Elevation of BDNF exon I-specific transcripts in the frontal cortex and midbrain of rat during spontaneous morphine withdrawal is accompanied by enhanced pCreb1 occupancy at the corresponding promoter.
Brain-derived neurotrophic factor (BDNF) is believed to play a crucial role in the mechanisms underlying opiate dependence; however, little is known about specific features and mechanisms regulating its expression in the brain under these conditions. The aim of this study was to investigate the effects of acute morphine intoxication and withdrawal from chronic intoxication on expression of BDNF exon I-, II-, IV-, VI- and IX-containing transcripts in the rat frontal cortex and midbrain. We also have studied whether alterations of BDNF exon-specific transcripts are accompanied by changes in association of well-known transcriptional regulators of BDNF gene-phosphorylated (active form) cAMP response element binding protein (pCreb1) and methyl-CpG binding protein 2 (MeCP2) with corresponding regulatory regions of the BDNF gene. Acute morphine intoxication did not affect levels of BDNF exons in brain regions, while spontaneous morphine withdrawal in dependent rats was accompanied by an elevation of the BDNF exon I-containing mRNAs both in the frontal cortex and midbrain. During spontaneous morphine withdrawal, increased associations of pCreb1 were found with promoter of exon I in the frontal cortex and promoters of exon I, IV and VI in the midbrain. The association of MeCP2 with BDNF promoters during spontaneous morphine withdrawal did not change. Thus, BDNF exon-specific transcripts are differentially expressed in brain regions during spontaneous morphine withdrawal in dependent rats and pCreb1 may be at least partially responsible for these alterations.
National Research Centre on Addictions, Ministry of Health and Social Development of the Russian Federation, Moscow, 119002, Russia.
Danil I
DI
Peregud
Leonid F
LF
Panchenko
Natalia V
NV
Gulyaeva
D000818:Animals; D001835:Body Weight; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005091:Exons / Q000235:genetics*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D009021:Morphine Dependence / Q000235:genetics* / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2