Antidepressants and protein kinases: desipramine treatment affects pineal gland cAMP-dependent protein kinase activity.

To further describe the molecular mechanisms involved in reductions in noradrenergic responsiveness induced by antidepressants, the effects of antidepressant treatment on the rat pineal gland cAMP-dependent protein kinase system were examined. The concentration of cyclic AMP-dependent protein kinase activity was reduced 24 h after acute treatment with desipramine, as well as in animals treated repeatedly with desipramine. Assays performed in the presence of cAMP protein kinase inhibitor showed no significant effects of either acute or repeated desipramine treatment on the concentration of cAMP-independent protein kinase activity. Neither acute nor repeated treatment with other antidepressants (zimelidine, iprindole or fluoxetine) significantly altered the concentration of cAMP-dependent or cAMP-independent protein kinase activity. Using activity ratios to judge the extent of activation of cAMP-dependent protein kinase in vivo, it was found that isoproterenol-induced increases in cAMP protein kinase activity were similar in control and acutely-treated animals, but were reduced with repeated desipramine treatment. The extent of protein kinase activation was also elevated by both acute and repeated treatment in the absence of isoproterenol. In further studies, desipramine (10 microM) did not directly affect activation of the kinase by cAMP or maximum kinase catalytic activity. These results show that the concentration and extent of activation of cAMP protein kinase is altered following desipramine treatment in the rat pineal gland and that modulation of cAMP protein kinase may be a locus of regulation for desipramine-mediated reduction in noradrenergic responsiveness.