Regulation of brain -derived neurotrophic factor mRNA expression by delta opioid receptor agonists and antidepressant drugs.

Delta opioid receptor agonists produce antidepressant-like effects in animal models, suggesting that these compounds may be valuable for the treatment of depression. Chronic administration of antidepressants has been shown to up-regulate the expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor (TrkB), and it has been hypothesized that increased growth factor activity may be responsible for the therapeutic effects of antidepressant drugs. Therefore, a treatment that directly or indirectly increases BDNF or TrkB activity may produce clinical antidepressant effects. In addition, rapid regulation of this system may produce antidepressant effects more quickly and with fewer side effects. The present study examined the ability of delta opioid receptor agonists to increase BDNF and TrkB mRNA expression, to further establish the potential of delta opioid receptor agonists as antidepressants. The selective, nonpeptidic delta opioid receptor agonist (+)BW373U86 was administered to rats and BDNF and TrkB mRNA expression was measured by in situ hybridization. (+)BW373U86 was found to increase BDNF mRNA expression in the frontal cortex, hippocampus, basolateral amygdala, endopiriform nucleus, and olfactory cortex within 3 hours of a single administration, but had no effect on TrkB expression. In addition, the peptidic agonists DPDPE, Deltorphin II, and H-Dmt-Tic-NH-CH2-Bid also produced antidepressant-like effects in the forced swim test and increased BDNF mRNA expression in the frontal cortex or hippocampus. Tolerance develops to several effects of delta opioid receptor agonists; however, administration of (+)BW373U86 for up to 8 days continued to increase BDNF mRNA expression in the frontal cortex, while tolerance developed to the antidepressant-like behavioral effects and to increases in BDNF expression in other brain regions. Finally, while some reports suggest that chronic antidepressant treatment increases BDNF mRNA expression, in this study, tranylcypromine was the only antidepressant that significantly increased BDNF mRNA expression. Fluoxetine, desipramine, and bupropion had either no effect or decreased BDNF mRNA expression in the hippocampus. In conclusion, it is unclear if increased BDNF mRNA expression is necessary for clinical antidepressant effects. However, delta opioid receptors are promising targets for the treatment of depression and other disorders because of their ability to rapidly up-regulate BDNF mRNA expression.Ph.D.Biological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125240/2/3186775.pd