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Volume 8, Issue 5 (Suppl) J Addict Res Ther, an open access journal
ISSN: 2155-6105
6th World Congress on
August 29-31, 2017 | Prague, Czech Republic
Addiction Disorder & Addiction Therapy
Addiction Congress 2017
August 29-31, 2017
Accumulation of highly stable ΔFosB-Isoforms and its targets inside the reward system of chronic drug
abusers
Monika Heidemarie Seltenhammer
Medical University of Vienna, Austria
Background: The ~33kD transcription factor ΔFosB, a Fos-family protein and 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. ΔFosB forms
heterodimers with Jun proteins to generate active activator protein-1 (AP-1) complexes. They bind to AP-1 sites in the promoter
regions of many neural genes. To date, several downstream target genes for ΔFosB 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 ΔFosB is replaced by robust ~35-37 kD isoforms due to epigenetic splicing and different phosphorylation steps. The result is
that 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. These stabilized ~35-37 kD ΔFosB derivatives linger in the brain for several weeks
or longer even though the chronic stimulus has been removed – a fact that seems to be responsible for the development of sustained
neuronal plasticity, (drug associated) long-term potentiation (LTP) and memory. In case of chronic drug abuse, the end result is
addictive behavior and may be a crucial factor for high relapse rates.
Research Questions: Is it possible to detect these highly stable ΔFosB isoforms in post-mortem brain-tissue samples of chronic drug
abusers? Can this accumulation also be regarded as source of dependence-memory and high relapse rates?
Methods: ΔFosB and cAMP response element binding protein (CREB), brain derived neurotrophic factor (BDNF), JunD, nuclear
factor kappa B (NFκB), and cyclin-dependent kinase 5 (Cdk5) in both of the NAc and HPC of deceased chronic human opioid addicts
were proven by immunohistochemistry even with a prolonged postmortem interval (PMI) of 8.47±2.61 days. Moreover accumulated
~35-37 kD DFosB isoforms could be detected in the NAc of the same samples by immunoblotting.
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-Two-Sample Test. Further, accumulated ~35-37 kD ΔFosB 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-Two-Sample Test.
Key Conclusions: Taken together with the results of already published functional in-vivo animal experiments, our findings provide
additional evidence of the potential strong impact of ΔFosB on its downstream transcriptional targets, which are in turn responsible
for sustainable effects and serious adaptations in the brain that lead to addictive behavior and dependence memory.
Biography
Monika Heidemarie Seltenhammer completed her VMD and PhD from VMU in Austria and Post-doctoral studies from Veterinary University of Vienna, Max Perutz
Laboratories and Medical University of Vienna in Austria, where her core area of scientific work mainly comprised of cancer research (melanoma) and pathology,
but also immunology, neurology and virology. She has received several honor and awards. She is a Leading Member of the Scientific Staff of Dr. Daniele Ugo Risser
at the Department of Forensic Medicine of the Medical University Vienna, where she specializes in Neurobiology and Addiction Behavior.
Monika Heidemarie Seltenhammer, J Addict Res Ther 2017, 8:5 (Suppl)
DOI: 10.4172/2155-6105-C1-033