Psychopharmacology

, Volume 107, Issue 1, pp 125–131 | Cite as

Locomotor responses to benzodiazepines, barbiturates and ethanol in diazepam-sensitive (DS) and -resistant (DR) mice

  • Tamara J. Phillips
  • Edward J. Gallaher
Original Investigations

Abstract

Diazepam-sensitive (DS) and -resistant (DR) mice were selectively bred for increased and reduced sensitivity to the ataxic effects of diazepam (40 mg/kg). Other response differences between DS and DR mice may reflect pleiotropic effects of the genes fixed during their selection. These mice were tested for their sensitivity to the locomtor stimulant effects of several doses of diazepam, flunitrazepam, pentobarbital, phenobarbital, and ethanol. DR mice were more sensitive than DS mice to the locomotor stimulant effects of all drugs except phenobarbital. These results largely support the hypothesis that a common biological mechanism mediates sensitivity to the stimulant effects of sedative-hypnotic drugs. Receptor mediation of the benzodiazepine effects was examined by administering the benzodiazepine receptor antagonist, RO15-1788. Locomotor depression produced by diazepam and flunitrazepam in DS mice was blocked by RO15-1788. However, while the locomotor stimulation produced by diazepam in DR mice was antagonized, the stimulant effect of flunitrazepam was not. This suggests that binding of flunitrazepam to the GABAA-benzodiazepine receptor is not necessary for production of locomotor stimulation.

Key words

DS mice DR mice Selective breeding Locomotor stimulation Benzodiazepines Alcohol Ethanol Barbiturates 

