The initial aim is to continue to define the pharmacologic factors which govern the development of functional (cellular) and dipositional (metabolic) tolerance to and physical dependence on sedative-hypnotic drugs. Our reference standard barbiturate animal model has enabled us to determine the effects of altering (a) the level of chronic dosing (b) the frequency and (c) the duration of drug administration. We will focus on the frequency of drug administration relative to its elimination half-life in order to rationally design chronic sedative-hypnotic dosing regimens which minimize the risks of producing functional tolerance and physical dependence. Tolerance and physical dependence produced by benzodiazepine (initially diazepam) chronic dosing methods which are """"""""chronically equivalent"""""""" to our """"""""low"""""""" dose barbiturate will be characterized and compared to their ethanol and barbiturate dependence. We will continue our studies of the effects of chronic barbiturates, ethanol and benzodiazepines (initially diazepam, later triazolum) on normal sleep cycles.
The aim i s to further refine the criteria for optimal chronic dosing schedules in order to minimize hypnotic tolerance, withdrawal insomnia and REM rebound. Functional tolerance will be further characterized in our reference standard barbiturate model: (a) the cardiorespiratory center of the intermediate zone of the ventral surface of the medulla in situ to evaluate the development of functional tolerance to respiratory depression produced by barbiturate (b) the spinal segmental reflex system to study the time course of development of the loss of inhibitory mechanisms, in particular Renshaw cell recurrent inhibition. (c) Using global behavioral measures of CNS depression, we will continue our quantitative analysis of cross-tolerance between barbiturate and ethanol. The time course of recovery from dispositional and functional tolerance will be studied by extensive pharmacokinetic and concentration-response studies in vivo and also in vitro using microsomal oxydative enzyme activity measurements in sequentially biopsied liver samples. Neurophysiologic alterations during withdrawal will be examined in segmental reflex pathways which have been chronically decentralized by spinal section at the T4 level in rats made physically dependent on barbiturate and ethanol. We will investigate the ability of steroid anesthetics to suppress the barbiturate and ethanol. We will investigate the ability of steroid anesthetic to suppress the bartiburate withdrawal syndrome in our animal model. Ultimately we will expand this phase of the study by monitoring changes in the HYPAC system (ACTH and adrenalcorticoid activities) and in circadian rhythms (in relation to sleep) caused by chronic barbiturate treatment and withdrawal.
| Okamoto, M; Rao, S N; Aaronson, L M et al. (1985) Ethanol drug interaction with chlordiazepoxide and pentobarbital. Alcohol Clin Exp Res 9:516-21 |
| Okamoto, M; Rao, S N; Reyes, J et al. (1985) Recovery from dispositional and pharmacodynamic tolerance after chronic pentobarbital treatment. J Pharmacol Exp Ther 235:26-31 |
