Abstract
Abnormal BDNF signaling contributes to the structural and behavioral plasticity induced by drugs of abuse. However, the mechanisms regulating expression of Bdnf in drug addiction remain elusive. In the present study, using the conditioned place preference (CPP) model, we showed that expression of Bdnf IV is upregulated in the nucleus accumbens (NAc) of conditioned animals while Bdnf I is upregulated in cocaine-treated mice irrespective of conditioning. The methylation level of a putative c-MYB binding site in the promoter region of Bdnf IV was significantly decreased in the NAc under cocaine CPP conditioning but remained unchanged without conditioning, concurrently with increased binding of c-MYB to this site. Exon IV promoter/luciferase reporter assays revealed that transactivation of Bdnf by c-MYB was blocked by methylation of this c-MYB binding site. Administration of methionine, a precursor of SAM, inhibited cocaine CPP, reversed demethylation of c-MYB binding site and induction of Bdnf IV expression by cocaine CPP. Our results imply that Bdnf IV demethylation at c-MYB binding site is involved in cocaine-triggered seeking behavior, whereas Bdnf I responds to the immediate pharmacological effects of cocaine.
Highlights
Brain-derived neurotrophic factor (BDNF) plays a crucial role in synaptic plasticity and memory processing in the adult brain[1]
The current study demonstrated that expression of total Bdnf and Bdnf I was upregulated in both cocaine-conditioned and non-conditioned mice, whereas the expression of Bdnf IV was only upregulated in the nucleus accumbens (NAc), and only in conditioned mice
Our findings suggest that Bdnf IV might contribute to cocaine reward seeking behavior, whereas Bdnf I responds to the direct pharmacological effects of cocaine
Summary
Brain-derived neurotrophic factor (BDNF) plays a crucial role in synaptic plasticity and memory processing in the adult brain[1]. As the dopaminergic projection from the VTA to the NAc contributes to reward and reinforcement associated with drug addiction, the level of NAc BDNF is suggested to play an important role in cocaine rewarding effects[7]. Accumulated evidence strongly supported the roles of DNA methylation in cocaine addiction[12,13,14,15], it is still unknown whether DNA methylation plays a role in controlling splice-variant specific transcription of Bdnf splice forms in cocaine rewarding memory. We investigated the effects of cocaine conditioned place preference (CPP) training on DNA methylation status in the promoter regions of different Bdnf splice variants in the NAc and established a correlation between DNA methylation at –148 sites of Bdnf IV promoter and expression of the Bdnf IV splice variant. To determine whethter a causal relationship exists between methylation and expression of Bdnf IV, we measured the effects of treatment with methionine, a methyl group donor, on DNA methylation of the Bdnf IV promoter, Bdnf IV expression and cocaine CPP
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