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References

  1. Ahtee L, Shillito E (1970) The effect of benzodiazepines and atropine on exploratory behaviour and motor activity of mice. Br J Pharmacol 40:361–371Google Scholar
  2. Allan AM, Gallaher EJ, Gionet SE, Harris RA (1988) Genetic selection for benzodiazepine ataxia produces functional changes in the gamma-aminobutyric acid receptor chloride channel complex. Brain Res 452:118–126Google Scholar
  3. Benuck M, Lajtha A, Reith MEA (1987) Pharmacokinetics of systemically administered cocaine and locomotor stimulation in mice. J Pharmacol Exp Ther 243:144–149Google Scholar
  4. Bushnell PJ (1986) Differential effects of amphetamine and related compounds on locomotor activity and metabolic rate in mice. Pharmacol Biochem Behav 25:161–170Google Scholar
  5. Clarke PBS, Jakubovic A, Fibiger HC (1988) Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions ofd-amphetamine and apomorphine. Psychopharmacology 96:511–520Google Scholar
  6. Crabbe JC (1983) Sensitivity to ethanol in inbred mice: genotypic correlations among several behavioral responses. Behav Neurosci 97:280–289Google Scholar
  7. Crabbe JC (1986) Genetic differences in locomotor activation in mice. Pharmacol Biochem Behav 25:289–292Google Scholar
  8. Crabbe JC, Young ER, Deutsch CM, Tam BR, Kosobud A (1987) Mice genetically selected for differences in open-field activity after ethanol. Pharmacol Biochem Behav 27:577–581Google Scholar
  9. Crabbe JC, Phillips TJ, Kosobud A, Belknap JK (1990) Estimation of genetic correlation: interpretation of experiments using selectively bred and inbred animals. Alcohol Clin Exp Res 14:141–151Google Scholar
  10. Crawley JN, Davis LG (1982) Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains. Brain Res Bull 8:609–612Google Scholar
  11. Dudek BC, Fanelli RJ (1980) Effects of gamma-butyrolactone, amphetamine, and haloperidol in mice differing in sensitivity to alcohol. Psychopharmacology 68:89–97Google Scholar
  12. Dudek BC, Phillips TJ (1983) Locomotor stimulant and intoxicant properties of methanol, ethanol, tertiary butanol and pentobarbital in Long-Sleep and Short-Sleep mice. Subst Alcohol Actions/Misuse 4:31–36Google Scholar
  13. Dudek BC, Phillips TJ (1990) Distinctions among sedative, disinhibitory, and ataxic properties of ethanol in inbred and selectively bred mice. Psychopharmacology 101:93–99Google Scholar
  14. Dudek BC, Phillips TJ, Hahn ME (1991) Genetic analyses of the biphasic nature of the alcohol dose-response curve. Alcohol Clin Exp Res 15:262–269Google Scholar
  15. File SE, Pellow S (1985) No cross-tolerance between the stimulatory and depressant actions of benzodiazepines in mice. Behav Brain Res 17:1–7Google Scholar
  16. File SE, Wilks LJ (1990) Effects of sodium phenobarbital on motor activity and exploration in the mouse: development of tolerance and incidence of withdrawal responses. Pharmacol Biochem Behav 35:317–320Google Scholar
  17. File SE, Wilks LJ, Mabbutt PS (1989) The role of the benzodiazepine receptor in mediating long-lasting anticonvulsant effects and the late-appearing reductions in motor activity and exploration. Psychopharmacology 97:349–354Google Scholar
  18. Frye GD, Breese GR (1981) An evaluation of the locomotor stimulating action of ethanol in rats and mice. Psychopharmacology 75:372–379Google Scholar
  19. Gallaher EJ, Gionet SE (1988) Initial sensitivity and tolerance to ethanol in mice genetically selected for diazepam sensitivity. Alcohol Clin Exp Res 12:77–80Google Scholar
  20. Gallaher EJ, Hollister LE, Gionet SE, Crabbe JC (1987) Mouse lines selected for genetic differences in diazepam sensitivity. Psychopharmacology 93:25–30Google Scholar
  21. Gwynn GJ, Domino EF (1984) Genotype-dependent behavioral sensitivity to mu vs. kappa opiate agonists. I. Acute and chronic effects on mouse locomotor activity. J Pharmacol Exp Ther 231:306–311Google Scholar
  22. Imperato and Di Chiara (1986) Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. J Pharmacol Exp Ther 239:219–228Google Scholar
  23. Keppel G (1973) Design and analysis. A researcher's handbook. Prentice-Hall New JerseyGoogle Scholar
  24. Kitahama K, Valatx J-L (1979) Strain differences in amphetamine sensitivity in mice. I. A diallel analysis of open field activity. Psychopharmacology 66:189–194Google Scholar
  25. McClearn GE, Kakihana R (1981) Selective breeding for ethanol sensitivity: Short-Sleep and Long-Sleep mice. In: McClearn GE, Deitrich RA, Erwin VG (eds) Development of animal models as pharmacogenetic tools. NIAAA Research Monograph-6, US Govt. Printing Office, Washington, DC, pp 147–159Google Scholar
  26. Moskowitz AS, Terman GW, Carter KR, Morgan MJ, Liebeskind JC (1985) Analgesic, locomotor and lethal effects of morphine in the mouse: strain comparisons. Brain Res 361:46–51Google Scholar
  27. Phillips TJ, Gallaher EJ (1988) Ethanol and diazepam effects on locomotor activity in mice selectively bred for diazepam sensitivity. In: Kuriyama K, Takada A, Ishii H (eds) Biomedical and social aspects of alcohol and alcoholism. Elsevier, The Netherlands, pp 251–254Google Scholar
  28. Phillips TJ, Feller DJ, Crabbe JC (1989) Selected mouse lines, alcohol and behavior. Experientia 45:805–827Google Scholar
  29. Phillips TJ, Burkhart-Kasch S, Terdal ES, Crabbe JC (1991a) Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization. Psychopharmacology 103:557–566Google Scholar
  30. Phillips TJ, Burkhart-Kasch S, Gwiazdon CC, Crabbe JC (1992b) Acute sensitivity of FAST and SLOW mice to the effects of abused drugs on locomotor activity. J Pharmacol Exp Ther (in press)Google Scholar
  31. Ruth JA, Ullman EA, Collins AC (1988) An analysis of cocaine effects on locomotor activities and heart rate in four inbred mouse strains. Pharmacol Biochem Behav 29:157–162Google Scholar
  32. Saito H (1990) Inhibitory and stimulatory effects of morphine on locomotor activity in mice: biochemical and behavioral studies. Pharmacol Biochem Behav 35:231–235Google Scholar
  33. Sanders B, Sharpless SK, Collins AC, McClearn GE, Flanagan C (1978) Activating and anesthetic effects of general depressants. Psychopharmacology 56:185–189Google Scholar
  34. Soderpalm B, Svensson L, Hulthe P, Johannessen K, Engel JA (1991) Evidence for a role for dopamine in the diazepam locomotor stimulating effect. Psychopharmacology 104:97–102Google Scholar
  35. Swerdlow NR, Koob GF (1985) Separate neural substrates of the locomotor-activating properties of amphetamine, heroin, caffeine and corticotropin releasing factor (CRF) in the rat. Pharmacol Biochem Behav 23:303–307Google Scholar
  36. Tang M, Lau CE, Falk JL (1988) Midazolam and discriminative motor control: chronic administration, withdrawal and modulation by the antagonist RO15-1788. J Pharmacol Exp Ther 246:1053–1060Google Scholar
  37. Vaccarino FJ, Amalric M, Swerdlow NR, Koob GF (1986) Blockade of amphetamine but not opiate-induced locomotion following antagonism of dopamine function in the rat. Pharmacol Biochem Behav 24:61–65Google Scholar
  38. Vetulani J, Pavone F, Battaglia M, Sansone M (1989) Pentobarbital-induced hyperactivity in mice: negligible role of opioid mechanisms. Pharmacol Biochem Behav 33:927–929Google Scholar
  39. Wee BEF, Turek FW (1989) Midazolam, a short-acting benzodiazepine, resets the circadian clock of the hamster. Pharmacol Biochem Behav 32:901–906Google Scholar
  40. Wenger GR (1986) Behavioral effects of the isomers of pentobarbital and secobarbital in mice and rats. Pharmacol Biochem Behav 25:375–380Google Scholar
  41. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Tamara J. Phillips
    • 1
  • Edward J. Gallaher
    • 1
  1. 1.Research Service, VA Medical Center, and Departments of Medical Psychology and PharmacologyOregon Health Sciences UniversityPortlandUSA

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