Editing Dopamine (section)

===Drug addiction and psychostimulants===
{{Main|Addiction}}
[[File:DAT1 regulation.svg|class=skin-invert-image|thumb|right|Cocaine increases dopamine levels by blocking [[dopamine transporter]]s (DAT), which transport dopamine back into a synaptic terminal after it has been emitted.|alt=Diagram describes the mechanisms by which cocaine and amphetamines reduce dopamine transporter activity.]]

[[Cocaine]], substituted amphetamines (including [[methamphetamine]]), [[Adderall]], [[methylphenidate]] (marketed as [[Ritalin]] or [[Concerta]]), and other [[stimulant|psychostimulants]] exert their effects primarily or partly by increasing dopamine levels in the brain by a variety of mechanisms.<ref name=Ghodse/> Cocaine and methylphenidate are dopamine transporter blockers or [[reuptake inhibitor]]s;<ref>{{cite journal | vauthors = Siciliano CA, Jones SR | title = Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration | journal = Neuropsychopharmacology | volume = 42 | issue = 9 | pages = 1893–1904 | date = August 2017 | pmid = 28139678 | pmc = 5520781 | doi = 10.1038/npp.2017.24 }}</ref> they [[non-competitive inhibition|non-competitively inhibit]] dopamine reuptake, resulting in increased dopamine concentrations in the synaptic cleft.<ref name=Heal>{{cite journal | vauthors = Heal DJ, Pierce DM | title = Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system | journal = CNS Drugs | volume = 20 | issue = 9 | pages = 713–38 | year = 2006 | pmid = 16953648 | doi = 10.2165/00023210-200620090-00002 | s2cid = 39535277 }}</ref><ref name=Freye>{{cite book| vauthors = Freye E |title=Pharmacology and abuse of cocaine, amphetamines, ecstasy and related designer drugs a comprehensive review on their mode of action, treatment of abuse and intoxication |year=2009 |publisher=Springer |location=Dordrecht |isbn=978-90-481-2448-0}}</ref>{{rp|54–58}} Like cocaine, substituted amphetamines and amphetamine also increase the concentration of dopamine in the [[synaptic cleft]], but by different mechanisms.<ref name="Miller">{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–76 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref><ref name=Freye/>{{rp|147–150}}

The effects of psychostimulants include increases in heart rate, body temperature, and sweating; improvements in alertness, attention, and endurance; increases in pleasure produced by rewarding events; but at higher doses agitation, anxiety, or even [[psychosis|loss of contact with reality]].<ref name=Ghodse>{{cite book | vauthors = Ghodse H|title=Ghodse's Drugs and Addictive Behaviour: A Guide to Treatment |date=2010 |publisher=Cambridge University Press |isbn=978-1-139-48567-8|pages=87–92|edition=4th}}</ref> Drugs in this group can have a high addiction potential, due to their activating effects on the dopamine-mediated reward system in the brain.<ref name=Ghodse/> However some can also be useful, at lower doses, for treating attention deficit hyperactivity disorder (ADHD) and [[narcolepsy]].<ref name=Kimko/><ref>{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–52 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref> An important differentiating factor is the onset and duration of action.<ref name=Ghodse/> Cocaine can take effect in seconds if it is injected or inhaled in free base form; the effects last from 5 to 90 minutes.<ref name=Zimmerman>{{cite journal | vauthors = Zimmerman JL | title = Cocaine intoxication | journal = Critical Care Clinics | volume = 28 | issue = 4 | pages = 517–26 | date = October 2012 | pmid = 22998988 | doi = 10.1016/j.ccc.2012.07.003 }}</ref> This rapid and brief action makes its effects easily perceived and consequently gives it high addiction potential.<ref name=Ghodse/> Methylphenidate taken in pill form, in contrast, can take two hours to reach peak levels in the bloodstream,<ref name=Kimko>{{cite journal | vauthors = Kimko HC, Cross JT, Abernethy DR | s2cid = 397390 | title = Pharmacokinetics and clinical effectiveness of methylphenidate | journal = Clinical Pharmacokinetics | volume = 37 | issue = 6 | pages = 457–70 | date = December 1999 | pmid = 10628897 | doi = 10.2165/00003088-199937060-00002 }}</ref> and depending on formulation the effects can last for up to 12&nbsp;hours.<ref>{{Cite web|title=Quillivant XR – methylphenidate hydrochloride suspension, extended release|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0157005-6e3e-4763-b910-9eb0937608c9|access-date=2020-07-11|website=dailymed.nlm.nih.gov}}</ref> These longer acting formulations have the benefit of reducing the potential for abuse, and improving adherence for treatment by using more convenient dosage regimens.<ref>{{cite journal | vauthors = López FA, Leroux JR | title = Long-acting stimulants for treatment of attention-deficit/hyperactivity disorder: a focus on extended-release formulations and the prodrug lisdexamfetamine dimesylate to address continuing clinical challenges | journal = Attention Deficit and Hyperactivity Disorders | volume = 5 | issue = 3 | pages = 249–65 | date = September 2013 | pmid = 23564273 | pmc = 3751218 | doi = 10.1007/s12402-013-0106-x }}</ref>

