Editing Dopamine (section)

==Disease, disorders, and pharmacology==
{{See also|List of dopaminergic drugs}}

The dopamine system plays a central role in several significant medical conditions, including [[Parkinson's disease]], [[attention deficit hyperactivity disorder]], [[Tourette syndrome]], [[schizophrenia]], [[bipolar disorder]], and [[addiction]]. Aside from dopamine itself, there are many other important drugs that act on dopamine systems in various parts of the brain or body. Some are used for medical or recreational purposes, but [[neurochemist]]s have also developed a variety of research drugs, some of which bind with high affinity to specific types of dopamine receptors and either [[agonist|agonize]] or [[receptor antagonist|antagonize]] their effects, and many that affect other aspects of dopamine physiology,<ref>{{cite book |title=Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy | vauthors = Standaert DG, Walsh RR |chapter=Pharmacology of dopaminergic neurotransmission |pages=186–206 | veditors = Tashjian AH, Armstrong EJ, Golan DE |isbn=978-1-4511-1805-6 |year=2011 |publisher=Lippincott Williams & Wilkins}}</ref> including [[dopamine transporter]] inhibitors, VMAT inhibitors, and [[enzyme inhibitors]].

=== Aging brain ===
{{Main|Aging brain}}
A number of studies have reported an age-related decline in dopamine synthesis and dopamine receptor density (i.e., the number of receptors) in the brain.<ref name="Hof 2009">{{cite book | vauthors = Mobbs CV, Hof PR |title=Handbook of the neuroscience of aging |publisher=Elsevier/Academic Press |location=Amsterdam |year=2009 |isbn=978-0-12-374898-0 |oclc= 299710911 }}</ref> This decline has been shown to occur in the striatum and [[extrastriate cortex|extrastriatal]] regions.<ref>{{cite journal | vauthors = Ota M, Yasuno F, Ito H, Seki C, Nozaki S, Asada T, Suhara T | title = Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA | journal = Life Sciences | volume = 79 | issue = 8 | pages = 730–36 | date = July 2006 | pmid = 16580023 | doi = 10.1016/j.lfs.2006.02.017 }}</ref> Decreases in the [[Dopamine receptor D1|D<sub>1</sub>]], [[Dopamine receptor D2|D<sub>2</sub>]], and [[Dopamine receptor D3|D<sub>3</sub>]] receptors are well documented.<ref name="Kaasinen 2000">{{cite journal | vauthors = Kaasinen V, Vilkman H, Hietala J, Någren K, Helenius H, Olsson H, Farde L, Rinne J | s2cid = 40871554 | title = Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain | journal = Neurobiology of Aging | volume = 21 | issue = 5 | pages = 683–68 | year = 2000 | pmid = 11016537 | doi = 10.1016/S0197-4580(00)00149-4 }}</ref><ref name="Wang 1998">{{cite journal | vauthors = Wang Y, Chan GL, Holden JE, Dobko T, Mak E, Schulzer M, Huser JM, Snow BJ, Ruth TJ, Calne DB, Stoessl AJ | title = Age-dependent decline of dopamine D1 receptors in human brain: a PET study | journal = Synapse | volume = 30 | issue = 1 | pages = 56–61 | date = September 1998 | pmid = 9704881 | doi = 10.1002/(SICI)1098-2396(199809)30:1<56::AID-SYN7>3.0.CO;2-J | s2cid = 31445572 }}</ref><ref name="Wong 1984">{{cite journal | vauthors = Wong DF, Wagner HN, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH | s2cid = 24278577 | title = Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain | journal = Science | volume = 226 | issue = 4681 | pages = 1393–96 | date = December 1984 | pmid = 6334363 | doi = 10.1126/science.6334363 | bibcode = 1984Sci...226.1393W }}</ref> The reduction of dopamine with aging is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased [[Rigidity (neurology)|rigidity]].<ref name="Wang Snyder 1998">{{cite book | vauthors = Wang E, Snyder SD |year=1998 |title=Handbook of the aging brain |location=San Diego, California |publisher=Academic Press |isbn=978-0-12-734610-6 |oclc=636693117}}</ref> Changes in dopamine levels may also cause age-related changes in cognitive flexibility.<ref name="Wang Snyder 1998"/>

