|Glossario della Dipendenza e Tossicodipendenza|
La famiglia di geni FOS è composta da 4 forme: FOS, FosB, FOSL1, e FOSL2. Questi geni codificano proteine cerniera di leucine che può dimerizzare proteine della famiglia JUN (ad esempio, c-Jun, Jund), formando così il fattore di trascrizione complesso AP-1. Come tali, le proteine FOS sono state implicate nella regolazione della proliferazione cellulare, differenziamento e trasformazione. FosB e il suo splicing alternativo ΔFosB e Δ2ΔFosB sono tutti coinvolti nell'osteosclerosi, anche se Δ2ΔFosB manca di un noto dominio di transattivazione, impedendogli di influenzare la trascrizione genica attraverso il complesso AP-1.
La variante di splicing ΔFosB è stata identificata giuocare un ruolo centrale e cruciale (condizione necessaria e sufficiente) nello sviluppo e il mantenimento di un comportamento patologico e nella plasticità neurale coinvolta nel en:Behavioral addiction (associata con ricompense naturali) e la dipendenza .
- Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B, su ncbi.nlm.nih.gov.
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- Nestler EJ, Cellular basis of memory for addiction, in Dialogues Clin. Neurosci., vol. 15, nº 4, dicembre 2013, pp. 431–443, PMC 3898681, PMID 24459410.
«Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction.... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41.... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.».
- ^ Malenka RC, Nestler EJ, Hyman SE, Chapter 15: Reinforcement and Addictive Disorders, in Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York, McGraw-Hill Medical, 2009, pp. 364–375, ISBN 978-0-07-148127-4.
- ^ Glossary of Terms, su Mount Sinai School of Medicine, Department of Neuroscience. URL consultato il 9 febbraio 2015.
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- Ruffle JK, Molecular neurobiology of addiction: what's all the (Δ)FosB about?, in The American Journal of Drug and Alcohol Abuse, vol. 40, nº 6, Nov 2014, pp. 428–37, DOI:10.3109/00952990.2014.933840, PMID 25083822.
«ΔFosB as a therapeutic biomarker. The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein....Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NF-κB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.».