[[File:Crystal Meth Rock.jpg|thumb|right|[[Methamphetamine#Physical properties|Methamphetamine hydrochloride]] also known as crystal meth|alt=A shiny translucent white crystal of methamphetamine, held between the ends of a finger and thumb]]
A variety of addictive drugs produce an increase in reward-related dopamine activity.<ref name=Ghodse/> Stimulants such as [[nicotine]], cocaine and methamphetamine promote increased levels of dopamine which appear to be the primary factor in causing addiction. For other addictive drugs such as the [[opioid]] heroin, the increased levels of dopamine in the reward system may play only a minor role in addiction.<ref name=Nutt>{{cite journal | vauthors = Nutt DJ, Lingford-Hughes A, Erritzoe D, Stokes PR | s2cid = 205511111 | title = The dopamine theory of addiction: 40 years of highs and lows | journal = Nature Reviews. Neuroscience | volume = 16 | issue = 5 | pages = 305–12 | date = May 2015 | pmid = 25873042 | doi = 10.1038/nrn3939 | url = https://kclpure.kcl.ac.uk/ws/files/44680387/Nutt_and_Stokes_Nature_Reviews_Neuroscience_2015_institutional_repository.pdf }}</ref> When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with [[alcohol withdrawal syndrome|alcohol withdrawal]] or [[drug withdrawal|withdrawal]] from opiates; instead they experience craving, an intense desire for the drug characterized by irritability, restlessness, and other arousal symptoms,<ref name="Sinha">{{cite journal | vauthors = Sinha R | title = The clinical neurobiology of drug craving | journal = Current Opinion in Neurobiology | volume = 23 | issue = 4 | pages = 649–54 | date = August 2013 | pmid = 23764204 | pmc = 3735834 | doi = 10.1016/j.conb.2013.05.001 }}</ref> brought about by [[psychological dependence]].

The dopamine system plays a crucial role in several aspects of addiction. At the earliest stage, genetic differences that alter the expression of dopamine receptors in the brain can predict whether a person will find stimulants appealing or aversive.<ref name="Volkow">{{cite journal | vauthors = Volkow ND, Baler RD | title = Addiction science: Uncovering neurobiological complexity | journal = Neuropharmacology | volume = 76 | issue= Pt B | pages = 235–49 | date = January 2014 | pmid = 23688927 | pmc = 3818510 | doi = 10.1016/j.neuropharm.2013.05.007 }}</ref> Consumption of stimulants produces increases in brain dopamine levels that last from minutes to hours.<ref name=Ghodse/> Finally, the chronic elevation in dopamine that comes with repetitive high-dose stimulant consumption triggers a wide-ranging set of structural changes in the brain that are responsible for the behavioral abnormalities which characterize an addiction.<ref name="Nestler">{{cite journal | vauthors = Nestler EJ | title = Transcriptional mechanisms of drug addiction | journal = Clinical Psychopharmacology and Neuroscience | volume = 10 | issue = 3 | pages = 136–43 | date = December 2012 | pmid = 23430970 | pmc = 3569166 | doi = 10.9758/cpn.2012.10.3.136 }}</ref> Treatment of stimulant addiction is very difficult, because even if consumption ceases, the craving that comes with psychological withdrawal does not.<ref name=Sinha/> Even when the craving seems to be extinct, it may re-emerge when faced with stimuli that are associated with the drug, such as friends, locations and situations.<ref name=Sinha/> [[Cerebral cortex#Association areas|Association networks]] in the brain are greatly interlinked.<ref>{{cite journal | vauthors = Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, Roffman JL, Smoller JW, Zöllei L, Polimeni JR, Fischl B, Liu H, Buckner RL | title = The organization of the human cerebral cortex estimated by intrinsic functional connectivity | journal = Journal of Neurophysiology | volume = 106 | issue = 3 | pages = 1125–65 | date = September 2011 | pmid = 21653723 | pmc = 3174820 | doi = 10.1152/jn.00338.2011 }}</ref>