Dopamine antagonist

Dopamine receptor antagonist Dopaminergic blockers
Drug class
Skeletal structural formula of Haloperidol, a typical antipsychotic
Class identifiers
Use	Schizophrenia, bipolar disorder, nausea and vomiting, etc.
ATC code	N05A
Biological target	Dopamine receptors
External links
MeSH	D012559
In Wikidata

Not to be confused with dopamine reuptake inhibitor.

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. ^[1] Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

Receptor pharmacology

Dopamine receptor flow chart

Dopamine receptors are all G protein–coupled receptors, and are divided into two classes based on which G-protein they are coupled to. ^[2] The D₁-like class of dopamine receptors is coupled to Gα_s/olf and stimulates adenylate cyclase production, whereas the D₂-like class is coupled to Gα_i/o and thus inhibits adenylate cyclase production. ^[2]

D₁-like receptors: D₁ and D₅

D1-like receptors – D₁ and D₅ are always found post-synaptically. The genes coding these receptors lack introns, so there are no splice variants.

D₁ receptors

• D₁ receptors are found mainly on neurons in the nucleus accumbens ^[3] as well as substantia nigra, ^[2] striatum, ^[2] amygdala, ^[2] frontal cortex ^[2] and olfactory bulb and retina ^[2]
• Also found (in lower levels) in the hypothalamus, thalamus, cerebellum and hippocampus ^[2]
• Peripherally, these receptors have been found in the renal artery, mesenteric artery, and splenic artery where activation leads to vasodilation. ^[4] In addition, D₁ receptors have been found in the kidney ^[4]

D₅ receptors

• Low levels of D₅ receptors have been found in the hypothalamus, prefrontal cortex and cingulate cortex; as well as memory areas such as hippocampus, dentate gyrus and entorhinal cortex. ^[2]
• In addition, D₅ receptors have been found in the kidney ^[4]

D₂-like receptors: D₂, D₃ and D₄

D₂-like receptors unlike the D₁-like class, these receptors are found pre and post-synaptically. The genes that code these receptors have introns, leading to many alternately spliced variants.

D₂ receptors

• D₂ receptors are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tubercle. ^[2]
• These receptors have also been found in the retina and pituitary gland. ^[2]
• Peripherally, these receptors have been found in the renal, mesenteric, and splenic arteries as well as on the adrenal cortex and medulla and within the kidney. ^[4]

D₃ receptors

• D₃ receptors are highly expressed on neurons in islands of Calleja and nucleus accumbens shell and lowly expressed in areas such as the substantia nigra pars compacta, hippocampus, septal area, and ventral tegmental area. ^{[2] [3]}
• Additional studies have found these receptors peripherally in the kidney ^[4]

D₄ receptors

• D₄ receptors are found in amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney ^{[2] [4]}

Implications in disease

The dopaminergic system has been implicated in a variety of disorders. Parkinson's disease results from loss of dopaminergic neurons in the striatum. ^[5] Furthermore, most effective antipsychotics block D₂ receptors, suggesting a role for dopamine in schizophrenia. ^{[5] [6] [7]} Additional studies hypothesize dopamine dysregulation is involved in Huntington's disease, ADHD, Tourette's syndrome, major depression, manic depression, addiction, hypertension and kidney dysfunction. ^{[5] [7] [8]} Dopamine receptor antagonists are used for some diseases such as schizophrenia, bipolar disorder, nausea and vomiting. ^[5]

• Melatonin suppresses dopamine activity ^[9] as part of normal circadian rhythm functions, although pathological imbalances have been implicated in Parkinson's disease ^[10]

Side effects

They may include one or more of the following and last indefinitely even after cessation of the dopamine antagonist, especially after long-term or high-dosage use:

• Cardiovascular disease ^{[11] [12]}

  

• Extrapyramidal symptoms (EPS) associated with typical antipsychotics:
  • Early stage – occurs at onset of treatment or following increased dose, patients recover when dose is decreased ^[13]
    • Acute dystonias ^[13] – muscle spasms and sustained abnormal postures and onset occurs within a few days; can be treated with anticholinergics
      • risk factors include age, gender and family history ^[13]
    • Akathisia ^{[13] [14]} - pacing and restlessness and onset occurs within the first few months; can be treated with beta blockers and benzodiazepines
    • Parkinsonism due to effects on the nigrostriatal pathway ^{[13] [14]} - includes tremors, bradykinesia and muscle rigidity
      • risk factors include age and gender ^[13]
  • Late stage – occurs after prolonged (months-years) treatment, symptoms persist even after dose is decreased ^[13]
    • Tardive dyskinesia ^{[13] [14]} - includes involuntary and repetitive facial movements
      • risk factors include age, race and gender ^[13]
  • It is hypothesized that these effects are due to chronic blockade of the D₂ receptor ^[14]
• Hyperprolactinaemia due to blockade of the D₂ receptors in the anterior pituitary leading to increased prolactin release ^{[11] [15]}
• Increased appetite including increased craving and binge eating that lead to weight gain ^{[11] [16] [17]}
• Increased risk for insulin resistance ^[16]
• Sexual dysfunction ^{[11] [12]}
• Metabolic changes with increased risk of obesity and diabetes mellitus type 2 ^{[11] [16]}
• Sedation ^{[11] [12]}
• Neuroleptic Malignant Syndrome ^[18] is a medical emergency caused by a decrease in dopaminergic activity, resulting in a central D₂ receptor blockade. ^[18]

