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?
| Autor: | Christian Schöfer, Johann Sölkner, Rainer de Martin, Daniele Risser, Monika Seltenhammer, Ulrike Resch, Jaqueline Seigner, Martin Stichenwirth, W. Vycudilik, Christoph Reisinger Cm |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gene isoform Brain-derived neurotrophic factor biology business.industry Addiction media_common.quotation_subject Cyclin-dependent kinase 5 Long-term potentiation Pharmacology Nucleus accumbens CREB 03 medical and health sciences 030104 developmental biology 0302 clinical medicine biology.protein Medicine business Transcription factor 030217 neurology & neurosurgery media_common |
| Zdroj: | Journal of Addiction Research & Therapy. 7 |
| ISSN: | 2155-6105 |
| DOI: | 10.4172/2155-6105.1000297 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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