Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
Dopamine receptors are implicated in many neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders. Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.
- 1 Dopamine receptor subtypes
- 2 Role of dopamine receptors in the central nervous system
- 3 Non-CNS dopamine receptors
- 4 Dopamine receptors in disease
- 5 Dopamine regulation
- 6 See also
- 7 External links
- 8 References
Dopamine receptor subtypes
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The existence of multiple types of receptors for dopamine was first proposed in 1976. There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 receptors are members of the D2-like family. There is also some evidence that suggests the existence of possible D6 and D7 dopamine receptors, but such receptors have not been conclusively identified.
At a global level, D1 receptors have widespread expression throughout the brain. Furthermore, D1-2 receptor subtypes are found at 10-100 times the levels of the D3-5 subtypes.
Activation of D1-like family receptors is coupled to the G protein Gsα, which subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).
- D2 is encoded by the Dopamine receptor D2 gene (DRD2), of which there are two forms: D2Sh (short) and D2Lh (long):
- The D2Sh form is pre-synaptically situated, having modulatory functions (viz., autoreceptors, which regulate neurotransmission via feedback mechanisms. It affects synthesis, storage, and release of dopamine into the synaptic cleft).
- The D2Lh form may function as a classical post-synaptic receptor, i.e., transmit information (in either an excitatory or an inhibitory fashion) unless blocked by a receptor antagonist or a synthetic partial agonist.
- D3 is encoded by the Dopamine receptor D3 gene (DRD3). Maximum expression of dopamine D3 receptors is noted in the islands of Calleja and nucleus accumbens.
- D4 is encoded by the Dopamine receptor D4 gene (DRD4). The D4 receptor gene displays polymorphisms that differ in a variable number tandem repeat present within the coding sequence of exon 3. Some of these alleles are associated with greater incidence of certain diseases. For example, the D4.7 alleles have an established association with attention-deficit hyperactivity disorder.
Role of dopamine receptors in the central nervous system
Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory. Although dopamine receptors are widely distributed in the brain, different areas have different receptor types densities, presumably reflecting different functional roles.
Non-CNS dopamine receptors
In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood. In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs.
D4 receptors have been identified in the atria of rat and human hearts. Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.
Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density. In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the glomeruli, zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionic sympathetic nerve terminals. Dopamine signaling affects diuresis and natriuresis.
Dopamine receptors in disease
Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia, Tourette's syndrome, Parkinson's disease, schizophrenia, neuroleptic malignant syndrome, attention-deficit hyperactivity disorder (ADHD), and drug and alcohol dependence.
Attention-deficit hyperactivity disorder
Dopamine receptors have been recognized as important components in the etiology of ADHD for many years. Drugs used to treat ADHD, including methylphenidate and amphetamine, have significant effects on neuronal dopamine signaling. Studies of gene association have implicated several genes within dopamine signaling pathways; in particular, the D4.7 variant of D4 has been consistently shown to be more frequent in ADHD patients. ADHD patients with the 4.7 allele also tend to have better cognitive performance and long-term outcomes compared to ADHD patients without the 4.7 allele, suggesting that the allele is associated with a more benign form of ADHD.
Recreational drug use and abuse
Dopamine is the primary neurotransmitter involved in the reward pathways in the brain. Thus, drugs that increase dopamine signaling may produce euphoric effects. Many recreational drugs, such as cocaine and substituted amphetamines, inhibit the dopamine transporter (DAT), the protein responsible for removing dopamine from the neural synapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling. When this occurs, particularly in the nucleus accumbens, increased D1 and D2 receptor signaling mediates the "rewarding" stimulus of drug intake.
While there is evidence that the dopamine system is involved in schizophrenia, the theory that hyperactive dopaminergic signal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, indirectly increase dopamine signaling; large doses and prolonged use can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D2 receptors.
Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels (via stimulants or antipsychotics mainly) can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors. With stimulants, downregulation is typically associated with loss of interest in pleasureable activities, shortened attention span, and drug seeking behavior. With antipsychotics, associated upregulation can cause temporary dyskinesia, or tardive dyskinesia (fine muscles e.g. facial muscles, twitch involuntarily).
Haloperidol, and some other antipsychotics, have been shown to increase the binding capacity of the D2 receptor when used over long periods of time (i.e. increasing the number of such receptors). Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.
There are differing reports of abused stimulants, and up/down regulation. According to one study, cocaine, heroin, amphetamine, alcohol, and nicotine cause decreases in D2 receptor quantity. A similar association has been linked to food addiction, with a low availability of dopamine receptors present in people with greater food intake. A recent news article summarized a U.S. DOE Brookhaven National Laborotory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days.
Working memory training has been associated with dopamine D1 receptor downregulation, which is believed to have an important role in working memory tasks.
- D1-D2 Dopamine receptor heteromer
- D2 short (presynaptic)
- Category:Dopamine agonists
- Category:Dopamine antagonists
- "Dopamine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)
- Scholarpedia article on Dopamine anatomy
- Girault JA, Greengard P (2004). "The neurobiology of dopamine signaling". Arch. Neurol. 61 (5): 641–4. doi:10.1001/archneur.61.5.641. PMID 15148138.
- Cools AR, Van Rossum JM (1976). "Excitation-mediating and inhibition-mediating dopamine-receptors: a new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data". Psychopharmacologia 45 (3): 243–254. PMID 175391.
- Ellenbroek BA, Homberg J, Verheij M, Spooren W, van den Bos R, Martens G (2014). "Alexander Rudolf Cools (1942-2013)". Psychopharmacology (Berl.) 231 (11): 2219–2222. doi:10.1007/s00213-014-3583-5. PMID 24770629.
- Contreras F, Fouillioux C, Bolívar A, Simonovis N, Hernández-Hernández R, Armas-Hernandez MJ et al. (2002). "Dopamine, hypertension and obesity". J Hum Hypertens. 16 Suppl 1: S13–7. doi:10.1038/sj.jhh.1001334. PMID 11986886. Vancouver style error (help)
- Hurley MJ, Jenner P (2006). "What has been learnt from study of dopamine receptors in Parkinson's disease?". Pharmacol. Ther. 111 (3): 715–28. doi:10.1016/j.pharmthera.2005.12.001. PMID 16458973.
- Neves SR, Ram PT, Iyengar R (2002). "G protein pathways". Science 296 (5573): 1636–9. Bibcode:2002Sci...296.1636N. doi:10.1126/science.1071550. PMID 12040175.
- Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G (1998). "D3 dopamine receptor mRNA is widely expressed in the human brain". Brain Res. 779 (1-2): 58–74. doi:10.1016/S0006-8993(97)01078-0. PMID 9473588.
- NCBI Database
- Manor I, Tyano S, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP (2002). "The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA)". Mol. Psychiatry 7 (7): 790–4. doi:10.1038/sj.mp.4001078. PMID 12192625.
- Langley K, Marshall L, van den Bree M, Thomas H, Owen M, O'Donovan M et al. (2004). "Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD". Am J Psychiatry 161 (1): 133–8. doi:10.1176/appi.ajp.161.1.133. PMID 14702261.
- Kustanovich V, Ishii J, Crawford L, Yang M, McGough JJ, McCracken JT et al. (2004). "Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5". Mol. Psychiatry 9 (7): 711–7. doi:10.1038/sj.mp.4001466. PMID 14699430.
- Williams GV, Castner SA (2006). "Under the curve: critical issues for elucidating D1 receptor function in working memory". Neuroscience 139 (1): 263–76. doi:10.1016/j.neuroscience.2005.09.028. PMID 16310964.
