Chronic treatment with desipramine and fluoxetine modulate BDNF, CaMKKalpha and CaMKKbeta mRNA levels in the hippocampus of transgenic mice expressing antisense RNA against the glucocorticoid receptor.
Antidepressants up-regulate the cAMP response element binding protein (CREB) and the brain-derived neurotrophic factor (BDNF) in hippocampus and these effects contribute to the protection of hippocampal neurons from stressful stimuli such as high glucocorticoid levels. CREB can be activated by both protein kinase A and by Ca2+-calmodulin-dependent protein kinases (CaMKs), which are in turn phosphorylated by their upstream activators CaMKKalpha and CaMMKKbeta. Using in situ hybridization, we examined the effects of chronic treatment with fluoxetine (FLU) or desipramine (DMI) on BDNF, CaMKKalpha and CaMKKbeta mRNAs in the hippocampus of wild-type (Wt) and transgenic (TG) mice characterized by glucocorticoid receptor (GR) dysfunction. Basal levels of CaMKKbeta were down regulated in the CA3 region of TG mice. DMI decreased the expression of both CaMKKalpha and CaMMKKbeta in the CA3 region of Wt mice. FLU up-regulated BDNF mRNA levels in the CA3 of TG animals while both FLU and DMI increased BDNF gene expression in the dentate gyrus (DG) of TG animals. Our results demonstrate a different regulation of BDNF expression by antidepressant drugs in the hippocampus of Wt and TG animals. Moreover, for the first time, a role for CaMKKs in the mechanism of action of antidepressant agents, at least in the hippocampus, is reported. These data are discussed in view of interactions existing between CaMK pathway and GR-mediated gene transcription.
Vinet
Jonathan
J
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, via Campi, 183, 41100 Modena, Italy.
Carra
Serena
S
Blom
Joan M C
JM
Brunello
Nicoletta
N
Barden
Nicholas
N
Tascedda
Fabio
F
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D003891:Desipramine / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D015347:RNA Probes; D016372:RNA, Antisense / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000235:genetics*
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D015347:RNA Probes; D016372:RNA, Antisense; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D003891:Desipramine