BARBITONE-INDUCED TOLERANCE TO THE EFFECTS OF SEDATIVE-HYPNOTICS AND RELATED COMPOUNDS ON OPERANT-BEHAVIOR IN THE RAT

Pretreatment doses of barbitone, pentobarbitone, ethanol, and phenytoin (diphenylhydantoin) in non‐tolerant rats produced increases in operant responding at low doses and at higher doses resulted in decreases in responding. Daily barbitone injections (100 mg/kg, i.p.) resulted in the development of functional tolerance to both the stimulant and depressant effects of barbitone on responding. Barbitone tolerance development did not result in any change in the brain or plasma pharmacokinetics of barbitone. Barbitone‐tolerant rats were cross‐tolerant to the behavioural effects of pentobarbitone, ethanol, and phenytoin. The dose‐effect curves for all of these drugs were shifted to the right in tolerant rats, compared to non‐tolerant rats. Comparison of the brain and plasma levels of these drugs in non‐tolerant and tolerant rats provided a means of separating functional cross‐tolerance from dispositional cross‐tolerance. Barbitone‐tolerant rats appeared to be functionally cross‐tolerant to ethanol in that there was no change in the brain and blood ethanol levels at times when the degree of behavioural impairment was substantially reduced. In contrast to ethanol, cross‐tolerance to phenytoin appeared to be due to a decrease in the brain and plasma levels (dispositional tolerance). Cross‐tolerance to pentobarbitone appeared to be comprised of both functional and dispositional cross‐tolerance. The usefulness of a multidisciplinary approach in the analysis of sedative hypnotic tolerance and cross‐tolerance is discussed. It is concluded that without the concurrent determination of both brain and plasma drug levels it would not be possible to distinguish between functional and dispositional tolerance. 1979 British Pharmacological Society