=== Multiple sclerosis ===
Studies reported that dopamine imbalance influences the fatigue in [[multiple sclerosis]].<ref name="Dopamine Imbalance">{{cite journal | vauthors = Dobryakova E, Genova HM, DeLuca J, Wylie GR | title = The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders | journal = Frontiers in Neurology | volume = 6 | pages = 52 | date = 12 March 2015 | pmid = 25814977 | pmc = 4357260 | doi = 10.3389/fneur.2015.00052 | doi-access = free }}</ref> In patients with multiple sclerosis, dopamine inhibits production of [[Interleukin 17|IL-17]] and [[IFN-γ]] by peripheral blood mononuclear cells.<ref>{{cite journal | vauthors = Marino F, Cosentino M | s2cid = 26319461 | title = Multiple sclerosis: Repurposing dopaminergic drugs for MS—the evidence mounts | journal = Nature Reviews. Neurology | volume = 12 | issue = 4 | pages = 191–92 | date = April 2016 | pmid = 27020558 | doi = 10.1038/nrneurol.2016.33 }}</ref>

===Parkinson's disease===

Parkinson's disease is an age-related disorder characterized by [[movement disorder]]s such as stiffness of the body, slowing of movement, and trembling of limbs when they are not in use.<ref name=Jankovic>{{cite journal | vauthors = Jankovic J | title = Parkinson's disease: clinical features and diagnosis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 79 | issue = 4 | pages = 368–76 | date = April 2008 | pmid = 18344392 | doi = 10.1136/jnnp.2007.131045 | url = http://jnnp.bmj.com/content/79/4/368.full | doi-access = free }}</ref> In advanced stages it progresses to [[dementia]] and eventually death.<ref name=Jankovic/> The main symptoms are caused by the loss of dopamine-secreting cells in the substantia nigra.<ref name=Dickson>{{cite book | vauthors = Dickson DV|chapter=Neuropathology of movement disorders | veditors = Tolosa E, Jankovic JJ| title=Parkinson's disease and movement disorders |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |pages= 271–83 |isbn=978-0-7817-7881-7}}</ref> These dopamine cells are especially vulnerable to damage, and a variety of insults, including [[encephalitis]] (as depicted in the book and movie ''[[Awakenings]]''), repeated sports-related [[concussion]]s, and some forms of chemical poisoning such as [[MPTP]], can lead to substantial cell loss, producing a [[Parkinsonism|parkinsonian syndrome]] that is similar in its main features to Parkinson's disease.<ref name=Tuite>{{cite journal | vauthors = Tuite PJ, Krawczewski K | title = Parkinsonism: a review-of-systems approach to diagnosis | journal = Seminars in Neurology | volume = 27 | issue = 2 | pages = 113–22 | date = April 2007 | pmid = 17390256 | doi = 10.1055/s-2007-971174 | s2cid = 260319916 }}</ref> Most cases of Parkinson's disease, however, are [[idiopathic]], meaning that the cause of cell death cannot be identified.<ref name=Tuite/>

The most widely used treatment for parkinsonism is administration of L-DOPA, the metabolic precursor for dopamine.<ref name="Nice-pharma"/> L-DOPA is converted to dopamine in the brain and various parts of the body by the enzyme DOPA decarboxylase.<ref name=Musacchio/> L-DOPA is used rather than dopamine itself because, unlike dopamine, it is capable of crossing the [[blood–brain barrier]].<ref name="Nice-pharma">{{cite book| chapter=Symptomatic pharmacological therapy in Parkinson's disease| editor=The National Collaborating Centre for Chronic Conditions| title=Parkinson's Disease| chapter-url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English| access-date=24 September 2015| publisher=Royal College of Physicians| location=London| year=2006| isbn=978-1-86016-283-1| pages=59–100| archive-date=24 September 2010| archive-url=https://web.archive.org/web/20100924153546/http://guidance.nice.org.uk/CG35/Guidance/pdf/English| url-status=dead}}</ref> It is often co-administered with an [[enzyme inhibitor]] of peripheral [[decarboxylation]] such as [[carbidopa]] or [[benserazide]], to reduce the amount converted to dopamine in the periphery and thereby increase the amount of L-DOPA that enters the brain.<ref name="Nice-pharma"/> When L-DOPA is administered regularly over a long time period, a variety of unpleasant side effects such as [[dyskinesia]] often begin to appear; even so, it is considered the best available long-term treatment option for most cases of Parkinson's disease.<ref name="Nice-pharma"/>

