Dopamine receptors are a class ofG protein-coupled receptors that are prominent in thevertebratecentral nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signalling through different protein (dopamine receptor-interacting proteins) interactions.[1] Theneurotransmitterdopamine is the primaryendogenousligand for dopamine receptors.
Dopamine receptors are implicated in many neurological processes, including motivational and incentive salience, cognition, memory, learning, and fine motor control, as well as modulation ofneuroendocrine signalling. Abnormal dopamine receptor signalling and dopaminergic nerve function is implicated in several neuropsychiatric disorders.[2] Thus, dopamine receptors are common neurologic drug targets;antipsychotics are often dopaminereceptor antagonists whilepsychostimulants are typicallyindirect agonists of dopamine receptors.
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The existence of multiple types of receptors for dopamine was first proposed in 1976.[3][4] There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of theD1-like family of dopamine receptors, whereas the D2, D3, and D4 receptors are members of theD2-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.[5]
At a global level, D1 receptors have widespread expression throughout the brain. The relative amount of DA receptors is in the following order: D1 > D2 > D3 > D5 > D4.[6] D1-2 receptor subtypes are found at 10–100 times the levels of the D3-5 subtypes.[7]
TheD1-like family receptors are coupled to theG proteinGsα. D1 is also coupled toGolf.
Gsα subsequently activatesadenylyl cyclase, increasing the intracellular concentration of thesecond messengercyclic adenosine monophosphate (cAMP).[8]
TheD2-like family receptors are coupled to theG proteinGiα, which directly inhibits the formation ofcAMP by inhibiting the enzyme adenylyl cyclase.[9]
Dopamine receptors have been shown to heteromerize with a number of otherG protein-coupled receptors.[16] Especially the D2 receptor is considered a major hub within theGPCR heteromer network.[17]Protomers consist of
Non-isoreceptors
Dopamine receptor D1 andDopamine receptor D5 areGs coupled receptors that stimulateadenylyl cyclase to producecAMP, which in turn increases intracellular calcium and mediates a number of other functions. The D2 class of receptors produce the opposite effect, as they areGαi and/orGαo coupled receptors, which blocks the activity of adenylyl cyclase. cAMP mediatedprotein kinase A activity also results in the phosphorylation ofDARPP-32, an inhibitor ofprotein phosphatase 1. Sustained D1 receptor activity is kept in check byCyclin-dependent kinase 5. Dopamine receptor activation ofCa2+/calmodulin-dependent protein kinase II can be cAMP dependent or independent.[19]
The cAMP mediated pathway results in amplification of PKA phosphorylation activity, which is normally kept in equilibrium by PP1. The DARPP-32 mediated PP1 inhibition amplifies PKA phosphorylation of AMPA, NMDA, and inward rectifying potassium channels, increasing AMPA and NMDA currents while decreasing potassium conductance.[8]
D1 receptor agonism and D2 receptor blockade also increases mRNA translation by phosphorylatingribosomal protein s6, resulting in activation of mTOR. The behavioural implications are unknown. Dopamine receptors may also regulateion channels andBDNF independent of cAMP, possibly through direct interactions. There is evidence that D1 receptor agonism regulatesphospholipase C independent of cAMP, however implications and mechanisms remain poorly understood. D2 receptor signalling may mediateprotein kinase B,arrestin beta 2, andGSK-3 activity, and inhibition of these proteins results in stunting of the hyperlocomotion inamphetamine treated rats. Dopamine receptors can also transactivateReceptor tyrosine kinases.[19]
Beta Arrestin recruitment is mediated by G-protein kinases that phosphorylate and inactivate dopamine receptors after stimulation. While beta arrestin plays a role in receptor desensitization, it may also be critical in mediating downstream effects of dopamine receptors. Beta arrestin has been shown to form complexes with MAP kinase, leading to activation ofextracellular signal-regulated kinases. Furthermore, this pathway has been demonstrated to be involved in the locomotor response mediated by dopamine receptor D1. Dopamine receptor D2 stimulation results in the formation of an Akt/Beta-arrestin/PP2A protein complex that inhibits Akt through PP2A phosphorylation, therefore disinhibiting GSK-3.[20]
