Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
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 have key roles in many processes, including the control of motivation, learning, and fine motor movement, 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.
Dopamine receptor subtypes
There are 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.
D1-like family (excitatory)
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). Increased cAMP in neurons is typically excitatory and can induce an action potential by modulating the activity of ion channels.
D2-like family (inhibitory)
D2-like activation is coupled to the G protein Gαi, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.
- D2 (DRD2). There is a short version of D2 (D2Sh) and a long version of D2 (D2Lh):
- The D2Sh are pre-synaptic situated, having modulatory functions (called autoreceptor, they regulate the neurotransmission by feed-back mechanisms, i.e., synthesis, storage and release of dopamine into the synaptic cleft).
- The D2Lh may have the classic function of a post-synaptic receptor, i.e., keep going on the neurotransmission (excitatory or inhibitory) once blocked by a receptor antagonist or stimulated by the endogenous neurotransmitter itself or a synthetic full or partial agonist.
- D3 (DRD3) Maximum expression of dopamine D3 receptors is noted in the islands of Calleja and nucleus accumbens.
- D4 (DRD4). The D4 receptor has the following variants D4.2, D4.3a, D4.3b, D4.4a, D4.4b, D4.4c, D4.4d, D4.4e, D4.5a, D4.5b, D4.6a, D4.6b, D4.7a, D4.7b, D4.7c, D4.7d, D4.8, D4.10. These variants differ in a variable number tandem repeat domain 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.
Non-CNS dopamine receptors
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. 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 renal tubules, glomeruli, postganglionic sympathetic nerve terminals, and zona glomerulosa cells of the renal cortex. 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 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 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. 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.
The D4.7 allele has suppressed gene expression compared to other variants.
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 methamphetamine, 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, increased D1 and D2 receptor signaling mediates the "rewarding" stimulus of drug intake. 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; these changes can strengthen drug craving and alter cognitive pathways, with drug abuse potentially creating drug addiction and drug dependence.
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.
Dopamine receptor mutations can cause genetic hypertension in humans. This can occur in animal models and humans with defective dopamine receptor activity, particularly D1.
- IUPHAR GPCR Database - Dopamine Receptors
- Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)
- ↑ Girault J, Greengard P (2004). "The neurobiology of dopamine signaling". Arch Neurol. 61 (5): 641–4. PMID 15148138.
- ↑ 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. PMID 11986886.
- ↑ Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res. 1998 Jan 1;779(1-2):58-74. PMID 9473588
- ↑ Williams G, Castner S (2006). "Under the curve: critical issues for elucidating D1 receptor function in working memory". Neuroscience. 139 (1): 263–76. 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. PMID 16968475.
- ↑ 6.0 6.1 6.2 6.3 Hussain T, Lokhandwala M (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. PMID 9730266.
- ↑ 8.0 8.1 8.2 Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets. 5 (1): 109–31. PMID 16613557.
- ↑ Fuxe K, Manger P, Genedani S, Agnati L (2006). "The nigrostriatal DA pathway and Parkinson's disease". J Neural Transm Suppl. 70: 71–83. PMID 17017512.
- ↑ 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.
- ↑ Faraone S, Khan S (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry. 67 Suppl 8: 13–20. PMID 16961425.
- ↑ 12.0 12.1 Hummel M, Unterwald E (2002). "D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action". J Cell Physiol. 191 (1): 17–27. PMID 11920678.
- ↑ 13.0 13.1 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. PMID 17171657.
- ↑ Schoots O, Van Tol H (2003). "The human dopamine D4 receptor repeat sequences modulate expression". Pharmacogenomics J. 3 (6): 343–8. PMID 14581929.
- ↑ 15.0 15.1 15.2 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. PMID 15464140.
- ↑ Jose P, Eisner G, Felder R (2003). "Regulation of blood pressure by dopamine receptors". Nephron Physiol. 95 (2): p19–27. PMID 14610323.