L-DOPA treatment cannot restore the dopamine cells that have been lost, but it causes the remaining cells to produce more dopamine, thereby compensating for the loss to at least some degree.<ref name="Nice-pharma"/> In advanced stages the treatment begins to fail because the cell loss is so severe that the remaining ones cannot produce enough dopamine regardless of L-DOPA levels.<ref name="Nice-pharma"/> Other drugs that enhance dopamine function, such as [[bromocriptine]] and [[pergolide]], are also sometimes used to treat Parkinsonism, but in most cases L-DOPA appears to give the best trade-off between positive effects and negative side-effects.<ref name="Nice-pharma"/>

Dopaminergic medications that are used to treat Parkinson's disease are sometimes associated with the development of a [[dopamine dysregulation syndrome]], which involves the overuse of dopaminergic medication and medication-induced compulsive engagement in [[natural reward]]s like gambling and sexual activity.<ref name="Natural and drug addictions">{{cite journal | vauthors = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = <!-- Notably, sensitization processes can also translate between drug and non-drug rewards (Fiorino and Phillips, 1999; Avena and Hoebel, 2003b; Robinson and Berridge, 2008). 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). --> }}</ref><ref name="DDS in PD">{{cite journal | vauthors = Ceravolo R, Frosini D, Rossi C, Bonuccelli U | s2cid = 19277026 | title = Spectrum of addictions in Parkinson's disease: from dopamine dysregulation syndrome to impulse control disorders | journal = Journal of Neurology | volume = 257 | issue = Suppl 2 | pages = S276–83 | date = November 2010 | pmid = 21080189 | doi = 10.1007/s00415-010-5715-0 }}</ref> The latter behaviors are similar to those observed in individuals with a [[behavioral addiction]].<ref name="Natural and drug addictions" />

===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>

===Psychosis and antipsychotic drugs===
{{Main|Psychosis}}
Psychiatrists in the early 1950s discovered that a class of drugs known as [[typical antipsychotic]]s (also known as major [[tranquilizer]]s), were often effective at reducing the [[psychotic]] symptoms of schizophrenia.<ref name=Healy/> The introduction of the first widely used antipsychotic, [[chlorpromazine]] (Thorazine), in the 1950s, led to the release of many patients with schizophrenia from institutions in the years that followed.<ref name=Healy/> By the 1970s researchers understood that these typical antipsychotics worked as [[receptor antagonists|antagonists]] on the D<sub>2</sub> receptors.<ref name=Healy/><ref name=Brunton>{{cite book | vauthors = Brunton L | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics|publisher=McGraw Hill|pages=417–55|edition=12th}}</ref> This realization led to the so-called [[dopamine hypothesis of schizophrenia]], which postulates that schizophrenia is largely caused by hyperactivity of brain dopamine systems.<ref name="Howes">{{cite journal | vauthors = Howes OD, Kapur S | title = The dopamine hypothesis of schizophrenia: version III—the final common pathway | journal = Schizophrenia Bulletin | volume = 35 | issue = 3 | pages = 549–62 | date = May 2009 | pmid = 19325164 | pmc = 2669582 | doi = 10.1093/schbul/sbp006 }}</ref> The dopamine hypothesis drew additional support from the observation that psychotic symptoms were often intensified by dopamine-enhancing stimulants such as methamphetamine, and that these drugs could also produce psychosis in healthy people if taken in large enough doses.<ref name=Howes/> In the following decades other [[atypical antipsychotics]] that had fewer serious side effects were developed.<ref name=Healy/> Many of these newer drugs do not act directly on dopamine receptors, but instead produce alterations in dopamine activity indirectly.<ref name=Horacek>{{cite journal | vauthors = Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, Höschl C | s2cid = 18226404 | title = Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia | journal = CNS Drugs | volume = 20 | issue = 5 | pages = 389–409 | year = 2006 | pmid = 16696579 | doi = 10.2165/00023210-200620050-00004 }}</ref> These drugs were also used to treat other psychoses.<ref name=Healy>{{Cite book |title=The Creation of Psychopharmacology | vauthors = Healy D |year=2004 |publisher=Harvard University Press |pages=37–73  |isbn=978-0-674-01599-9 }}</ref> [[Antipsychotic drugs]] have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis.<ref name=Brunton/>

