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Genotypic Differences Between C57BL/6 and A Inbred Mice in Anxiolytic and Sedative Actions of Diazepam

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Abstract

The role of genotype in susceptibility to the behavioral actions of benzodiazepines is not well characterized. To develop a model for such studies, we have characterized the anxiolytic and sedative activities of diazepam in C57BL/6J and A/J inbred mice. C57BL/6J mice were more responsive than A/J mice to diazepam-induced anxiolytic-like activity in the mirrored chamber aversion assay and the elevated plus-maze assay. Basal activity of the two strains did not differ in either assay. In contrast, the two strains were equally responsive to the anxiolytic effects of the 5-HT1Areceptor partial agonist, buspirone. C57BL/6J mice were also more susceptible to the sedative effects of diazepam than were A/J mice. Flumazenil blocked the effects of diazepam in these behavioral assays. Measurement of diazepam and nordiazepam in blood and brain suggested that the response differences are of a pharmacodynamic rather than a pharmacokinetic nature. Taken together, these findings indicate that C57BL/6J and A/J mice provide a valuable tool for behavioral genetic studies of the mechanisms underlying the pharmacological actions of benzodiazepines.

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REFERENCES

  • Baldessarini, R. J. (1995). Drugs and the treatment of psychiatric disorders: Psychosis and anxiety. In Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W., and Gillman, A. G. (eds.), The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, pp. 399–430.

    Google Scholar 

  • Cao, W., Burkholder, T., Wilkins, L., and Collins, A. C. (1993). A genetic comparison of behavioral actions of ethanol and nicotine in the mirrored chamber.Pharmacol. Biochem. Behav. 45:803–809.

    Google Scholar 

  • Chapouthier, G., Bondoux, D., Martin, B., Desforges, C., and Launay, J. M. (1991). Genetic differences in sensitivity to beta-carbolines: Evidence for the involvement of brain benzodiazepine receptors.Brain Res. 553:342–346.

    Google Scholar 

  • Cooper, S. J. (1985). Bidirectional control of palatable food consumption through a common benzodiazepine receptor: Theory and evidence.Brain Res. Bull. 15:397–410.

    Google Scholar 

  • Crabbe, J. C., and Belknap, J. K. (1992). Genetic approaches to drug dependence.Trends Neurosci. 13:212–219.

    Google Scholar 

  • Crawley, J. N., and Davis, L. G. (1982). Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains.Brain. Res. Bull. 8:609–612.

    Google Scholar 

  • Davies, M. F., Onaivi, E. S., Chen, S.-W., Maguire, P. A., Tsai, N. F., and Loew, G. H. (1994). Evidence for central benzodiazepine receptor heterogeneity from behavior tests.Pharmacol. Biochem. Behav. 49:47–56.

    Google Scholar 

  • Eison, A. S., and Eison, M. S. (1994). Serotonergic mechanisms in anxiety.Prog. Neuro-Psychopharmacol. Biol. Psychiatry 18:47–62.

    Google Scholar 

  • File, S. E., Greenblatt, D. J., Martin, I. L., and Brown, C. (1985). Long-lasting anticonvulsant effects of diazepam in different mouse strains: Correlations with brain concentrations and receptor occupancy.Psychopharmacology 86:137–141.

    Google Scholar 

  • Gallaher, E. J., Hollister, L. E., Gionet, S. E., and Crabbe, J. C. (1987). Mouse lines selected for genetic differences in diazepam sensitivity.Psychopharmacology 93:25–30.

    Google Scholar 

  • Gallaher, E. J., Gionet, S. E., and Feller, D. J. (1991). Behavioral and neurochemical studies in diazepam-sensitive and-resistant mice.J. Addict. Dis. 10:45–60.

    Google Scholar 

  • 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.

    Google Scholar 

  • Greenblatt, D. J., Shader, R. I., and Abernethy, D. R. (1983). Drug therapy. Current status of benzodiazepines.N. Engl. J. Med. 309:410–416.

    Google Scholar 

  • Hendel, J., Elsass, P., Sorensen, K. H., Moller, I. W., Havidberg, E. F., and Hansen, T. (1980). Anxiety and sedation during a stressful situation after a single dose of diazepam versus N-desmethyldiazepam—A controlled study.Psychopharmacology 70:303–305.

    Google Scholar 

  • Hirsch, J. D., Garrett, K. M., and Beer, B. (1985). Heterogeneity of benzodiazepine binding sites: A review of recent research.Pharmacol. Biochem. Behav. 23:681–685.

