Abstract
Female NMRI mice were pretreated for 2 weeks with diazepam (D: 20 mg/kg/day), secobarbital (S: 23 mg/kg/day), or combination (D+S: 19 mg/kg/day, each) by means of the drinking fluid. A fourth group remained untreated. One day after this period the mice received an i.p. injection of one out of 16 drug combinations (crossover design: 0, 2, 4, 6 mg/kg D combined with 0, 6, 12, 18 mg/kg S). Open field behaviour, motor performance, and rectal body temperature were measured.
In non-pretreated animals, D and S induced immobility, impairment of coordination and hypothermia in a dose-dependent manner. Excitation appeared after low doses of D (2 mg/kg) and high doses of S (12–18 mg/kg). Acute interactions between D and S were studied by means of isobolographic analysis. Dose-additivity indicating a common mechanism of action was confirmed for immobility, impairment of coordination, and hypothermia whereas excitation revealed a non-additive interaction and was reduced after combined administrations. After chronic pretreatment, the mode of acute drug interaction (dose-additive and non-additive, resp.) remained unchanged. Shifts of the isoboles indicated tolerance, cross-tolerance or sensitization. There was an asymmetry concerning the pretreatment with D and S. Chronic administration of D induced a tolerance to D in regard to all responses and a sensitization to S-effected motor incordination. Chronic administration of S sensitized the sedative and hypothermic responses to acute D. Metabolic tolerance could not account for the subchronic effects since distinct functional responses were concerned in different ways.
The results support the hypothesis that in spite of a partially common mechanism of acute action, chronic adaptation at the GABAA-receptor is differently mediated by barbiturates and benzodiazepines according to regionally and functionally distinct patterns. Excitation contrasts with all the other behavioural of responses. The isoboles indicate separate mechanisms for D and S without any relationship to the sedative effects of the drugs.
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References
Bodnoff SR, Suranyi-Cadotte BE, Quirion R, Meaney MJ (1989) Role of the central benzodiazepine receptor system in behavioral habituation to novelty. Behav Neuroscience 103:209–212
Coper H, Rommelspacher H, Wolffgramm J (1990) The ‘point of no return’ as a target of experimental research on drug dependence. Drug Alcohol Depend 25:129–134
Downes H, Perry RS, Ostlund RE, Karler R (1970) A study of the excitatory effects of barbiturates. J Pharmacol Exp Ther 175:692–699
Gerischer C (1990) Environmental interactions to excitation and sedation in mice after application of diazepam, caffeine and combinations. Naunyn Schmiedebergs Arch Pharmacol (Suppl) 341:R101
Harris RA (1990) Distinct actions of alcohol, barbiturates and benzodiazepines on GABA-activated chloride channels. Alcohol 7: 273–275
Heninger C, Gallager DW (1988) Altered gamma-aminobutyric acid/benzodiazepine interaction after chronic diazepam exposure. Neuropharmacology 27:1073–1076
Heyne A, Wolffgramm W (1990) Avoidance behavior against an anxiogenic stimulus: interaction between social deprivation and anxiolysis. In: Elsner N, Roth G (eds) Brain — perception — cognition. Thieme, Stuttgart, p 442
Ho IK, Yu S (1991) Effects of barbiturates on GABA system: comparison to alcohol and benzodiazepines. Keio J Med 40:183–186
Hu WY, Reiffenstein RJ, Wong L (1986) Interaction between flurazepam and ethanol. Alcohol Drug Res 7:107–117
Kalant H (1977) Comparative aspects of tolerance to, and dependence on, alcohol, barbiturates and opiates. In: Gross MM (ed) Alcohol intoxication and withdrawal III. Plenum Press, New York, pp 169–186
Khanna JM, Le AD, Gougos A, Kalant H (1988) Effects of chronic pentobarbital treatment on the development of cross-tolerance to ethanol and barbital. Pharmacol Biochem Behav 31:179–186
van der Kleijn E, van Rossum JM, Muskens ETJM, Rijntjes NVM (1971) Pharmacokinetics of diazepam in dogs, mice and humans. Acta Pharmacol Toxicol 29, Suppl 3:109–127
Le AD, Khanna JM, Kalant H, Grossi F (1986) Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide. Pharmacol Biochem Behav 24:88–98