- Ricci A, Mignini F, Tomassoni D, Amenta F (2006). "Dopamine receptor subtypes in the human pulmonary arterial tree". Auton Autacoid Pharmacol 26 (4): 361–9. doi:10.1111/j.1474-8673.2006.00376.x. PMID 16968475.
- Hussain T, Lokhandwala MF (2003). "Renal dopamine receptors and hypertension". Exp. Biol. Med. (Maywood) 228 (2): 134–42. PMID 12563019.
- Ricci A, Bronzetti E, Fedele F, Ferrante F, Zaccheo D, Amenta F (1998). "Pharmacological characterization and autoradiographic localization of a putative dopamine D4 receptor in the heart". J Auton Pharmacol 18 (2): 115–21. doi:10.1046/j.1365-2680.1998.1820115.x. PMID 9730266.
- Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M (2000). "Low dopamine D(2) receptor binding potential in social phobia". Am J Psychiatry 157 (3): 457–459. doi:10.1176/appi.ajp.157.3.457. PMID 10698826.
- Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets 5 (1): 109–31. doi:10.2174/187152706784111560. PMID 16613557.
- Fuxe K, Manger P, Genedani S, Agnati L (2006). "The nigrostriatal DA pathway and Parkinson's disease". J. Neural Transm. Suppl. Journal of Neural Transmission. Supplementa 70 (70): 71–83. doi:10.1007/978-3-211-45295-0_13. ISBN 978-3-211-28927-3. PMID 17017512.
- Mihara K et al. (2003). "Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome". Am. J. Med. Genet. B Neuropsychiatr. Genet. 117B (1): 57–60. doi:10.1002/ajmg.b.10025. PMID 12555236.
- Faraone SV, Khan SA (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry. 67 Suppl 8: 13–20. PMID 16961425.
- Hummel M, Unterwald EM (2002). "D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action". J. Cell. Physiol. 191 (1): 17–27. doi:10.1002/jcp.10078. PMID 11920678.
- Gornick MC, Addington A, Shaw P, Bobb AJ, Sharp W, Greenstein D et al. (2007). "Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (3): 379–82. doi:10.1002/ajmg.b.30460. PMID 17171657.
- Schoots O, Van Tol HH (2003). "The human dopamine D4 receptor repeat sequences modulate expression". Pharmacogenomics J. 3 (6): 343–8. doi:10.1038/sj.tpj.6500208. PMID 14581929.
- Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C et al. (2004). "Dopamine and drug addiction: the nucleus accumbens shell connection". Neuropharmacology. 47 Suppl 1: 227–41. doi:10.1016/j.neuropharm.2004.06.032. PMID 15464140.
- Jose PA, Eisner GM, Felder RA (2003). "Regulation of blood pressure by dopamine receptors". Nephron Physiol 95 (2): p19–27. doi:10.1159/000073676. PMID 14610323.
- Silvestri S et al. (2000). "Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study". Psychopharmacology (Berl.) 152 (2): 174–80. doi:10.1007/s002130000532. PMID 11057521.
- Fehr C et al. (2008). "Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse". Am J Psychiatry 165 (4): 507–14. doi:10.1176/appi.ajp.2007.07020352. PMID 18316420.
- Paul Park (2007-08-09). "Food Addiction: From Drugs to Donuts, Brain Activity May be the Key".
- Paul M Johnson& Paul J Kenny (2010-03-28). "Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats". Nature Neuroscience Year published:(2010) doi:10.1038/nn.2519
- "Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol". 2008-04-18.
- Staley JK, Mash DC (1996). "Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities". J. Neurosci. 16 (19): 6100–6. PMID 8815892.
- McNab F, Varrone A, Farde L, Jucaite A, Bystritsky P, Forssberg H et al. (2009). "Changes in cortical dopamine D1 receptor binding associated with cognitive training". Science. 6 323 (5915): 800–8002. Bibcode:2009Sci...323..800M. doi:10.1126/science.1166102. PMID 19197069.