    Google Scholar 

  • Hobbs, W. R., Rall, T. W., and Verdoom, T. A. (1995). Hypnotics, sedatives: Ethanol. In Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W., and Gillman, A. G. (eds.), The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, pp. 361–396.

    Google Scholar 

  • Kaplan, S. A., and Jack, M. L. (1981). Pharmacokinetics and metabolism of anxiolytics. In Hoffmeister, F., and Stille, G. (eds.), Psychotropic Agents Part II: Anxiolytics, Gerontopsychopharmacological Agents and Psychomotor Stimulants, Springer-Verlag, New York, pp. 321–358.

    Google Scholar 

  • Klepner, C. A., Lippa, A. S., Benson, D. I., Sano, M. C., and Beer, B. (1979). Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors.Pharmacol. Biochem. Behav. 11:457–462.

    Google Scholar 

  • Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse.Psychopharmacology 92:180–185.

    Google Scholar 

  • Logan, L., Seale, T. W., and Carney, J. M. (1986). Inherent difference in response to methyl xanthines among inbred mouse strains.Pharmacol. Biochem Behav. 24:1281–1286.

    Google Scholar 

  • MacDonald, R. L., and Olsen, R. W. (1994). GABAAreceptor channels.Annu. Rev. Neurosci. 17:569–602.

    Google Scholar 

  • Marcucci, F., Guaitani, A., Kvetina, J., Mussini, E., and Garattini, S. (1968). Species difference in diazepam metabolism and anticonvulsant effect.Eur. J. Pharmacol. 4:467–470.

    Google Scholar 

  • Marley, R. J., Freund, R. K., and Wehner, J. M. (1988). Differential response to flurazepam in long-sleep and short-sleep mice.Pharmacol. Biochem. Behav. 31:453–458.

    Google Scholar 

  • Martin, B., Desforges, C., and Chapouthier, G. (1991). Comparison between patterns of convulsions induced by two beta-carbolines in 10 inbred strains of mice.Neurosci. Lett. 133:73–76.

    Google Scholar 

  • Mathis, C., Paul, S. M., and Crawley, J. N. (1994). Characterization of benzodiazepine-sensitive behaviors in the A/J and C57BL/6J inbred strains of mice.Behav. Genet. 24:171–180.

    Google Scholar 

  • Mathis, C., Neumann, P. E., Gershenfeld, H., Paul, S. M., and Crawley, J. N. (1995). Genetic analysis of anxiety-related behaviors and responses to benzodiazepine related drugs in AXB and BXA recombinant inbred mouse strains.Behav. Genet. 25:557–568.

    Google Scholar 

  • McIntyre, T. D., and Alpem, H. P. (1986). Thiopental, phenobarbital and chlordiazepoxide induce the same differences in narcotic reaction as ethanol in long-sleep and short-sleep selectively bred mice.Pharmacol. Biochem. Behav. 24:895–898.

    Google Scholar 

  • Möhler, H., and Okada, T. (1977). Benzodiazepine receptor: demonstration in the central nervous system.Science 198:849–851.

    Google Scholar 

  • Moser, P. C. (1989). An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone.Psychopharmacology 99:48–53.

    Google Scholar 

  • Pauwels, P. J., Van Gompel, P., and Leysen, J. E. (1993). Activity of serotonin (5-HT) receptor agonists, partial agonists and antagonists at cloned human 5-HT1A receptors that are negatively coupled to adenylate cyclase in permanently transfected HeLa cells.Biochem. Pharmacol. 45:375–383.

    Google Scholar 

  • Pellow, S., and File, S. E. (1986). Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plusmaze: A novel test of anxiety in the rat.Pharmacol. Biochem. Behav. 24:525–529.

    Google Scholar 

  • Pellow, S., Chopin, P., File, S. E., and Briley, M. (1985). Validation of open:closed arm entries in an elevated plusmaze as a measure of anxiety in the rat.J. Neurosci. Methods 14:149–167.

    Google Scholar 

  • Randall, L. O., Scheckel, C. L., and Banziger, R. F. (1965). Pharmacology of the metabolites of chlordiazepoxide and diazepam.Curr. Ther. Res. 7:590–606.

