Dopamine receptor

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Dopamine

Dopamine receptors are a class of metabotropic 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.[1] Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.

Dopamine receptor subtypes

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.[2]

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.[3]

D1-like family

Activation of D1-like family receptors is coupled to the G protein Gαs, which subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).[citation needed]

D2-like family

Activation of D2-like family receptors is coupled to the G protein Gαi, which directly inhibits the formation of cAMP by inhibiting the enzyme adenylate cyclase.[4]

  • 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 by feed-back mechanisms, affecting synthesis, storage, and release of dopamine into the synaptic cleft).[citation needed]
    • 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.[citation needed]

Role of dopamine receptors in the central nervous system

Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory.[10] 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

Cardio-pulmonary system

In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasorelaxive effects of dopamine in the blood.[11] In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs.[12]

D4 receptors have been identified in the atria of rat and human hearts.[13] Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.[2]

Renal system

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density.[12] In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the renal tubules, glomeruli, postganglionic sympathetic nerve terminals, and zona glomerulosa cells of the adrenal cortex.[12] Dopamine signaling affects diuresis and natriuresis.[2]

Dopamine receptors in disease

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia,[14] Tourette's syndrome,[15] Parkinson's disease,[16] schizophrenia,[15] neuroleptic malignant syndrome[17], attention-deficit hyperactivity disorder (ADHD),[18] and drug and alcohol dependence.[15][19]

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 dopamine signaling in the brain. 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.[20] 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.[20]

The D4.7 allele has suppressed gene expression compared to other variants.[21]

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 amphetamines, alter the functionality of 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,[22] increased D1[19] and D2[22] receptor signaling mediates the "rewarding" stimulus of drug intake.[22] Reward pathway signaling can affect other regions of the brain as well, inducing long-term changes in regions such as the nucleus accumbens and frontal cortex;[citation needed] these changes can strengthen drug craving and alter cognitive pathways, with drug abuse potentially creating drug addiction and drug dependence.[citation needed]

Schizophrenia

Main article: Dopamine hypothesis of schizophrenia

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, induce dramatic changes in dopamine signaling; large doses and prolonged usage can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D2 receptors.

Genetic hypertension

Dopamine receptor mutations can cause genetic hypertension in humans.[23] This can occur in animal models and humans with defective dopamine receptor activity, particularly D1.[12]

Dopamine regulation

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 tardive dyskinesia (fine muscles, like the face, twitch involuntarily), or just plain dyskinesia (same but only temporary).

Haloperidol, and some other antipsychotics, have been shown to increase the activity of the D2 receptor.[24] Haloperidol induced activity up to 98% higher than baseline in as many as two weeks, but yielded significant dyskinesia side effects. Another study [25] showed in a living subject, dopamine 2 receptors had increased approximately 90% after neuroleptic treatment.

There are differing reports of abused stimulants, and up/down regulation. According to one study,[26] cocaine, heroin, amphetamine, alcohol, and nicotine cause decreases in dopamine 2 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.[27][28] A recent news article [29] summarized a U.S. DOE Brookhaven National Laborotory study showing that increasing dopamine receptors with genetic therapy decreased cocaine consumption up to 75%, but only lasting for six days.

A contrasting study of cocaine[30] shows that cocaine upregulates D3 receptors in the nucleus accumbens, possibly contributing to drug seeking behavior.

See also

External links

References

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Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)
Other
Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)
Metabolites and
signaling molecules
CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other
Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate
Peptide
B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other
Miscellaneous
GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other
Class B: Secretin like
GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other
Class C: Metabotropic
glutamate / pheromone
TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other
Class F:
Frizzled / Smoothened
Frizzled
Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened
de:Dopamin-Rezeptor

fr:Récepteur dopaminergique ja:ドーパミン受容体 pt:Receptor de dopamina ru:Дофаминовый рецептор

th:ตัวรับโดปามีน
  1. ↑ Girault J, Greengard P (2004). "The neurobiology of dopamine signaling". Arch Neurol. 61 (5): 641–4. doi:10.1001/archneur.61.5.641. PMID 15148138. 
  2. ↑ 2.0 2.1 2.2 Contreras F, Fouillioux C, Bolívar A, Simonovis N, Hernández-Hernández R, Armas-Hernandez M, Velasco M (2002). "Dopamine, hypertension and obesity". J Hum Hypertens. 16 Suppl 1: S13–7. doi:10.1038/sj.jhh.1001334. PMID 11986886. 
  3. ↑ Hurley MJ, Jenner P (2006). "What has been learnt from study of dopamine receptors in Parkinson's disease?". Pharmacol Ther. 111 (3): 715. doi:10.1016/j.pharmthera.2005.12.001. PMID 16458973. 
  4. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  5. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. ↑ NCBI Database
  7. ↑ 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. 
  8. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  9. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  10. ↑ Williams G, Castner S (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. 
  11. ↑ 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. 
  12. ↑ 12.0 12.1 12.2 12.3 Hussain T, Lokhandwala M (2003). "Renal dopamine receptors and hypertension". Exp Biol Med (Maywood). 228 (2): 134–42. PMID 12563019. 
  13. ↑ 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. 
  14. ↑ 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. 
  15. ↑ 15.0 15.1 15.2 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. 
  16. ↑ Fuxe K, Manger P, Genedani S, Agnati L (2006). "The nigrostriatal DA pathway and Parkinson's disease". J Neural Transm Suppl. 70 (70): 71–83. doi:10.1007/978-3-211-45295-0_13. PMID 17017512. 
  17. ↑ Mihara K, Kondo T, Suzuki A; et al. (2003). "Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome". Am. J. Med. Genet. B Neuropsychiatr. Genet. 117 (1): 57–60. doi:10.1002/ajmg.b.10025. PMID 12555236. 
  18. ↑ Faraone S, Khan S (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry. 67 Suppl 8: 13–20. PMID 16961425. 
  19. ↑ 19.0 19.1 Hummel M, Unterwald E (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. 
  20. ↑ 20.0 20.1 Gornick M, Addington A, Shaw P, Bobb A, Sharp W, Greenstein D, Arepalli S, Castellanos F, Rapoport J (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. 144 (3): 379–82. doi:10.1002/ajmg.b.30460. PMID 17171657. 
  21. ↑ Schoots O, Van Tol H (2003). "The human dopamine D4 receptor repeat sequences modulate expression". Pharmacogenomics J. 3 (6): 343–8. doi:10.1038/sj.tpj.6500208. PMID 14581929. 
  22. ↑ 22.0 22.1 22.2 Di Chiara G, Bassareo V, Fenu S, De Luca M, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (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. 
  23. ↑ Jose P, Eisner G, Felder R (2003). "Regulation of blood pressure by dopamine receptors". Nephron Physiol. 95 (2): p19–27. doi:10.1159/000073676. PMID 14610323. 
  24. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  25. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  26. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  27. ↑ Paul Park (2007-08-09). "Food Addiction: From Drugs to Donuts, Brain Activity May be the Key". 
  28. ↑ 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:doi:10.1038/nn.2519
  29. ↑ "Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol". 18-04-2008.  Check date values in: |date= (help)
  30. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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