Acute and subchronic benzodiazepine-barbiturate-interactions on behaviour and physiological responses of the mouse

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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.