Interactions of tricyclic antidepressants and barbiturates in barbiturate-tolerant and nontolerant rats.

Pretreatment of rats with tricyclic antidepressants, imipramine, desipramine, amitriptyline and nortriptyline, at two doses (5 and 25 mg/kg) 20 minutes before administration of barbiturate markedly reduced the latent period of the response to barbital and prolonged the sleeping time induced by pentobarbital (PB) and barbital. The effects were dose-dependent. The prolonged sleeping time produced by PB was associated with decreases in the rates of disappearance of PB from the brain and plasma. The effect of tricyclic antidepressants on PB hypnosis in PB-tolerant and nontolerant rats was apparently not related to change in central nervous system (CNS) sensitivity to PB, since at the time of awakening there were no significant differences in the concentrations of unmetabolized PB in either the plasma or brain of tricyclic antidepressant-treated animals as compared to controls. As barbital is not metabolized, potentiation of barbital hypnosis by tricyclic antidepressants must be attributable to a direct effect on CNS rather than on liver microsomal enzymes. Direct evidence was provided by the findings that amitriptyline accelerated the brain uptake of barbital and that amitriptyline-treated animals lost and recovered the righting reflex at brain barbital levels lower than those of controls. Rats made tolerant to the hypnotic effect of barbital also became tolerant, in varying degrees, to the hyposis-prolonging properties of tricyclic antidepressants. It is concluded that tricyclic antidepressants prolong PB sleeping time in PB-tolerant and nontolerant rats by inhibiting its biotransformation in the liver. The action of tricyclic antidepressants to prolong the hypnotic action of barbital in normal rats is related to their direct effects on CNS sensitivity to barbital, but such effects are makedly diminished after animals become tolerant to barbital.