Figure 5 - uploaded by Monika Seltenhammer
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Another positive immunoreaction: brown nuclear staining patterns of ΔFosB of the medium spiny neurons (MSN) of NAc of a long-term drug abuser (DAB; 3,3´-diaminobenzidine), 200 X magnification; scale bar represents 100 µm.
Source publication
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. T...
Citations
... This is supported by research indicating that animals self-administering cocaine or receiving yoked drug injections show similar levels of ΔFosB induction in this brain area [77]. The 35-37 kD isoforms of ΔFosB build up with prolonged drug exposure because of their exceptionally long half-lives, enabling them to remain in neurons long after drug use has stopped [78]. ...
Levodopa-induced dyskinesia (LID) represents a significant complication associated with the long-term administration of levodopa (L-DOPA) for the treatment of Parkinson’s disease (PD). This review examines the critical role of ΔFosB, a transcription factor, in the pathogenesis of LID and explores potential therapeutic interventions. ΔFosB accumulates within the striatum in response to chronic dopaminergic stimulation, thereby driving maladaptive changes that culminate in dyskinesia. Its persistent expression modifies gene transcription, influencing neuronal plasticity and contributing to the sustained presence of dyskinetic movements. This study explains how ΔFosB functions at the molecular level, focusing on its connections with dopamine D1 receptors, the cAMP/PKA signaling pathway, and its regulatory effects on downstream targets such as DARPP-32 and GluA1 AMPA receptor subunits. Additionally, it examines how neuronal nitric oxide synthase (nNOS) affects ΔFosB levels and the development of LID. This review also considers the interactions between ΔFosB and other signaling pathways, such as ERK and mTOR, in the context of LID and striatal plasticity. Emerging therapeutic strategies targeting ΔFosB and its associated pathways include pharmacological interventions like ranitidine, 5-hydroxytryptophan, and carnosic acid. Furthermore, this study addresses the role of JunD, another component of the AP-1 transcription factor complex, in the pathogenesis of LID. Understanding the molecular mechanisms by which ΔFosB contributes to LID offers promising avenues for developing novel treatments that could mitigate dyskinesia and improve the quality of life for PD patients undergoing long-term L-DOPA therapy.
Graphical Abstract
... Besides preclinical studies, post-mortem analyses of the brain tissues of chronic opioid abusers have revealed enhanced expression of ΔFosB in the NAc that was followed by a rise in the level of its downstream targets such as Cdk5, NF-κB, CREB, brain-derived neurotrophic factor, and JunD in both the hippocampus and NAc (Seltenhammer et al., 2016). They confirmed that ΔFosB and its downstream transcriptional targets are critical to inducing sustainable brain changes and establishing a strong memory associated with drugs of abuse on the road to dependency and relapse (Seltenhammer et al., 2016). ...
... Besides preclinical studies, post-mortem analyses of the brain tissues of chronic opioid abusers have revealed enhanced expression of ΔFosB in the NAc that was followed by a rise in the level of its downstream targets such as Cdk5, NF-κB, CREB, brain-derived neurotrophic factor, and JunD in both the hippocampus and NAc (Seltenhammer et al., 2016). They confirmed that ΔFosB and its downstream transcriptional targets are critical to inducing sustainable brain changes and establishing a strong memory associated with drugs of abuse on the road to dependency and relapse (Seltenhammer et al., 2016). ...
From a neuroscientific point of view, one of the unique archetypes of substance use disorders is its road to relapse, in which the reward system plays a crucial role. Studies on the neurobiology of substance use disorders have highlighted the central role of a protein belonging to the Fos family of transcription factors, ΔFosB. Relying on the roles ΔFosB plays in the pathophysiology of substance use disorders, we endeavour to present some evidence demonstrating that N -acetylcysteine, a low-cost and well-tolerated over-the-counter medicine, may influence the downstream pathway of ΔFosB, thereby serving as a treatment strategy to mitigate the risk of relapse in cases of substance use.
... This may not be surprising since the FosB product implicated in addiction, ∆FosB, accumulates in brain reward regions in response to chronic drug exposure due to the intrinsic stability of the protein, with its mRNA not showing stable induction 40 . Importantly, such accumulation of ∆FosB has been observed in human nucleus accumbens in cocaine and opiate human addicts 41,42 . Whether it also accumulates in human dlPFC remains unknown. ...
Metabolic and functional alterations of neurons in the dorsolateral prefrontal cortex (dlPFC) are thought to contribute to impulsivity, which is a hallmark of addictive behaviors that underlie compulsive drug seeking and taking in humans. To determine if there is a transcriptional signature in dlPFC neurons of humans with cocaine use disorder, we performed total RNA-sequencing on neuronal nuclei isolated from post-mortem dlPFC of cocaine addicts and healthy controls. Our results point toward a transcriptional mechanism whereby cocaine alters specific gene networks in dlPFC neurons. In particular, we identified an AP-1 regulated transcriptional network in dlPFC neurons associated with cocaine use disorder that contains several differentially expressed hub genes. Several of these hub genes are GWAS hits for traits that might involve dysfunction of brain reward circuitry (Body-Mass Index, Obesity) or dlPFC (Bipolar disorder, Schizophrenia). Further study is warranted to determine their potential pathophysiological role in cocaine addiction.
it´s all about protein stabilities..;0)
in german-short:
https://www.meduniwien.ac.at/web/ueber-uns/news/detailseite/2016/news-im-dezember-2016/sucht-verlangen-ist-auch-noch-nach-dem-tod-nachweisbar/