Loewe S, Muischnek H (1926) Über Kombinationswirkungen. 1. Mitteilung: Hilfsmittel der Fragestellung. Naunyn Schmiedebergs Arch Exp Path Pharmakol 114:313–326
Marley RJ, Gallager DW (1989) Chronic diazepam treatment produces regionally specific changes in GABA-stimulated chloride influx. Eur J Pharmacol 159:217–223
Massotti M, Schlichting JL, Antonacci MD, Giusti P, Memo M, Costa E, Guidotti A (1991) Gamma-aminobutyric acidA receptor heterogeneity in rat central nervous system: studies with clonazepam and other benzodiazepine ligands. J Pharmacol Exp Ther 256: 1154–1160
Miller LG, Greenblatt DJ, Barnhill JG, Shader RT (1988) Chronic benzodiazepine administration. I. Tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. J Pharmacol Exp Ther 246:170–176
Miller LG, Woolverton S, Greenblatt DJ, Lopez F, Roy RB, Shader RI (1989) Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration. Biochem Pharmacol 38:3773–3777
Mitchell CL (1976) The design and analysis of experiments for the assessment of drug interactions. Ann NY Acad Sci 281:118–135
Morrow AL, Montpied P, Lingford-Hughes A, Paul SM (1990) Chronic ethanol and pentobarbital administration in the rat: effects on GABAA receptor function and expression in the brain. Alcohol 7:237–244
Ngur DO, Rosenberg HC, Chiu TH (1990) Modulation of GABA-stimulated Cl− flux by a benzodiazepin agonist and an ‘inverse agonist’ after chronic flurazepam treatment. Eur J Pharmacol 176:351–356
Phillips TJ, Gallager EJ (1992) Locomotor responses to benzodiazepines, barbiturates and ethanol in diazepam-sensitive (DS) and -resistant (DR) mice. Psychopharmacology (Berlin) 107:125–131
Ramsey VA, Tietz EI, Rosenberg HC (1991) Chronic flurazepam differentially regulates a behavioral effect of GABA agonists. Pharmacol Biochem Behav 38:659–663
Rommelspacher H, Wolffgramm J, Widjaja S (1989) Effects of desipramine on rat behavior are prevented by concomitant treatment with ethanol. Pharmacol Biochem Behav 32:533–542
Saunders PA, Ho Y, Baker ML, Hume AS, Ho IK (1990) Pentobarbital tolerance and withdrawal: correlation with effects on the GABAA receptor. Pharmacol Biochem Behav 37:343–348
Schütz H (1986) Dünnschichtchromatographische Suchanalyse für 1,4 Benzodiazepine in Harn, Blut und Mageninhalt. VCH Verlagsgesellschaft, Weinheim, Germany
Sigel E, Baur R, Trube G, Mohler H, Malherbe P (1990) The effect of subunit composition of rat brain GABAA receptors on channel function. Neuron 5:703–711
Trullas R, Havoundjian H, Zamir N, Paul S, Skolnick P (1987) Environmentally-induced modification of the benzodiazepine/GABA receptor coupled chloride ionophore. Psychopharmacology (Berlin) 91:348–390
Unkelbach HD, Pöch G (1988) Comparison of independence and additivity in drug combinations. Arzneim Forschg/Drug Res 38:1–6
Unkelbach HD, Wolf T (1984) Drug combinations-concepts and terminology. Arzneim Forschg/Drug Res 34:935–936
Wessinger WD (1986) Approaches to the study of drug interactions in behavioral pharmacology. Neurosci Biobehav Rev 10:103–113
Wolffgramm J (1991) An ethopharmacological approach to the development of drug addiction. Neurosci Biobehav Rev 15:515–519
Wolffgramm J, Lechner J, Coper H (1988) Interaction of two barbiturates and an antihistamine on body temperature and motor performance of mice. Arzneim Forschg/Drug Res 38:885–891
Wolffgramm J, Rommelspacher H, Buck E (1990) Ethanol reduces tolerance, sensitization and up-regulation of D2-receptor after subchronic haloperidol. Pharmacol Biochem Behav 36:907–914
Yu O, Chiu TH, Rosenberg HC (1988) Modulation of GABA-gated chloride ion flux in rat brain by acute and chronic benzodiazepine administration. J Pharmacol Exp Ther 246:107–113
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Correspondence to: J. Wolffgramm at the above address
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Wolffgramm, J., Mikolaiczyk, C. & Coper, H. Acute and subchronic benzodiazepine-barbiturate-interactions on behaviour and physiological responses of the mouse. Naunyn-Schmiedeberg's Arch Pharmacol 349, 279–286 (1994). https://doi.org/10.1007/BF00169294
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DOI: https://doi.org/10.1007/BF00169294