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?Monika H Seltenhammer1, Ulrike Resch2, Martin Stichenwirth1, Jaqueline Seigner2, Christoph Reisinger CM1, Walter Vycudilik1, Christian Schöfer3, Rainer De Martin2, Johann Sölkner4 and Daniele U Risser1*
- *Corresponding Author:
- Daniele U Risser
Department of Forensic Medicine
Medical University of Vienna, Sensengasse 2
A-1090 Vienna, Austria
E-mail: [email protected]
Received date: June 14, 2016; Accepted date: September 22, 2016; Published date: October 01, 2016
Citation: Seltenhammer MH, Resch U, Stichenwirth M, Seigner J, Reisinger CM (2016) 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?. J Addict Res Ther 7:297. doi:10.4172/2155-6105.1000297
Copyright: © 2016 Seltenhammer MH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: The ~33 kD 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 ~33 kD 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.
Method: 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 post-mortem interval (PMI) of 8.47 ± 2.61 days. Moreover accumulated ~35-37 kD ΔFosB 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-Mann-Whitney-U 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-Mann-Whitney-U Test.
Conclusion: 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.