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.
Similar content being viewed by others
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.
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.
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.
Cooper, S. J. (1985). Bidirectional control of palatable food consumption through a common benzodiazepine receptor: Theory and evidence.Brain Res. Bull. 15:397–410.
Crabbe, J. C., and Belknap, J. K. (1992). Genetic approaches to drug dependence.Trends Neurosci. 13:212–219.
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.
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.
Eison, A. S., and Eison, M. S. (1994). Serotonergic mechanisms in anxiety.Prog. Neuro-Psychopharmacol. Biol. Psychiatry 18:47–62.
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.
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.
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.
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.
Greenblatt, D. J., Shader, R. I., and Abernethy, D. R. (1983). Drug therapy. Current status of benzodiazepines.N. Engl. J. Med. 309:410–416.
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.
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.
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.
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.
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.
Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse.Psychopharmacology 92:180–185.
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.
MacDonald, R. L., and Olsen, R. W. (1994). GABAAreceptor channels.Annu. Rev. Neurosci. 17:569–602.
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.
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.
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.
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.
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.
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.
Möhler, H., and Okada, T. (1977). Benzodiazepine receptor: demonstration in the central nervous system.Science 198:849–851.
Moser, P. C. (1989). An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone.Psychopharmacology 99:48–53.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Shader, R. I., and Greenblatt, D. J. (1993). Use of benzodiazepines in anxiety disorders.N. Engl. J. Med. 328:1398–1405.
Squires, R. F., and Braestrup, C. (1977). Benzodiazepine receptors in rat brain.Nature 266:732–734.
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.
Sussman, N. (1993). Treating anxiety while minimizing abuse and dependence.J. Clin. Psychiat. 54(Suppl.):44–51.
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.
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.
Trullas, R., and Skolnick, P. (1993). Differences in fear motivated behaviors among inbred mouse strains.Psychopharmacology 111:323–331.
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.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1023/A:1021424108213