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. "

60. ^  _**a** _ _**b** _ Olsen CM (December 2011).  "Natural rewards, neuroplasticity, and non-drug addictions"  . _Neuropharmacology_ . **61** (7): 1109–1122.  doi  "Doi \(identifier\)") :  10.1016/j.neuropharm.2011.03.010  .  PMC  "PMC \(identifier\)")  3139704  .  PMID  "PMID \(identifier\)")  21459101  . " 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
 "

61. ^  _**a** _ _**b** _ Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". _Ann. Agric. Environ. Med_ . **19** (3): 491–496.  PMID  "PMID \(identifier\)")  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 "
62. ** ^  ** Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013).  "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator"  . _ The Journal of Neuroscience  _ . **33** (8): 3434–3442.  doi  "Doi \(identifier\)") :  10.1523/JNEUROSCI.4881-12.2013  .  PMC  "PMC \(identifier\)")  3865508  .  PMID  "PMID \(identifier\)")  23426671  . " Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity "
63. ** ^  ** Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". _Neuropharmacology_ . **101** : 154–164.  doi  "Doi \(identifier\)") :  10.1016/j.neuropharm.2015.09.023  .  PMID  "PMID \(identifier\)")  26391065  .  S2CID  "S2CID \(identifier\)")  25317397  .
64. ** ^  ** Robison AJ, Nestler EJ (November 2011).  "Transcriptional and epigenetic mechanisms of addiction"  . _Nat. Rev. Neurosci_ . **12** (11): 623–637.  doi  "Doi \(identifier\)") :  10.1038/nrn3111  .  PMC  "PMC \(identifier\)")  3272277  .  PMID  "PMID \(identifier\)")  21989194  . " ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the  c-fos  gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is  c-fos  gene repression. "
 Figure 4: Epigenetic basis of drug regulation of gene expression

65. ** ^  ** Hitchcock LN, Lattal KM (2014). "Histone-mediated epigenetics in addiction". _Epigenetics and Neuroplasticity—Evidence and Debate_ . Progress in Molecular Biology and Translational Science. Vol. 128. pp. 51–87.  doi  "Doi \(identifier\)") :  10.1016/B978-0-12-800977-2.00003-6  .  ISBN  "ISBN \(identifier\)")  9780128009772   .  PMC  "PMC \(identifier\)")  5914502  .  PMID  "PMID \(identifier\)")  25410541  .  ` {{  cite book  }} ` :  ` |journal= ` ignored ( [ help ](/wiki/Help:CS1_errors