Influence of acute and chronic treatment with desmethylimipramine on catecholamine effects in the rat

The effects of acute and chronic administration of desmethylimipramine (DMI) on the biochemical actions of catecholamines in rat brain, heart and diaphragm were studied. Single injections of DMI (10 mg/kg I.P.) did not affect either the basal synthesis of cyclic [³H]AMP or the norepinephrine-induced elevation of the nucleotide in rat brain slices. The increase in cardiac phosphorylase A caused by isoproterenol was also not altered by 1-day pretreatment with DMI. In contrast, administration of DMI (10 mg/kg, two times daily) for 7 or 10 days reduced the synthesis of either cyclic [³H]AMP or endogenous cyclic AMP stimulated by norepinephrine in rat brain slices. Chronic treatment of rats with DMI reduced the activation of phosphorylase A by isoproterenol in rat hearts, but pretreatment with DMI diminished neither the positive inotropic effect nor the increase in cyclic AMP produced by the amine. In rat diaphragm, which lacks sympathetic innervation, the activation of phosphorylase A produced by catecholamines was not diminished by chronic treatment of the animals with DMI. It is proposed that the increased biochemical response to catecholamines in rat brain may be due to the development of adrenergic receptor subsensitivity caused by chronic injection of DMI. In heart, however, the diminished phosphorylase A activation seen with chronic DMI treatment may be due to a different mechanism.