: An evaluation of research strategies. NIDA Res. Monogr. No. 54, USGPO, Washington, DC, pp. 50–69.
Shuster, L. (1986). Genetic markers of drug abuse in mouse models. In Braude, M. C., and Chao, H. M. (eds.),Genetic and Biological Markers in Drug Abuse and Alcoholism, NIDA Res. Monogr. 66, GSGPO, Washington, DC, pp. 71–85.
Shuster, L. (1989). Pharmacogenetics of drugs of abuse.Ann. N.Y. Acad. Sci. 562:56–73.
Silverman, B. W. (1986).Density Estimation for Statistics and Data Analysis, Chapman and Hall, London.
Smith, T. C., and Wollman, H. (1985). History and principles of anesthesiology. In Gilman et al. (eds.)The Pharmacological Basis of Therapeutics, 7th ed., Macmillan, New York, pp 260–275.
Smith, R. A., Winter, P. M., Smith, M., and Eger, E. I., II (1979). Convulsions in mice after anesthesia.Anesthesiology 50:501–504.
Sokal, R. R., and Rohlf, F. J. (1981).Biometry, W. H. Freeman, New York, pp. 122–124.
Taylor, B. A. (1978). Recombinant inbred strains: Use in gene mapping. In Morse, H. C. (ed.),Origins of Inbred Mice, Academic Press, New York, pp 423–438.
Taylor, B. A. (1989). Recombinant inbred strains. In Lyon, M. F., and Searle, A. G. (eds.),Genetic Variants and Strains of the Laboratory Mouse, 2nd ed., Oxford University Press, Oxford, pp. 773–789.
Wehner, J. M., Pounder, J. I., Parham, C., and Collins, A. C. (1992). A recombinant inbred strain analysis of sleeptime responses to several sedative-hypnotics.Alcohol. Clin. Exp. Res. 16:522–532.
Wilkinson, L. (1990).Systat: The System for Statistics, Systat, Inc., Evanston, IL.
Wollman, H., and Dripps, R. D. (1970). Uptake, distribution, elimination, and administration of inhalational anesthetics. In Goodman, L. S., and Gilman, A. (eds.),The Pharmacological Basis of Therapeutics, 4th ed., Macmillan, New York.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Belknap, J.K., Metten, P., Helms, M.L. et al. Quantitative trait loci (QTL) applications to substances of abuse: Physical dependence studies with nitrous oxide and ethanol in BXD mice. Behav Genet 23, 213–222 (1993). https://doi.org/10.1007/BF01067426
Issue Date:
DOI: https://doi.org/10.1007/BF01067426