Tranquilizers and antidepressants were investigated for their effect on the glycogen phosphorylase (α-1,4-glucan: orthophosphate glucosyltransferase; EC 2.4.1.1) activity of rat brain after sacrificing the animal with liquid nitrogen. The tranquilizers consisted of reserpine and four phenothiazines. Isoreserpine and promethazine, both not considered tranquilizers, were included as controls. All tranquilizers except prochlorperazine depressed the phosphorylase activity. The controls did not affect the phosphorylase level. A tentative explanation for the lack of effect of prochlorperazine is given. The antidepressants consisted of: two monoamine oxidase inhibitors, pargyline and iproniazid; a tricyclic antidepressant, desmethylimipramine; and a psychic stimulant, amphetamine. The antidepressants acted counter to tranquilizers, i.e. they enhanced the absolute or relative level of phosphorylase activity. However, the enhancing effect was best observed when rats were treated with reserpine before or after the drug. A unified explanation for the effect of most of both tranquilizers and antidepressants on the phosphorylase activity is given, based on a reasonable mode of action and a postulate stating that the phosphorylase activity is correlated with the availability of norepinephrine at the adrenergic receptor sites. These facts suggest that the phosphorylase activity of brain may be a barometer for CNS adrenergic activity. The results suggest that the glycogen phosphorylase of brain may be involved in actions of many drugs used as tranquilizers and antidepressants.