Diseases and disorders::Dopamine


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Diseases and disorders The dopamine system plays a central role in important medical conditions including Parkinson's disease, attention deficit hyperactivity disorder, schizophrenia, and drug addiction.

Parkinson's disease

Parkinson's disease is an age-related disorder characterized by stiffness of the body, slowing of movement, and trembling of limbs when they are not in use.<ref name=Jankovic>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In advanced stages it progresses to dementia and eventually death.<ref name=Jankovic/> The main symptoms are caused by a massive loss of dopamine-secreting cells in the substantia nigra.<ref name=Dickson>{{#invoke:citation/CS1|citation |CitationClass=book }}</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 concussions, and some forms of chemical poisoning such as MPTP, can lead to substantial cell loss, producing a parkinsonian syndrome that is similar in its main features to Parkinson's disease.<ref name=Tuite>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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"/> This 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"/> As this stage is approached, the metabolic regulatory mechanisms in the dopamine cells, operating far above their normal level, become erratic, producing dopamine dysregulation syndrome, in which patients fluctuate unpredictably between states of hyperactivity and paralysis.<ref name=Merims>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Other drugs that enhance dopamine function, such as bromocryptine and pergolide, are also sometimes used to treat Parkinsonism, but in most cases L-DOPA appears to give the best tradeoff between positive effects and negative side-effects.<ref name="Nice-pharma"/>

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">{{#invoke:citation/CS1|citation |CitationClass=book }}</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>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD.<ref name=Berridge2/> Some of the most effective therapeutic agents for ADHD are psychostimulants such as methylphenidate (Ritalin, Concerta) and amphetamine (Adderall, Dexedrine), drugs that increase both dopamine and norepinephrine levels in the brain.<ref name=Berridge3>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, stimulants produce unambiguous improvements in working memory, episodic memory, and inhibitory control in adults.<ref name="Unambiguous PFC D1 A2">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref name="Cognitive and motivational effects">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> These clinical effects of psychostimulants are mediated through the indirect activation of dopamine and norepinephrine receptors, specifically dopamine receptor D1 and adrenoceptor A2, in the prefrontal cortex.<ref name="Malenka ADHD neurosci" />

Drug addiction


A shiny translucent white crystal of methamphetamine, held between the ends of a finger and thumb
Metamphetamine hydrochloride also known as crystal meth

A variety of addictive drugs produce an increase in reward-related dopamine activity.<ref name=Ghodse/> For some addictive drugs such as heroin, altered dopamine levels in the reward system may play only a minor role in addiction, but for other drugs, including nicotine and psychomotor stimulants such as cocaine and methamphetamine, increased postsynaptic dopamine receptor activation or increased levels of synaptic dopamine appear to be the primary factor.<ref name=Nutt>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with withdrawal from alcohol or opiates; instead they experience "craving", an intense desire for the drug characterized by irritability, restlessness, and other arousal symptoms.<ref name=Sinha>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

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>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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 stimulant consumption triggers a wide-ranging set of structural changes in the brain, one of which is a reduction in responses to dopamine in the basal ganglia, with the consequence that every type of experience is perceived as less rewarding than before drug consumption began.<ref name="Nestler">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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 a person experiences environmental stimuli (friends, locations, situations, etc.) that are associated with the drug.<ref name=Sinha/>


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>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>


Nausea and vomiting are largely determined by activity in an area of the medulla of the brainstem known as the chemoreceptor trigger zone.<ref name=Flake>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> This area contains a large population of type D2 dopamine receptors.<ref name=Flake/> Consequently, drugs that activate D2 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>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In some cases, D2-receptor antagonists such as metoclopramide are useful as anti-nausea drugs.<ref name=Flake/>


{{#invoke:main|main}} As outlined in the section above on antipsychotic drugs, psychiatrists in the early 1950s discovered that a class of drugs known as major tranquilizers were often effective at reducing the psychotic symptoms of schizophrenia.<ref name=Healy/> By the 1970s researchers came to an understanding that the primary neural effect of these antipsychotic drugs is to reduce the activity of dopamine systems.<ref name=Healy/> The realization that all then-known antipsychotic drugs reduce dopamine activity led researchers in the 1970s to propose the so-called dopamine hypothesis of schizophrenia, which postulates that schizophrenia is caused, at least in the majority of cases, by hyperactivity of brain dopamine systems.<ref name=Howes>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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 produce psychosis even in healthy people if taken in large doses.<ref name=Howes/>

Other 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/> Also, a variety of drugs acting by mechanisms that don't appear to involve dopamine can produce psychotic symptoms, most notably ketamine and phencyclidine (PCP), whose direct effects are on glutamate NMDA receptors.<ref name=Howes/> Perhaps most importantly, drugs that reduce dopamine activity are a very imperfect treatment for schizophrenia: they only reduce a subset of symptoms, while producing severe short-term and long-term side effects.<ref name=Muench/> 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/>

Dopamine sections
Intro  Structure  Biochemistry  Functions  Medical uses  Pharmacology  Diseases and disorders  Comparative biology and evolution  History and development  See also   References   

Diseases and disorders
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