Chronic pharmacological treatment with certain antidepressants alters the expression and DNA-binding activity of transcription factor AP-2.
Several of the genes in the serotonergic and the dopaminergic systems have consensus binding sites for the AP-2 transcription factor family in their regulatory regions. Imbalances in these systems have been implicated in many psychiatric disorders, including depression and bipolar affective disorder. We have made an effort to further elucidate the molecular mechanisms of drugs used for affective disorders. Recently, we analyzed the effects of chronic treatment with certain antidepressants on AP-2 in rat brain. The present study demonstrates that chronic administration of three different classes of antidepressants modulates the DNA-binding activity of AP-2 in the rat brain. Chronic administration of citalopram (10 mg/kg), imipramin (10 mg/kg) and lithium-chloride (40 mg/kg) significantly decreased DNA-binding activity of AP-2. Furthermore, citalopram (10 mg/kg) and imipramin (10 mg/kg) significantly decreased the amount of AP-2alpha protein as determined by ELISA. In addition, citalopram (10 mg/kg) significantly decreased the amount of AP-2beta protein. In contrast, chronic administration of lithium-chloride (40 mg/kg) did not affect the amount of the two AP-2 isoforms. An increased understanding of the function of transcription factors and their involvement in human disease, such as depression, could make it possible in the future to selectively modulate relevant target genes directly.
Damberg
M
M
Department of Neuroscience, Section of Pharmacology, Uppsala University, Sweden.
Ekblom
J
J
Oreland
L
L
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004586:Electrophoresis; D004797:Enzyme-Linked Immunosorbent Assay; D007099:Imipramine / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis; D015345:Oligonucleotide Probes; D051381:Rats; D017207:Rats, Sprague-Dawley; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D015283:Citalopram; D004247:DNA; D008094:Lithium; D007099:Imipramine