瘾有分為物質成癮及行為成癮，行為成癮是和物质无关的强迫症，如赌瘾和网瘾。在这几种通常的用法中，瘾是描述一种某人高频率反复从事可能对其身心健康和社交生活有害的活动的一种强迫行为。而精神疾病診斷與統計手冊的第五版DSM-5中有將赌瘾（gambling disorder）列入。有時成瘾（addiction）會和物質依賴（substance dependence）混淆。兩者主要的不同是：物質依賴者在中斷物質使用後，會出現戒斷症狀，甚至造成更多的使用該物質，而成瘾是強制性的攝取某種物質或從事特定行為，不一定有戒斷症狀。
转录因子ΔFosB是各種成癮（行為成癮或物質成癮）發展中的關鍵成份及共同因素。二十多年針對ΔFosB在成瘾當中的研究，結果指出成瘾的出現以及伴隨的强迫行为加剧或减弱，都和伏隔核中D1型中度多刺神經元中ΔFosB的基因過度表現（genetic overexpression）有關。因為ΔFosB基因表現與成瘾之間有因果關係，ΔFosB在臨床前研究中常作為成瘾的生物標記。ΔFosB在這些神經元的表現會一方面會直接調高藥物Self-administration及犒賞敏感度，也會透過正增強達到這些效果，另一方面也會降低對厭惡（aversion）的敏感度[note 1]。
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Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with "addiction" when in fact dependence can be a normal body response to a substance.
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Drug abuse and addiction exact an astoundingly high financial and human toll on society through direct adverse effects, such as lung cancer and hepatic cirrhosis, and indirect adverse effects—for example, accidents and AIDS—on health and productivity.
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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. ...
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 NFkB (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.
- Olsen CM. Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology. December 2011, 61 (7): 1109–1122. PMC 3139704. PMID 21459101. doi:10.1016/j.neuropharm.2011.03.010.
Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."
Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers"
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Initial drug use can be attributed to the ability of the drug to act as a reward (ie, a pleasurable emotional state or positive reinforcer), which can lead to repeated drug use and dependence.8,9 A great deal of research has focused on the molecular and neuroanatomical mechanisms of the initial rewarding or reinforcing effect of drugs of abuse. ... At present, no pharmacological therapy has been approved by the FDA to treat psychostimulant addiction. Many drugs have been tested, but none have shown conclusive efficacy with tolerable side effects in humans.172 ...A new emphasis on larger-scale biomarker, genetic, and epigenetic research focused on the molecular targets of mental disorders has been recently advocated.212 In addition, the integration of cognitive and behavioral modification of circuit-wide neuroplasticity (ie, computer-based training to enhance executive function) may prove to be an effective adjunct-treatment approach for addiction, particularly when combined with cognitive enhancers.198,213–216 Furthermore, in order to be effective, all pharmacological or biologically based treatments for addiction need to be integrated into other established forms of addiction rehabilitation, such as cognitive behavioral therapy, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities.
- Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T. Epigenetic regulation in drug addiction. Ann. Agric. Environ. Med. 2012, 19 (3): 491–496. PMID 23020045.
For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
- Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. November 2011, 12 (11): 623–637. PMC 3272277. PMID 21989194. doi:10.1038/nrn3111.
ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
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The environment also plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse.
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