Examples

First-generation antipsychotics (typical)

First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects. ^[19] They inhibit dopaminergic neurotransmission in the brain by blocking about 72% of the D2 dopamine receptors. ^[20] They can also block noradrenergic, cholinergic, and histaminergic activity. ^[20]

• Benperidol ^[19] binds D₂ and some serotonin receptors. ^[21] It is absorbed very easily and has a high first pass effect. ^[21]
• Chlorpromazine binds D₃ with the highest affinity, but also binds D₁, D₂, D₄ and D₅ ^{[22] [23]}

Chemical Structure of typical antipsychotic chlorpromazine

• Clopenthixol ^[19]
• Droperidol is used as an antipsychotic and antiemetic. ^[19]
• Haloperidol binds D₂, D₃ and D₄ with the highest affinity, but also binds D₁ and D_5. ^{[19] [22] [23]} Haloperidol also has a risk for QTc prolongation. ^[24]
• Fluphenazine binds D₂ and D₃ with the highest affinity but D₁ and D₅ as well ^{[19] [22]}
• Flupentixol binds D₁, D₂, D₃, and D₅ ^[22] and is also used as an antidepressant. ^[19]
• Fluspirilene ^[19]
• Penfluridol ^[19]
• Perazine ^[19]

• Perphenazine ^[19]
• Pimozide binds D₂ and D₃ with high affinity, also binds D₄ receptors ^{[19] [22]}

• Spiperone binds D₂, D₃ and D₄ with high affinity; can also bind D₁ ^{[19] [22]}

• Sulpiride binds D₂ and D₃ ^{[19] [22]} and is also used as an antidepressant. ^[19]
• Thioridazine binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅ at higher concentrations ^[22] Thioridazine has the highest associated risk of QTc prolongation among neuroleptics. ^[24]

Second-generation antipsychotics (atypical)

These drugs are not only dopamine antagonists at the receptor specified, but also act on serotonin receptor 5HT_2A. ^{[20] [25]} (Citation inappropriate) These drugs have less extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics. ^[26]

• Amisulpride binds D₂ and D₃ ^[27] and is used as an antipsychotic, antidepressant and also treats bipolar disorder. ^[25] It treats both the positive and negative symptoms of schizophrenia. ^[28]
• Asenapine binds D₂, D₃ and D₄ ^[29] and is used to treat bipolar disorder and schizophrenia. ^[30] Its side effects include weight gain but there is lower risk for orthostatic hypotension and hyperprolactinemia.
• Aripiprazole binds D₂ as a partial agonist but antagonizes D_3. ^[31] In addition, aripiprazole treats schizophrenia, bipolar disorder (mania), ^[32] depression, ^[25] and tic disorders ^[31]

Clozapine

• Clozapine binds D₁ and D₄ with the highest affinity but still binds D₂ and D₃. ^[33] Clozapine is unique because it is only prescribed when treatment with at least two other antipsychotics has failed due to its very harsh side effects. ^[34] It also requires weekly white blood cell counts to monitor potential neutropenia. ^[34]

• Loxapine binds D₂, D₃ and D₄ with high affinity; can also bind D_1. ^[35] Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia. ^[36]
• Nemonapride binds D₃, D₄ and D_5. ^[37]
• Olanzapine binds all receptors ^[38] and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression. ^[39] It has been associated with significant weight gain. ^[40]

• Quetiapine binds D₁, D₂ and D₃ and can bind D₄ at high concentrations. ^[38] It is used to treat the positive symptoms of schizophrenia, ^[40] bipolar disorder and depression. ^[39] Of the second generation antipsychotics, quetiapine may produce fewer parkinsonian side effects. ^[41]
• Paliperidone binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅. ^[42]

• Remoxipride binds D₂ receptors with relatively low affinity. ^{[38] [43] [39]}
• Risperidone binds D₂, D₃ and D₄ receptors. ^{[39] [38] [42]} Risperidone not only treats the positive and negative symptoms of schizophrenia ^[40] but also treats bipolar disorder. ^[39]

• Tiapride blocks D₂ and D₃ and is used as an antipsychotic. ^[39] It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence. ^[44]
• Ziprasidone blocks the D₂ receptor ^[45] and is used to treat schizophrenia, depression and bipolar disorder. ^[39] There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects. ^[40] Ziprasidone can also cause QTc prolongation. ^[24]

Dopamine antagonists used to treat nausea and vomiting

• Domperidone is a peripherally selective dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent and galactagogue.
• Bromopride binds enteric D₂ receptors ^[46] and also treats gastroparesis. ^[47]
• Metoclopramide also treats gastroparesis ^[47]

Antagonists used only in research settings

• Eticlopride binds D₂ and D₃ with high affinity but also binds D4 ^{[48] [49] [50]}
• Nafadotride binds D₂ and D₃ ^{[47] [48] [49]}
• Raclopride binds D₂ and D₃ ^{[47] [48]} and can be radiolabeled and used in PET imaging to identify disease progression in Huntington's Disease ^[51]

References

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External links

• Dopamine+antagonists at the U.S. National Library of Medicine Medical Subject Headings (MeSH)