Later observations, however, have caused the dopamine hypothesis to lose popularity, at least in its simple original form.<ref name=Howes/> For one thing, patients with schizophrenia do not typically show measurably increased levels of brain dopamine activity.<ref name=Howes/> Even so, many psychiatrists and neuroscientists continue to believe that schizophrenia involves some sort of dopamine system dysfunction.<ref name=Healy/> As the "dopamine hypothesis" has evolved over time, however, the sorts of dysfunctions it postulates have tended to become increasingly subtle and complex.<ref name=Healy/>

[[Psychopharmacology|Psychopharmacologist]] [[Stephen Stahl|Stephen M. Stahl]] suggested in a review of 2018 that in many cases of psychosis, including schizophrenia, three interconnected networks based on dopamine, serotonin, and glutamate – each on its own or in various combinations – contributed to an overexcitation of dopamine D<sub>2</sub> receptors in the [[ventral striatum]].<ref name="pmid29954475">{{cite journal| vauthors = Stahl SM| title=Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. | journal=CNS Spectr | year= 2018 | volume= 23 | issue= 3 | pages= 187–91 | pmid=29954475 | doi=10.1017/S1092852918001013 | s2cid=49599226 | url=https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3E9E50ED717219011DD1B570365010E8/S1092852918001013a.pdf/beyond_the_dopamine_hypothesis_of_schizophrenia_to_three_neural_networks_of_psychosis_dopamine_serotonin_and_glutamate.pdf |archive-url=https://web.archive.org/web/20200429212444/https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3E9E50ED717219011DD1B570365010E8/S1092852918001013a.pdf/beyond_the_dopamine_hypothesis_of_schizophrenia_to_three_neural_networks_of_psychosis_dopamine_serotonin_and_glutamate.pdf |archive-date=2020-04-29 |url-status=live }}</ref>

===Attention deficit hyperactivity disorder===
{{Main|Attention deficit hyperactivity disorder}}
Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), a condition associated with impaired [[cognitive control]], in turn leading to problems with regulating attention ([[attentional control]]), inhibiting behaviors ([[inhibitory control]]), and forgetting things or missing details ([[working memory]]), among other problems.<ref name="Malenka ADHD neurosci">{{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 = 266, 318–23 | edition = 2nd | chapter = Chapters 10 and 13}}</ref> There are genetic links between dopamine receptors, the dopamine transporter, and ADHD, in addition to links to other neurotransmitter receptors and transporters.<ref name=Wu>{{cite journal | vauthors = Wu J, Xiao H, Sun H, Zou L, Zhu LQ | s2cid = 895006 | title = Role of dopamine receptors in ADHD: a systematic meta-analysis | journal = Molecular Neurobiology | volume = 45 | issue = 3 | pages = 605–20 | date = June 2012 | pmid = 22610946 | doi = 10.1007/s12035-012-8278-5 }}</ref> The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD.<ref name=Berridge3/> Some of the most effective therapeutic agents for ADHD are psychostimulants such as methylphenidate (Ritalin, Concerta) and [[amphetamine]] (Evekeo, Adderall, Dexedrine), drugs that increase both dopamine and norepinephrine levels in the brain.<ref name="Berridge3">{{cite journal | vauthors = Berridge CW, Devilbiss DM | title = Psychostimulants as cognitive enhancers: the prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder | journal = Biological Psychiatry | volume = 69 | issue = 12 | pages = e101–11 | date = June 2011 | pmid = 20875636 | pmc = 3012746 | doi = 10.1016/j.biopsych.2010.06.023 }}</ref> The clinical effects of these psychostimulants in treating ADHD are mediated through the [[indirect agonist|indirect activation]] of dopamine and norepinephrine receptors, specifically [[Dopamine receptor D1|dopamine receptor D<sub>1</sub>]] and [[Alpha-2 adrenergic receptor|adrenoceptor α<sub>2</sub>]], in the prefrontal cortex.<ref name="Malenka ADHD neurosci" /><ref name="Unambiguous PFC D1 A2">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex | journal = Biological Psychiatry | volume = 77 | issue = 11 | pages = 940–50 | date = June 2015 | pmid = 25499957 | pmc = 4377121 | doi = 10.1016/j.biopsych.2014.09.013 }}</ref><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | s2cid = 15788121 | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = Journal of Cognitive Neuroscience | volume = 27 | issue = 6 | pages = 1069–89 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | url = https://repository.upenn.edu/neuroethics_pubs/130 }}</ref>