    Google Scholar 

  • Sanger, D. J., Benavides, J., Perrault, G., Morel, E., Cohen, C., Joly, D., and Zivkovic, B. (1994). Recent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: Evidence for the functional significance of receptor subtypes.Neurosci. Biobehav. Rev. 3:355–372.

    Google Scholar 

  • Seale, T. W., Abla, K. A., Roderick, T. H., Rennert, O. M., and Carney, J. M. (1987a). Different genes specify hyporesponsiveness to seizures induced by caffeine and the benzodiazepine inverse agonist, DMCM.Pharmacol. Biochem. Behav. 27:451–456.

    Google Scholar 

  • Seale, T. W., Carney, J. M., Flux, M., Rennert, O. M., and Skolnick, P. (1987b). Coincident susceptibility to seizures induced by caffeine and the benzodiazepine inverse agonist, DMCM, in SWR and CBA inbred mice.Pharmacol. Biochem. Behav. 26:381–387.

    Google Scholar 

  • Seale, T. W., Roderick, T., and Skolnick, P. (1987c). Ontogeny of susceptibility to the convulsant, RO 5–4864, and its relationship to audiogenic seizure susceptibility in inbred mice.Life Sci. 40:1267–1276.

    Google Scholar 

  • Seale, T. W., Abla, K. A., Shamin, M. T., Carney, J. M., and Daly, J. W. (1988). 3,7-Dimethyl-1-propargylxanthine: A potent and relative in vivo antagonist for adenosine analogs.Life Sci. 43:1671–1684.

    Google Scholar 

  • Seale, T. W., Niekrasz, I., and Garrett, K. M. (1996). Anxiolysis by ethanol, diazepam and buspirone in a novel murine behavioral assay.Neuroreport 7:1803–1808.

    Google Scholar 

  • Shader, R. I., and Greenblatt, D. J. (1993). Use of benzodiazepines in anxiety disorders.N. Engl. J. Med. 328:1398–1405.

    Google Scholar 

  • Squires, R. F., and Braestrup, C. (1977). Benzodiazepine receptors in rat brain.Nature 266:732–734.

    Google Scholar 

  • Study, R. E., and Barker, J. L. (1981). Diazepam and (−)-pentobarbital: Fluctuation analysis reveals different mechanisms for potentiation of γ-aminobutyric acid responses in cultured central neurons.Proc. Natl. Acad. Sci. USA 78:7180–7184.

    Google Scholar 

  • Sussman, N. (1993). Treating anxiety while minimizing abuse and dependence.J. Clin. Psychiat. 54(Suppl.):44–51.

    Google Scholar 

  • Suzuki, T., Lu, M. S., Montegi, M., Yoshii, T., and Misawa, M. (1992). Genetic differences in the development of physical dependence upon diazepam in Lewis and Fisher 344 inbred rat strains.Pharmacol. Biochem. Behav. 43:387–393.

    Google Scholar 

  • Toubas, P. L., Abla, K. A., Cao, W., and Seale, T. W. (1990). Latency to enter a mirrored chamber: A novel behavioral assay for anxiolytic agents.Pharmacol. Biochem. Behav. 35:121–126.

    Google Scholar 

  • Trullas, R., and Skolnick, P. (1993). Differences in fear motivated behaviors among inbred mouse strains.Psychopharmacology 111:323–331.

    Google Scholar 

  • Van der Laan, J. W., de Boer, S. F., Van der Gugten, J., and de Groot, G. (1991). Differences in the duration of sedative and anxiolytic effects of desmethyl diazepam in two outbred Wistar strains.Pharmacol. Biochem. Behav. 39:149–153.

    Google Scholar 

  • Woods, S. W., and Charney, D. S. (1988). Benzodiazepines. A review of benzodiazepine treatment of anxiety disorders: pharmacology, efficacy and implications for pathophysiology. In Last, C. G., and Hersen, M. (eds.), Handbook of Anxiety Disorders, Pergamon Press, New York, pp. 413–444.

    Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, USA

    Kennon M. Garrett & Dewan Haque

  2. Department of Pediatrics, USA

    Iwona Niekrasz

  3. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 73190

    K. Michael Parker

  4. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 73190

    Thomas W. Seale

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  1. Kennon M. Garrett
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Garrett, K.M., Niekrasz, I., Haque, D. et al. Genotypic Differences Between C57BL/6 and A Inbred Mice in Anxiolytic and Sedative Actions of Diazepam. Behav Genet 28, 125–136 (1998). https://doi.org/10.1023/A:1021424108213

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