Effect of chronic antidepressant treatment on β-receptor coupled signal transduction cascade.: Which effect matters most?

Background: beta-Receptor down-regulation has been described as a common biochemical effect of chronic treatment with many but not all antidepressant drugs. beta-Receptor activation leads to elevated intracellular levels of cAMP followed by the activation of several protein kinases which in turn activate various transcription factors. One of those, CREP has received increasing interest as an relevant component within the antidepressant drug modulated signal cascade as it represents a down-stream signal not only of the beta-receptor but also of serotonin receptor activation. Chronic treatment with many antidpressant drugs has been shown to alter CREP levels in several brain regions. While beta-receptor down-regulation by chronic antidepressant treatment has been a consistent finding, alterations of CREP levels have been observed in both direction. Similary divergent findings have been reported for BDNF a major gene targeted of CREB, where most but not all findings suggest up-regulation at least at the message level following chronic antidepressant treatment. Methods: Because of these rather divergent data, we investigated the possible effects of chronic treatment (9 or 19 days) with three different antidepressant drugs (reboxetme, citalopram, imipramine) on the individual parameters of the beta-receptor coupled signal transduction cascade. All animals were also tested for possible antidepressant effects using the forced swimming test. Results: While beta-receptor density was downregulated by reboxetine and imipramine but not citalopram, CREB protein was only mildly elevated after 9 days, and not changed or slightly reduced after 19 days. BDNF protein levels were not or only slightly enhanced, but only for the 9 days treatment. Citalopram was most active. Under the conditions chosen, all three drugs were active in the forced swimming test. Conclusion: Taken together, the findings reported make it difficult to identify one single component of the beta-receptor coupled signal transduction cascade as common final target of chronic antidepressant treatment.