Elsevier

Neuroscience

Volume 139, Issue 3, 2006, Pages 1017-1029
Neuroscience

Molecular neuroscience
Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: Differential regulation of specific exons by antidepressants and corticosterone

https://doi.org/10.1016/j.neuroscience.2005.12.058Get rights and content

Abstract

Earlier studies have implicated brain-derived neurotrophic factor in stress and in the mechanism of action of antidepressants. It has been shown that antidepressants upregulate, whereas corticosterone downregulates, brain-derived neurotrophic factor expression in rat brain. Whether various classes of antidepressants reverse corticosterone-mediated downregulation of brain-derived neurotrophic factor is unclear. Also not known is how antidepressants or corticosterone regulates brain-derived neurotrophic factor expression. To clarify this, we examined the effects of various classes of antidepressants and corticosterone, alone and in combination, on the mRNA expression of total brain-derived neurotrophic factor and of individual brain-derived neurotrophic factor exons, in rat brain. Normal or corticosterone pellet-implanted (100 mg, 21 days) rats were injected with different classes of antidepressants, fluoxetine, desipramine, or phenelzine, intraperitoneally for 21 days and killed 2 h after the last injection. mRNA expression of total brain-derived neurotrophic factor and of exons I–IV was measured in frontal cortex and hippocampus. Given to normal rats, fluoxetine increased total brain-derived neurotrophic factor mRNA only in hippocampus, whereas desipramine or phenelzine increased brain-derived neurotrophic factor mRNA in both frontal cortex and hippocampus. When specific exons were examined, desipramine increased expression of exons I and III in both brain areas, whereas phenelzine increased exon I in both frontal cortex and hippocampus but exon IV only in hippocampus. On the other hand, fluoxetine increased only exon II in hippocampus. Corticosterone treatment of normal rats decreased expression of total brain-derived neurotrophic factor mRNA in both brain areas, specifically decreasing exons II and IV. Treatment with desipramine or phenelzine of corticosterone pellet-implanted rats reversed the corticosterone-induced decrease in total brain-derived neurotrophic factor expression in both brain areas; however, fluoxetine reversed the decrease only partially in hippocampus. Interestingly, antidepressant treatment of corticosterone pellet-implanted rats increased only those specific exons that are increased during treatment of normal rats with each particular antidepressant. We found that although corticosterone and antidepressants both modulate brain-derived neurotrophic factor expression, and antidepressants reverse the corticosterone-induced brain-derived neurotrophic factor decrease, antidepressants and corticosterone differ in how they regulate the expression of brain-derived neurotrophic factor exon(s).

Section snippets

Animals

Virus-free Sprague–Dawley male rats initially weighing 220–250 g were used. Rats were housed in groups of three under standard laboratory conditions (temperature 21±1 °C, humidity 55±5%, 12-h light/dark cycle). Animals were provided free access to food. Rats were acclimatized for one week before the start of experiments. Each treatment group contained six rats.

Corticosterone treatment

All the experiments were carried out in accordance with the National Institutes of Health guide for the care and use of laboratory

Serum corticosterone levels

Serum corticosterone levels were measured in sham, corticosterone-treated and corticosterone-treated rats given antidepressants. We also measured serum corticosterone levels in normal and antidepressant-treated rats. The serum corticosterone levels are given in Table 1. As in our earlier studies, we found that corticosterone level was significantly higher in corticosterone pellet-implanted rats (Dwivedi and Pandey 2000, Dwivedi et al 2000), and that desipramine or phenelzine normalized the

Discussion

This comprehensive examination of the effects of corticosterone or antidepressants, and of antidepressant effects of corticosterone on BDNF in rat brain, which showed deceptively simple results of decrease versus increase in total BDNF, revealed complex regulation processes when the effects on individual BDNF exons were examined (Table 2).

Conclusion

In conclusion, our study for the first time reveals the regulation of selective BDNF exons by corticosterone and also suggests that there is a complex interaction between antidepressants and corticosterone in regulating BDNF exons. We observed that the various classes of antidepressants administered chronically to rats increase different exons, which suggests that there is no unified mechanism of regulation of BDNF by antidepressants. In addition, antidepressants also regulate BDNF exons other

Acknowledgments

This work was supported by RO1MH68777 from the National Institute of Mental Health and a Career Development Award (KO1MH 01836) from the National Institute of Mental Health to Dr. Yogesh Dwivedi and by RO1MH56528 from the National Institute of Mental Health to Dr. G. N. Pandey. Technical assistance provided by Ms. Miljana Petkovic is acknowledged.

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