Brainstem levels of transcription factor AP-2 in rat are changed after treatment with phenelzine, but not with citalopram

Cecilia Berggard,Mattias Damberg,Lars Oreland

doi:10.1186/1471-2210-5-1

Abstract

BackgroundBefore therapeutic effect is obtained after treatment with antidepressant drugs, like serotonin selective reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) there is an initial lag-period of a few weeks. Neuronal adaptations on a molecular level are supposed to be involved in the initiation of the antidepressant effect. Transcription factor AP-2 is essential for neuronal development and many genes involved in the brainstem monoaminergic systems have binding sites for AP-2 in their regulatory regions. The genotype of the AP-2β isoform has been associated with e.g. anxiety-related personality traits and with platelet MAO activity. In addition, previous studies have shown that the levels of AP-2α and AP-2β in rat whole brain were decreased after 10 days of treatment with citalopram (SSRI) and imipramine (TCA), and were increased with phenelzine (MAO-I).ResultsIn the present study, we report that treatment with citalopram for 1, 7 or 21 days did not have effect on the AP-2 levels in rat brainstem. However, after treatment with phenelzine for 1, 7 or 21 days the levels of AP-2α and AP-2β had increased after 7 days, but had returned to control levels at day 21.ConclusionThe decrease in AP-2 levels in rat whole brain previously seen after treatment with citalopram does not seem to be localised to the brainstem, it may rather occur in the monoaminergic terminal projection areas. The present data suggest that the increase in AP-2 levels previously seen in rat whole brain after subchronic treatment with phenelzine is located in the brainstem. It cannot, however, be excluded that other brain regions are involved.

Highlights

Before therapeutic effect is obtained after treatment with antidepressant drugs, like serotonin selective reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) there is an initial lag-period of a few weeks
We have reported that citalopram changes the levels of AP-2α and AP-2β in rat whole brain in a time-dependent manner, i.e., AP-2 levels were decreased after 7 days of treatment but returned to control levels after 21 days of treatment [34]
The mean relative amounts of AP-2α and AP-2β protein ± standard deviation (SD) for each of the citalopram, phenelzine- and saline treated animal groups are shown in tables 1 and 2, respectively

Summary

Introduction

Before therapeutic effect is obtained after treatment with antidepressant drugs, like serotonin selective reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) there is an initial lag-period of a few weeks. Gaining more knowledge about molecular mechanisms involved in the initial lag-period may prove important for the discovery of new antidepressant drug targets and for the knowledge of the mechanisms of action of antidepressants. Transcription factors, with their specific ability to regulate gene expression, have been suggested as prominent novel drug targets [7,8,9,10,11]. The AP-2β genotype has been associated to CSF-levels of homovanillic acid (HVA) in women [32]

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Conclusion