Cyclic AMP Phosphodiesterase Activity in Rat Brain Following Chronic Treatment with Lithium, Imipramine, Reserpine, and Combinations of Lithium with Imipramine or Reserpine

Abstract

The adaptability of the cAMP phosphodiesterase (PDE) following chronic treatment (4-6 wk) with Li, reserpine, imipramine, and combinations of Li with imipramine or reserpine was studied in rat brain tissue. All drugs except Li were given i.p. once a day. Control animals received only vehicle. Li was given in the diet in a concentration yielding a plasma level of 0.5-0.6 mmol/l. The PDE activity was measured in homogenates from cerebral cortex and limbic forebrain. These 2 brain areas both contained 3 types of PDE activity. One was mainly associated with the pellet after a 10,000 .times. g centrifugation for 10 min. This enzyme hydrolyzed both cAMP and cGMP with a Km value of 130 .+-. 48 .mu.M for cAMP but was insensitive to Ca and calmodulin. Two types were mainly found in the supernatant after the centrifugation with Km values for cAMP of 300 .+-. 108 .mu.M and 4 .+-. 3 .mu.M, respectively. The former hydrolyzed both cAMP and cGMP and was stimulated 7-fold by Ca and calmodulin, while the latter only hydrolyzed cAMP and was insensitive to Ca and calmodulin. None of the treatments affected the pellet enzyme or the low affinity enzyme from the supernatant. Li treatment, even combined with reserpine or imipramine, increased the high affinity enzyme. This increase was also apparent in the DEAE-ion exchange chromatographic profile of the PDE enzymes.