Summary: Researchers report addictive cravings can be detected in the brain after death.
Source: Medical University of Vienna.
A protein known as FosB in the reward centre of the brain alters in chronically ill people suffering from an addictive disorder (e.g. heroin addiction): it is genetically modified, split off and shortened. This modification under the stimulus of the drug results in the protein being more stable and therefore remaining longer in this part of the brain than in its original form – even as much as several weeks after withdrawal of the drug. This means that a craving for this stimulus persists. This addictive craving is stored in a sort of “memory” function and, surprisingly, can still be detected after death. This has now been demonstrated by MedUni Vienna scientists from the Department of Forensic Medicine.
FosB is a transcription factor in the brain which, together with other molecules, is involved in so-called signal transduction (transmission of stimuli to the cells), that is to say conveys genetic information between the cells and also determines whether certain genes are activated or not. FosB is itself part of the activating protein AP1. Due to the constant supply of drugs such as heroin, FosB turns into DeltaFosB, which is increasingly stimulated in cases of chronic use and even influences growth factors and structural changes (neuronal plasticity) in the brain – approximately in the region where memory is formed.
Led by Monika Seltenhammer of MedUni Vienna’s Department of Forensic Medicine it has now been shown in a study published in the “Journal of Addiction Research & Therapy” that the effects of this chronic stimulus can even be identified post-mortem as “dependence memory”. The study involved examining tissue samples from the nucleus accumbens (an area of the brain) of 15 deceased heroin addicts. Seltenhammer: “Using highly sensitive detection methods, DeltaFosB was still detectable nine days after death.” The researchers are assuming that this period will be much longer in live subjects, possibly even months.
According to the MedUni Vienna forensic medicine experts, these results will in turn impact upon the future treatment and management of people with opiate dependencies and heroin addicts, particularly when it comes to drug withdrawal: “If the addictive craving persists in the brain for months, it is very important to provide protracted after-care and corresponding psychological support,” says Seltenhammer. “Our results show that forensics and forensic medicine can also be of direct benefit to the living,” emphasises Risser.
In a follow-on project to be conducted in collaboration with MedUni Vienna’s Institute of Pharmacology and Center for Addiction Research and Science (AddRess) and, in particular, with drug and dopamine expert Harald Sitte, amongst others, the objective is now to find out whether, and, if so, how, activation of DeltaFosB can be prevented and how this highly promising starting point can be used to treat the onset of addictive behaviour.
Source: Medical University of Vienna
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Original Research: Full open access research for “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?” by M. Seltenhammer, U. Resch, M. Stichenwirth, J. Seigner, C. Reisinger W. Vycudilik, C. Schöfer, R. De Martin, J. Sölkner and D. U. Risser in Journal of Addiction Research & Therapy. Published online October 1 2016 doi:10.4172/2155-6105.1000297
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?
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.
“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?” by M. Seltenhammer, U. Resch, M. Stichenwirth, J. Seigner, C. Reisinger W. Vycudilik, C. Schöfer, R. De Martin, J. Sölkner and D. U. Risser in Journal of Addiction Research & Therapy. Published online October 1 2016 doi:10.4172/2155-6105.1000297