Dopamine receptors are all G protein–coupled receptors, and are divided into two classes based on which G-protein they are coupled to.[1] 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.[1]
Peripherally, these receptors have been found in the renal artery, mesenteric artery, and splenic artery where activation leads to vasodilation.[3] In addition, D1 receptors have been found in the kidney[3]
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 are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tubercle.[1]
These receptors have also been found in the retina and pituitary gland.[1]
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.[3]
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.[1][2]
Additional studies have found these receptors peripherally in the kidney[3]
D4 receptors are found in amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney[1][3]
The dopaminergic system has been implicated in a variety of disorders. Parkinson's disease results from loss of dopaminergic neurons in the striatum.[1] Furthermore, most effective antipsychotics block D2 receptors, suggesting a role for dopamine in schizophrenia.[1][4][3] Additional studies hypothesize dopamine dysregulation is involved in Huntington's disease, ADHD, Tourette's syndrome, major depression, manic depression, addiction, hypertension and kidney dysfunction.[1][3][5] Dopamine receptor antagonists are used for some diseases such as schizophrenia, bipolar disorder, nausea and vomiting.[1]
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:
First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects.[1] They inhibit dopaminergic neurotransmission in the brain by blocking about 72% of the D2 dopamine receptors.[15] They can also block noradrenergic, cholinergic, and histaminergic activity.[15]
Pimozide binds D2 and D3 with high affinity, also binds D4 receptors[1][2]
Spiperone binds D2, D3 and D4 with high affinity; can also bind D1[1][2]
Sulpiride binds D2 and D3[1][2] and is also used as an antidepressant.[1]
Thioridazine binds D2, D3 and D4 with high affinity; can also bind D1 and D5 at higher concentrations[2] Thioridazine has the highest associated risk of QTc prolongation among neuroleptics.[17]
These drugs are not only dopamine antagonists at the receptor specified, but also act on serotonin receptor 5HT2A.[15][1] These drugs have fewer extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics.[11]
Amisulpride binds D2 and D3[2] and is used as an antipsychotic, antidepressant and also treats bipolar disorder.[1] It treats both the positive and negative symptoms of schizophrenia.[13]
Asenapine binds D2, D3 and D4[18] and is used to treat bipolar disorder and schizophrenia.[19] 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 D3.[20] In addition, aripiprazole treats schizophrenia, bipolar disorder (mania),[21] depression,[1] and tic disorders[20]
Clozapine
Clozapine binds D1 and D4 with the highest affinity but still binds D2 and D3.[2] 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.[13] It also requires weekly white blood cell counts to monitor potential neutropenia.[13]
Loxapine binds D2, D3 and D4 with high affinity; can also bind D1.[22] Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia.[23]
Olanzapine binds all receptors[2] and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression.[1] It has been associated with significant weight gain.[13]
Quetiapine binds D1, D2 and D3 and can bind D4 at high concentrations.[2] It is used to treat the positive symptoms of schizophrenia,[13] bipolar disorder and depression.[1] Of the second generation antipsychotics, quetiapine may produce fewer parkinsonian side effects.[24]
Paliperidone binds D2, D3 and D4 with high affinity; can also bind D1 and D5.[25]
Risperidone binds D2, D3 and D4 receptors.[1][2][25] Risperidone not only treats the positive and negative symptoms of schizophrenia[13] but also treats bipolar disorder.[1]
Tiapride blocks D2 and D3 and is used as an antipsychotic.[1] It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence.[26]
Ziprasidone blocks the D2 receptor[27] and is used to treat schizophrenia, depression and bipolar disorder.[1] There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects.[13] Ziprasidone can also cause QTc prolongation.[17]
Dopamine antagonists used to treat nausea and vomiting[edit]
Domperidone is a peripherally selective dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent and galactagogue.
^ abcdefghijklmnopqrsSokoloff 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. PMID16613552.
^Zisapel N (December 2001). "Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting". Cellular and Molecular Neurobiology. 21 (6): 605–16. doi:10.1023/A:1015187601628. PMID12043836. S2CID25508148.
^Willis GL (2008). "Parkinson's disease as a neuroendocrine disorder of circadian function: dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process". Reviews in the Neurosciences. 19 (4–5): 245–316. doi:10.1515/revneuro.2008.19.4-5.245. PMID19145986. S2CID29375454.
^ abcdefYoung SL, Taylor M, Lawrie SM (April 2015). ""First do no harm." A systematic review of the prevalence and management of antipsychotic adverse effects". Journal of Psychopharmacology. 29 (4): 353–62. doi:10.1177/0269881114562090. PMID25516373. S2CID8345032.
^ abcArana GW (2000). "An overview of side effects caused by typical antipsychotics". The Journal of Clinical Psychiatry. 61 (Suppl 8): 5–11, discussion 12–3. PMID10811237.
^Stoner SC, Pace HA (May 2012). "Asenapine: a clinical review of a second-generation antipsychotic". Clinical Therapeutics. 34 (5): 1023–40. doi:10.1016/j.clinthera.2012.03.002. PMID22494521.
^Pollack CV (July 2016). "Inhaled loxapine for the urgent treatment of acute agitation associated with schizophrenia or bipolar disorder". Current Medical Research and Opinion. 32 (7): 1253–60. doi:10.1185/03007995.2016.1170004. PMID27121764. S2CID4402288.
^Dose M, Lange HW (January 2000). "The benzamide tiapride: treatment of extrapyramidal motor and other clinical syndromes". Pharmacopsychiatry. 33 (1): 19–27. doi:10.1055/s-2000-7964. PMID10721880. S2CID260238868.
^Stahl SM, Shayegan DK (2003). "The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice". The Journal of Clinical Psychiatry. 64 (Suppl 19): 6–12. PMID14728084.
