The aim is to continue to define the adverse reactions produced by the chronic use of sedative-hypnotics or ethanol. Our reference standard animal model, developed in our laboratory, has enabled us to determine the pharmacologic factors which govern the production of tolerance and physical dependence; (1) the level of chronic dosing, (2) the frequency of drug administration in relation to the elimination half-life and (3) the duration of drug administration. These results formulated the chronic dosing schedule which leads to minimal risk in producing tolerance and physical dependence to sedative-hypnotics. We now propose to investigate the more subtle biological responses which are produced by the less intense chronic barbiturate or ethanol treatments. The treatment schedules have been developed to produce minimal to no overt behavioral withdrawal signs upon abrupt termination of the drug. Subtle responses will be monitored by EEG and sleep patterns; i.e. analysis of NREM and REM sleep along with any behavioral abnormality. The hypothalamic temperature regulatory center has been implicated as an important center for the production of normal sleep. We will investigate the alteration in the ultradian and circadian type CNS temperature rhythm at preoptic area in relation to the production of sleep, insomnia, and NREM-REM rebound. Hypothalamic pituitary adrenocorticol function is altered by chronic barbiturates and ethanol treatment. We investigate the effects of chronic barbiturates and ethanol and their withdrawal on corticotropine releasing hormone, ACTH and cortisol during the treatment and withdrawal, relative to the time course of other responses. Central and peripheral contributions on the overall drug withdrawal reaction have not been dissociated. Contribution by adrenocorticoids was significant in the overall expression of overt behavioral withdrawal in our experiment. Accordingly, we investigate the effects of cortexlone, cortisol receptor blockers and pregnenedione on behavior, EEG and sleep patterns, and how they are altered by these pharmacologic manipulations. We study the pattern changes of the biogenic amine system from the sequentially sampled from CSF and plasma concurrently with behavior and sleep. Norepinephrine, epinephrine, dopamine, 5-OH triptamine, their precursors and metabolites will be quantitated by HPLC with an EC detector system. Past results are inconclusive and not correlated in time with the behavioral and/or physiological measurements expressed during drug withdrawal. Our results incidate distinct time related phasic responses for recovery of each.
| 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 |
