Monika Heldemarie Seltenhammer
Medical University of Vienna, Austria
Title: Accumulation of highly stable ΔFosB-isoforms and its targets inside the reward system of chronic drug abusers – A source of dependence memory and high relapse rate?
Biography
Biography: Monika Heldemarie Seltenhammer
Abstract
Background: The ~33kD transcription factor DFosB, a Fos-family protein, belonging to the immediate early genes (IEGs), is initiated in the acute phase as a response to a wide range of effects such as drugs, stress, and several external stimuli. DFosB forms heterodimers with Jun proteins to generate active activator-protein-1 (AP-1)-complexes. Currently, several downstream target genes for DFosB have been identified being involved in molecular pathways concerning addictive behavior, memory and learning. In answer to chronic stimuli, the rather unstable ~33kD transcription factor DFosB is replaced by robust ~35-37 kD isoforms due to epigenetic splicing and phosphorylation steps. These highly stable isoforms accumulate in the nucleus accumbens (NAc), a structure close to the hippocampus (HPC), playing a key role within the reward center of the brain. The stabilized ~35-37 kD DFosB derivatives linger in the brain for very long time; even beyond cessation of the chronic stimulus. A fact that seems to be responsible for the development of sustained neuronal plasticity, (drug-associated) long-term potentiation (LTP) and memory, and finally high relapse rates.
Method: DFosB and cAMP response element binding protein (CREB), brain derived neurotrophic factor (BDNF), JunD, nuclear factor kappa B (NFkB), and cyclin-dependent kinase 5 (Cdk5) in both of the NAc and HPC of deceased chronic human opioid addicts were proven by immunohistochemistry. Immunoblots were positive for accumulated ~35-37 kD DFosB isoforms.
Results: All determined proteins showed a significant increased staining pattern in brain samples of chronic drug abusers in comparison non-drug users (p<0.05) according to Wilcoxon-Mann-Whitney-U Test. Further, accumulated ~35-37 kD DFosB isoforms were detectable in NAc samples of long-term drug addicts by immunoblotting in contrast to the control group, where no trace of any isoform was verifiable (p<0.05) according to Wilcoxon-Mann-Whitney-U Test.
Conclusion: Our findings provide additional evidence of the potential strong impact of DFosB on its downstream transcriptional targets, which are in turn responsible for sustainable effects and serious adaptations in the brain leading to addictive behavior and dependence memory.