Editing Nicotine (section)

====Central nervous system====
[[File:NicotineDopaminergic WP1602.png|thumb|right|class=skin-invert-image|Effect of nicotine on dopaminergic neurons]]
By binding to [[nicotinic acetylcholine receptor]]s in the brain, nicotine elicits its psychoactive effects and increases the levels of several [[neurotransmitter]]s in various brain structures&nbsp;– acting as a sort of "volume control".<ref name=Pomerleau1984>{{cite journal | vauthors = Pomerleau OF, Pomerleau CS | title = Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation | journal = Neuroscience and Biobehavioral Reviews | volume = 8 | issue = 4 | pages = 503–13 | year = 1984 | pmid = 6151160 | doi = 10.1016/0149-7634(84)90007-1 | s2cid = 23847303 }}</ref><ref>{{cite journal | vauthors = Pomerleau OF, Rosecrans J | title = Neuroregulatory effects of nicotine | journal = Psychoneuroendocrinology | volume = 14 | issue = 6 | pages = 407–23 | year = 1989 | pmid = 2560221 | doi = 10.1016/0306-4530(89)90040-1 | hdl = 2027.42/28190 | s2cid = 12080532 | hdl-access = free }}</ref> Nicotine has a higher affinity for nicotinic receptors in the brain than those in [[skeletal muscle]], though at toxic doses it can induce contractions and respiratory paralysis.<ref>{{cite book | vauthors = Katzung BG |title=Basic and Clinical Pharmacology |publisher=McGraw-Hill Medical |location=New York |year=2006 |pages=99–105 }}</ref> Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.<ref name="pmid19252481">{{cite journal | vauthors = Xiu X, Puskar NL, Shanata JA, Lester HA, Dougherty DA | title = Nicotine binding to brain receptors requires a strong cation-pi interaction | journal = Nature | volume = 458 | issue = 7237 | pages = 534–7 | date = March 2009 | pmid = 19252481 | pmc = 2755585 | doi = 10.1038/nature07768 | bibcode = 2009Natur.458..534X }}</ref> Nicotine is unusual in comparison to most drugs, as its profile changes from [[stimulant]] to [[sedative]] with increasing [[dose (biochemistry)|dosages]], a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969.<ref>Nesbitt P <!-- note: not [[Paul Nesbitt]] -->(1969). Smoking, physiological arousal, and emotional response. Unpublished doctoral dissertation, Columbia University.</ref><ref name=Parrott1998>{{cite journal | vauthors = Parrott AC | title = Nesbitt's Paradox resolved? Stress and arousal modulation during cigarette smoking | journal = Addiction | volume = 93 | issue = 1 | pages = 27–39 | date = January 1998 | pmid = 9624709 | doi = 10.1046/j.1360-0443.1998.931274.x | citeseerx = 10.1.1.465.2496 }}</ref> At very high doses it dampens [[neuronal activity]].<ref name=Wadgave2016>{{cite journal | vauthors = Wadgave U, Nagesh L | title = Nicotine Replacement Therapy: An Overview | journal = International Journal of Health Sciences | volume = 10 | issue = 3 | pages = 425–35 | date = July 2016 | pmid = 27610066 | pmc = 5003586 | doi=10.12816/0048737}}</ref> Nicotine induces both behavioral stimulation and anxiety in animals.<ref name="inchem" /> Research into nicotine's most predominant metabolite, [[cotinine]], suggests that some of nicotine's psychoactive effects are mediated by cotinine.<ref>{{cite journal | vauthors = Grizzell JA, Echeverria V | title = New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine | journal = Neurochemical Research | volume = 40 | issue = 10 | pages = 2032–46 | date = October 2015 | pmid = 24970109 | doi = 10.1007/s11064-014-1359-2 | s2cid = 9393548 }}</ref>

Nicotine activates nicotinic receptors (particularly [[α4β2 nicotinic receptor]]s, but also [[Alpha5 Nicotinic Acetylcholine Receptor|α5 nAChRs]]) on neurons that innervate the [[ventral tegmental area]] and within the [[mesolimbic pathway]] where it appears to cause the release of [[dopamine]].<ref name="Nicotine reinforcement and euphoria">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |pages=369, 372–373 |edition=2nd }}</ref><ref name="Cholinergic-dopaminergic reward link" /> This nicotine-induced dopamine release occurs at least partially through activation of the [[cholinergic–dopaminergic reward link]] in the [[ventral tegmental area]].<ref name="Cholinergic-dopaminergic reward link">{{cite journal | vauthors = Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E | title = The role of the central ghrelin system in reward from food and chemical drugs | journal = Molecular and Cellular Endocrinology | volume = 340 | issue = 1 | pages = 80–7 | date = June 2011 | pmid = 21354264 | doi = 10.1016/j.mce.2011.02.017 | url = https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf | quote = This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. | hdl = 2077/26318 | s2cid = 206815322 | access-date = 23 September 2019 | archive-date = 4 August 2020 | archive-url = https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf }}</ref><ref name="Picciotto2014">{{cite journal | vauthors = Picciotto MR, Mineur YS | title = Molecules and circuits involved in nicotine addiction: The many faces of smoking | journal = Neuropharmacology | volume = 76 | issue = Pt B | pages = 545–53 | date = January 2014 | pmid = 23632083 | pmc = 3772953 | doi = 10.1016/j.neuropharm.2013.04.028 | quote = Rat studies have shown that nicotine administration can decrease food intake and body weight, with greater effects in female animals (Grunberg et al., 1987). A similar nicotine regimen also decreases body weight and fat mass in mice as a result of β4* nAChR-mediated activation of POMC neurons and subsequent activation of MC4 receptors on second order neurons in the paraventricular nucleus of the hypothalamus (Mineur et al., 2011). | type = Review }}</ref> Nicotine can modulate the firing rate of the ventral tegmental area neurons.<ref name="Picciotto2014"/> These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of [[euphoria]];<ref name="Nicotine reinforcement and euphoria" /> however, mild euphoria from nicotine use can occur in some individuals.<ref name="Nicotine reinforcement and euphoria" /> Chronic nicotine use inhibits class I and II [[histone deacetylases]] in the [[striatum]], where this effect plays a role in nicotine addiction.<ref>{{cite journal | vauthors = Levine A, Huang Y, Drisaldi B, Griffin EA, Pollak DD, Xu S, Yin D, Schaffran C, Kandel DB, Kandel ER | title = Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ra109 | date = November 2011 | pmid = 22049069 | pmc = 4042673 | doi = 10.1126/scitranslmed.3003062 }}</ref><ref>{{cite journal | vauthors = Volkow ND | title = Epigenetics of nicotine: another nail in the coughing | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ps43 | date = November 2011 | pmid = 22049068 | pmc = 3492949 | doi = 10.1126/scitranslmed.3003278 }}</ref>