===Pain===
Dopamine plays a role in [[pain]] processing in multiple levels of the central nervous system including the spinal cord, [[periaqueductal gray]], [[thalamus]], basal ganglia, and [[cingulate cortex]].<ref name="Wood" /> Decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease.<ref name="Wood" /> Abnormalities in dopaminergic neurotransmission also occur in several painful clinical conditions, including [[burning mouth syndrome]], [[fibromyalgia]], and restless legs syndrome.<ref name=Wood>{{cite journal | vauthors = Wood PB | s2cid = 24325199 | title = Role of central dopamine in pain and analgesia | journal = Expert Review of Neurotherapeutics | volume = 8 | issue = 5 | pages = 781–97 | date = May 2008 | pmid = 18457535 | doi = 10.1586/14737175.8.5.781 }}</ref>

===Nausea===
Nausea and [[vomiting]] are largely determined by activity in the [[area postrema]] in the [[medulla oblongata|medulla]] of the [[brainstem]], in a region known as the [[chemoreceptor trigger zone]].<ref name=Flake>{{cite journal | vauthors = Flake ZA, Scalley RD, Bailey AG | title = Practical selection of antiemetics | journal = American Family Physician | volume = 69 | issue = 5 | pages = 1169–74 | date = March 2004 | pmid = 15023018 | url = http://www.aafp.org/afp/2004/0301/p1169.html }}</ref> This area contains a large population of type D<sub>2</sub> dopamine receptors.<ref name=Flake/> Consequently, drugs that activate D<sub>2</sub> receptors have a high potential to cause nausea.<ref name=Flake/> This group includes some medications that are administered for Parkinson's disease, as well as other [[dopamine agonists]] such as [[apomorphine]].<ref name=Connolly>{{cite journal | vauthors = Connolly BS, Lang AE | title = Pharmacological treatment of Parkinson disease: a review | journal = JAMA | volume = 311 | issue = 16 | pages = 1670–83 | year = 2014 | pmid = 24756517 | doi = 10.1001/jama.2014.3654 }}</ref> In some cases, D<sub>2</sub>-receptor antagonists such as [[metoclopramide]] are useful as [[anti-emetics|anti-nausea drugs]].<ref name=Flake/>

'''Fear and anxiety'''

Simultaneous [[positron emission tomography]] (PET) and [[functional magnetic resonance imaging]] (fMRI), have shown that the amount of dopamine release is dependent on the strength of conditioned fear response and is linearly coupled to learning-induced activity in the amygdala.<ref>{{cite journal | vauthors = Frick A, Björkstrand J, Lubberink M, Eriksson A, Fredrikson M, Åhs F | title = Dopamine and fear memory formation in the human amygdala | journal = Molecular Psychiatry | volume = 27 | issue = 3 | pages = 1704–1711 | date = March 2022 | pmid = 34862441 | doi = 10.1038/s41380-021-01400-x | pmc = 9095491 }}</ref> Dopamine is generally linked to reward learning, but it also plays a key role in fear learning and extinction by helping to form, store and update fear memories through its interaction with other brain regions like amygdala, ventromedial prefrontal cortex and striatum.<ref>{{cite journal | vauthors = Hamati R, Ahrens J, Shvetz C, Holahan MR, Tuominen L | title = 65 years of research on dopamine's role in classical fear conditioning and extinction: A systematic review | journal = The European Journal of Neuroscience | volume = 59 | issue = 6 | pages = 1099–1140 | date = March 2024 | pmid = 37848184 | doi = 10.1111/ejn.16157 | doi-access = free }}</ref>