Editing Nicotine (section)

===Reinforcement disorders===
{{See also|Nicotine withdrawal|Smoking cessation}}
{{Annotated image 4
| caption = Top: this depicts the initial effects of high dose exposure to an addictive drug on [[gene expression]] in the [[nucleus accumbens]] for various Fos family proteins (i.e., [[c-Fos]], [[FosB]], [[ΔFosB]], [[Fra1]], and [[Fra2]]).<br />Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these [[phosphorylated]] (35–37&nbsp;[[kilodalton]]) ΔFosB [[isoform]]s persist in the [[D1-type]] [[medium spiny neurons]] of the nucleus accumbens for up to 2&nbsp;months.<ref name="pmid11572966">{{cite journal | vauthors = Nestler EJ, Barrot M, Self DW | title = DeltaFosB: a sustained molecular switch for addiction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11042–6 | date = September 2001 | pmid = 11572966 | pmc = 58680 | doi = 10.1073/pnas.191352698 | quote = Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal&nbsp;... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well. | bibcode = 2001PNAS...9811042N | doi-access = free }}</ref><ref name="Nestler2">{{cite journal | vauthors = Nestler EJ | title = Transcriptional mechanisms of drug addiction | journal = Clinical Psychopharmacology and Neuroscience | volume = 10 | issue = 3 | pages = 136–143 | date = December 2012 | pmid = 23430970 | pmc = 3569166 | doi = 10.9758/cpn.2012.10.3.136 | quote = The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives.&nbsp;... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure.&nbsp;... ΔFosB overexpression in nucleus accumbens induces NFκB }}</ref>
| header = ΔFosB accumulation from excessive drug use
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| alt = ΔFosB accumulation graph
| image = ΔFosB accumulation.svg
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Nicotine is highly [[addictive]] but paradoxically has quite weak reinforcing property compared to other drugs of abuse in various animals.<ref name=Grana2014>{{cite journal | vauthors = Grana R, Benowitz N, Glantz SA | title = E-cigarettes: a scientific review | journal = Circulation | volume = 129 | issue = 19 | pages = 1972–1986 | date = May 2014 | pmid = 24821826 | pmc = 4018182 | doi = 10.1161/circulationaha.114.007667 }}</ref><ref name=Siqueira2016/><ref>{{cite journal | vauthors = Dougherty J, Miller D, Todd G, Kostenbauder HB | title = Reinforcing and other behavioral effects of nicotine | journal = Neuroscience and Biobehavioral Reviews | volume = 5 | issue = 4 | pages = 487–495 | date = December 1981 | pmid = 7322454 | doi = 10.1016/0149-7634(81)90019-1 | s2cid = 10076758 }}</ref><ref name="Belluzzi Wang Leslie 2005">{{cite journal | vauthors = Belluzzi JD, Wang R, Leslie FM | title = Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats | journal = Neuropsychopharmacology | volume = 30 | issue = 4 | pages = 705–712 | date = April 2005 | pmid = 15496937 | doi = 10.1038/sj.npp.1300586 }}</ref> Its addictiveness depends on how it is administered and also depends upon form in which nicotine is used.<ref name="assets.publishing.service.gov.uk"/> Animal research suggests that [[monoamine oxidase inhibitors]], [[acetaldehyde]]<ref name="Belluzzi Wang Leslie 2005"/><ref>{{cite web | url=https://www.rivm.nl/en/tobacco/harmful-substances-in-tobacco-smoke/acetaldehyde | title=Acetaldehyde &#124; RIVM }}</ref> and other constituents in tobacco smoke may enhance its addictiveness.<ref name="RCP" /><ref name="SmithMAO"/> [[Nicotine dependence]] involves aspects of both [[psychological dependence]] and [[physical dependence]], since discontinuation of extended use has been shown to produce both [[affect (psychology)|affective]] (e.g., anxiety, irritability, craving, [[anhedonia]]) and [[somatic nervous system|somatic]] (mild motor dysfunctions such as [[tremor]]) withdrawal symptoms.<ref name="Dependence-withdrawal">{{cite journal | vauthors = D'Souza MS, Markou A | title = Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments | journal = Addiction Science & Clinical Practice | volume = 6 | issue = 1 | pages = 4–16 | date = July 2011 | pmid = 22003417 | pmc = 3188825 | quote = Withdrawal symptoms upon cessation of nicotine intake: Chronic nicotine use induces neuroadaptations in the brain's reward system that result in the development of nicotine dependence. Thus, nicotine-dependent smokers must continue nicotine intake to avoid distressing somatic and affective withdrawal symptoms. Newly abstinent smokers experience symptoms such as depressed mood, anxiety, irritability, difficulty concentrating, craving, bradycardia, insomnia, gastrointestinal discomfort, and weight gain (Shiffman and Jarvik, 1976; Hughes et al., 1991). Experimental animals, such as rats and mice, exhibit a nicotine withdrawal syndrome that, like the human syndrome, includes both somatic signs and a negative affective state (Watkins et al., 2000; Malin et al., 2006). The somatic signs of nicotine withdrawal include rearing, jumping, shakes, abdominal constrictions, chewing, scratching, and facial tremors. The negative affective state of nicotine withdrawal is characterized by decreased responsiveness to previously rewarding stimuli, a state called anhedonia. }}</ref> Withdrawal symptoms peak in one to three days<ref name=DasProchaska2017>{{cite journal | vauthors = Das S, Prochaska JJ | title = Innovative approaches to support smoking cessation for individuals with mental illness and co-occurring substance use disorders | journal = Expert Review of Respiratory Medicine | volume = 11 | issue = 10 | pages = 841–850 | date = October 2017 | pmid = 28756728 | pmc = 5790168 | doi = 10.1080/17476348.2017.1361823 }}</ref> and can persist for several weeks.<ref name="HKS2010">{{cite journal | vauthors = Heishman SJ, Kleykamp BA, Singleton EG | title = Meta-analysis of the acute effects of nicotine and smoking on human performance | journal = Psychopharmacology | volume = 210 | issue = 4 | pages = 453–69 | date = July 2010 | pmid = 20414766 | pmc = 3151730 | doi = 10.1007/s00213-010-1848-1 | quote = The significant effects of nicotine on motor abilities, attention, and memory likely represent true performance enhancement because they are not confounded by withdrawal relief. The beneficial cognitive effects of nicotine have implications for initiation of smoking and maintenance of tobacco dependence. }}</ref> Even though other drugs of dependence can have withdrawal states lasting 6 months or longer, this does not appear to occur with cigarette withdrawal.<ref>{{cite journal | vauthors = Hughes JR | title = Effects of abstinence from tobacco: valid symptoms and time course | journal = Nicotine & Tobacco Research | volume = 9 | issue = 3 | pages = 315–327 | date = March 2007 | pmid = 17365764 | doi = 10.1080/14622200701188919 }}</ref>

Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms.<ref name=Parrott2003/> These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette.<ref name=Parrott2003/> Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking.<ref name=Parrott2003/> Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.<ref>{{cite journal | vauthors = Dugas EN, Sylvestre MP, O'Loughlin EK, Brunet J, Kakinami L, Constantin E, O'Loughlin J | title = Nicotine dependence and sleep quality in young adults | journal = Addictive Behaviors | volume = 65 | pages = 154–160 | date = February 2017 | pmid = 27816041 | doi = 10.1016/j.addbeh.2016.10.020 }}</ref><ref>{{cite journal | vauthors = Cohrs S, Rodenbeck A, Riemann D, Szagun B, Jaehne A, Brinkmeyer J, Gründer G, Wienker T, Diaz-Lacava A, Mobascher A, Dahmen N, Thuerauf N, Kornhuber J, Kiefer F, Gallinat J, Wagner M, Kunz D, Grittner U, Winterer G | title = Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence | journal = Addiction Biology | volume = 19 | issue = 3 | pages = 486–96 | date = May 2014 | pmid = 22913370 | doi = 10.1111/j.1369-1600.2012.00487.x | hdl = 11858/00-001M-0000-0025-BD0C-B | s2cid = 1066283 | hdl-access = free }}</ref>

In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.<ref name=Bruijnzeel2012>{{cite journal | vauthors = Bruijnzeel AW | title = Tobacco addiction and the dysregulation of brain stress systems | journal = Neuroscience and Biobehavioral Reviews | volume = 36 | issue = 5 | pages = 1418–41 | date = May 2012 | pmid = 22405889 | pmc = 3340450 | doi = 10.1016/j.neubiorev.2012.02.015 | quote = Discontinuation of smoking leads to negative affective symptoms such as depressed mood, increased anxiety, and impaired memory and attention...Smoking cessation leads to a relatively mild somatic withdrawal syndrome and a severe affective withdrawal syndrome that is characterized by a decrease in positive affect, an increase in negative affect, craving for tobacco, irritability, anxiety, difficulty concentrating, hyperphagia, restlessness, and a disruption of sleep. Smoking during the acute withdrawal phase reduces craving for cigarettes and returns cognitive abilities to pre-smoking cessation level }}</ref> The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal.<ref name=Parrott2003/> Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.<ref name=Parrott2003>{{cite journal | vauthors = Parrott AC | title = Cigarette-derived nicotine is not a medicine | journal = The World Journal of Biological Psychiatry | volume = 4 | issue = 2 | pages = 49–55 | date = April 2003 | pmid = 12692774 | doi = 10.3109/15622970309167951 | s2cid = 26903942 }}</ref>

Nicotine activates the [[mesolimbic pathway]] and [[Inducible gene|induces]] long-term [[ΔFosB]] expression (i.e., produces [[phosphorylated]] ΔFosB [[isoform]]s) in the [[nucleus accumbens]] when inhaled or injected frequently or at high doses, but not necessarily when ingested.<ref name="Nestler 2013Rev">{{cite journal | vauthors = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues in Clinical Neuroscience | volume = 15 | issue = 4 | pages = 431–443 | date = December 2013 | pmid = 24459410 | pmc = 3898681 | doi =  10.31887/DCNS.2013.15.4/enestler}}</ref><ref name="Addiction molecular neurobiology">{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–37 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | s2cid = 19157711 | quote = The knowledge of ΔFosB induction in chronic drug exposure provides a novel method for the evaluation of substance addiction profiles (i.e. how addictive they are). Xiong et al. used this premise to evaluate the potential addictive profile of propofol (119). Propofol is a general anaesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine),&nbsp;...<br /><br />Conclusions<br />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). }}</ref><ref name="RouteDFosB Primary">{{cite journal | vauthors = Marttila K, Raattamaa H, Ahtee L | title = Effects of chronic nicotine administration and its withdrawal on striatal FosB/DeltaFosB and c-Fos expression in rats and mice | journal = Neuropharmacology | volume = 51 | issue = 1 | pages = 44–51 | date = July 2006 | pmid = 16631212 | doi = 10.1016/j.neuropharm.2006.02.014 | s2cid = 8551216 }}</ref> Consequently, high daily exposure (possibly excluding [[oral route]]) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.<ref name="Nestler 2013Rev"/><ref name="Addiction molecular neurobiology"/>