Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms

The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4 B, and PDE4D) was examined. The treatments tested included representatives of four major classes of antidepressants: selective reuptake inhibitors of serotonin (sertraline and fluoxetine) or norepinephrine (desipramine), a mo noamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Expression of PDE4A and PDE4B, but not PDE4D, mRNA and immunoreactivity we re significantly increased in rat frontal colter by chronic administration of each of the four classes of antidepressants. We also found that antidepr essant administration significantly increased the expression of PDE4B mRNA in the nucleus accumbens, a brain region thought to mediate pleasure and re ward that could also contribute to the anhedonia often observed in depresse d patients. In contrast, expression of PDE4A and PDE4B were not influenced by short-term treatment (1 or 7 d) and were not influenced by chronic admin istration of nonantidepressant psychotropic drugs (cocaine or haloperidol), demonstrating the time dependence and pharmacological specificity of these effects. Upregulation of PDE4A and PDE4B may represent a compensatory resp onse to antidepressant treatment and activation of the cAMP system. The pos sibility that targeted inhibition of these PDE4 subtypes may produce an ant idepressant effect is discussed.