Release of norepinephrine in the central nervous system by theophylline and caffeine

Abstract

The effect of caffeine and theophylline on the disposition of brain norepinephrine was studied. Neither drug changed the endogenous concentration of norepinephrine in the rat brain following acute or chronic administration. However, both lowered the concentration of norepinephrine following inhibition of norepinephrine synthesis with alpha-methyltyrosine or 5-hydroxy-alpha-methyltryptophan. In the guinea-pig caffeine either alone or following blockade of norepinephrine synthesis lowered brainstem norepinephrine levels. Following inhibition of monoamine oxidase in the rat, theophylline and to a lesser extent caffeine elevated brainstem norepinephrine levels while theobromine was without effect. Caffeine increased brainstem norepinephrine synthesis in the guinea-pig. The data were consistent with the conclusion that caffeine and theophylline can release norepinephrine and suggest consideration of an adrenergic component in examining their effects. There was no correlation between release of norepinephrine in brain and central nervous system stimulation. Large or multiple doses of caffeine which by themselves produced little effect, resulted in marked hyperthermia and increased toxicity when given in combination with a monoamine oxidase inhibitor.