Dopamine antagonist

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Dopamine receptor antagonist
Dopaminergic blockers
Drug class
Haloperidol
Class identifiers
UseSchizophrenia, bipolar disorder, nausea and vomiting, etc.
ATC codeN05A
Biological targetDopamine receptors
External links
MeSHD012559
In Wikidata

A dopamine antagonist (antidopaminergic) 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[edit]

Dopamine Receptor Flow Chart

All dopamine receptors are G-protein coupled and are divided into 2 classes based on which G-protein they are coupled to.[2] The D1-like class of dopamine receptors is coupled to Gαs/olf and stimulates adenylate cyclase production, whereas the D2-like class is coupled to Gαi/o and thus inhibits adenylate cyclase production.[2]

D1-like receptors: D1 and D5[edit]

These receptors are always found post-synaptically. The genes coding these receptors lack introns, so there are no splice variants.

D1 receptors[edit]

D5 receptors[edit]

D2-like receptors: D2, D3 and D4[edit]

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[edit]

  • D2 receptors are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tuburcle[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[edit]

  • These 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 periperally in the kidney[4]

D4 receptors[edit]

  • These receptors are found in amygdala, hippocamps, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney [2][4]

Implications in Disease[edit]

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].

Side effects[edit]

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:

Examples[edit]

First Generation Antipsychotics (Typical antipsychotics)[edit]

First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects[18].

Chemical Structure of typical antipsychotic chlorpromazine
  • Sulpiride - binds D2 and D3[18][20] and is also used as an antidepressant.[18]
  • Thioridazine - binds D2, D3 and D4 with high affinity; can also bind D1 and D5 at higher concentrations[20]

Second Generation Antipsychotics (Atypical Antipsychotics)[edit]

These drugs are not only dopamine antagonists at the receptor specified, but also act on serotonin receptor 5HT2A.[22] These drugs have less extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics. [23]

  • Amisulpride binds D2 and D3[24] and is used as an antipsychotic, antidepressant and also treats bipolar disorder.[22] It treats both the positive and negative symptoms of schizophrenia. [25]
  • Asenapine binds D2, D3 and D4[26] and is used to treat bipolar disorder and schizophrenia.[27] Its side effects include weight gain but there is lower risk for orthostatic hypotension, hyperprolactinemia
  • Aripriprazole binds D2 as a partial agonist but antagonizes D3.[28] In addition, aripriprazole treats schizophrenia, bipolar disorder (mania)[29], depression,[22] and tic disorders [28]
Clozapine
  • Clozapine - binds D1 and D4 with the highest affinity but still binds D2 and D3.[30] 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.[31] It also requires weekly white blood cell counts to monitor potential neutropenia.[31]
  • Loxapine binds D2, D3 and D4 with high affinity; can also bind D1.[32] Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia. [33]
  • Nemonapride binds D3, D4 and D5. [34]
  • Olanzapine binds all receptors[35] and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression.[36] It has been associated with significant weight gain.[37]
  • Quetiapine binds D1, D2 and D3 and can bind D4 at high concentrations.[35] It is used to treat the positive symptoms of schizophrenia[37], bipolar disorder and depression.[36]
  • Paliperidone binds D2, D3 and D4 with high affinity; can also bind D1 and D5[38].
  • Tiapride blocks D2 and D3 and is used as an antipsychotic[36]. It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence.[40]
  • Ziprasidone blocks the D2 receptor [41] and is used to treat schizophrenia, depression and bipolar disorder.[36] There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects. [37]

Dopamine antagonists used to treat nausea and vomiting[edit]

Antagonists used only in research settings[edit]

References[edit]

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  2. ^ a b c d e f g h i j k l m Beaulieu JM, Gainetdinov RR (March 2011). "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacological Reviews. 63 (1): 182–217. doi:10.1124/pr.110.002642. PMID 21303898.
  3. ^ a b Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, Gross C (February 2006). "The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders". CNS & Neurological Disorders Drug Targets. 5 (1): 25–43. doi:10.2174/187152706784111551. PMID 16613552.
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External links[edit]