Dopamine receptors control neural signalling that modulates many important behaviours, such asspatialworking memory.[21] Dopamine also plays an important role in thereward system,incentive salience,cognition,prolactin release,emesis, and motor function.[22]
In humans, thepulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account forvasodilatory effects of dopamine in the blood.[23] Such receptor subtypes have also been discovered in theepicardium,myocardium, andendocardium of the heart.[24] Inrats, D1-like receptors are present on thesmooth muscle of theblood vessels in most major organs.[25]
D4 receptors have been identified in theatria of rat and humanhearts.[26] Dopamine increasesmyocardial contractility andcardiac output, without changingheart rate, by signalling through dopamine receptors.[5]
Dopamine receptors are present along thenephron in thekidney, withproximal tubuleepithelial cells showing the highest density.[25] Inrats, D1-like receptors are present on thejuxtaglomerular apparatus and onrenal tubules, while D2-like receptors are present on theglomeruli,zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionicsympathetic nerve terminals.[25] Dopamine signalling affectsdiuresis andnatriuresis.[5]
The role of the pancreas[27] is to secretedigestive enzymes viaexocrine glands andhormones viaendocrine glands. Pancreatic endocrine glands, composed of dense clusters of cells called theIslets of Langerhans, secreteinsulin,glucagon, andother hormones essential for metabolism andglycemic control. Insulin secreting beta cells have been intensely researched due to their role indiabetes.[28]
Recent studies have found thatbeta cells, as well as other endocrine and exocrine pancreatic cells, express D2 receptors[29] and that beta cells co-secrete dopamine along with insulin.[30] Dopamine has been purported to be a negative regulator of insulin,[31][32] meaning that bound D2 receptors inhibit insulin secretion. The connection between dopamine and beta cells was discovered, in part, due to the metabolic side-effects of certainantipsychotic medications.[33][34]Traditional/typical antipsychotic medications function by altering the dopamine pathway in the brain, such as blocking D2 receptors.[35] Common side effects of these medications include rapid weight gain and glycemic dysregulation, among others.[36] The effects of these medications are not limited to the brain, so off-target effects in other organs such as the pancreas have been proposed as a possible mechanism.[37]
Dopamine receptorsD1,D2,D4, andD5 are present in human subcutaneous, visceral, and brown adipose tissue, and have been implicated in lipid and glucose metabolism, and thermogenesis.[38][39] Dopamine that reaches dopamine receptors in adipose tissue can originate from multiple sources: from the circulation, sympathetic nerves innervating adipose tissue that release dopamine from nerve terminals, local synthesis, or immune cells[40][41]
Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, includingsocial phobia,[42]Tourette's syndrome,[43]Parkinson's disease,[44]schizophrenia,[43]neuroleptic malignant syndrome,[45]attention-deficit hyperactivity disorder (ADHD),[46] anddrug andalcoholdependence.[43][47]
Dopamine receptors have been recognized as important components in the mechanism of ADHD for many years. Drugs used to treat ADHD, includingmethylphenidate andamphetamine, have significant effects on neuronal dopamine signalling. Studies ofgene association have implicated several genes within dopamine signalling pathways; in particular, the D4.7 variant of D4 has been consistently shown to be more frequent in ADHD patients.[48] 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.[48]
The D4.7 allele has suppressedgene expression compared to other variants.[49]
Dopamine is the primary neurotransmitter involved in thereward and reinforcement (mesolimbic) pathway in the brain. Although it was a long-held belief that dopamine was the cause of pleasurable sensations such as euphoria, many studies and experiments on the subject have demonstrated that this is not the case; rather, dopamine in the mesolimbic pathway is responsible for behaviour reinforcement ("wanting") without producing any "liking" sensation on its own.[50][51][52][53] Mesolimbic dopamine and its related receptors are a primary mechanism through which drug-seeking behaviour develops (Incentive Salience), and manyrecreational drugs, such ascocaine andsubstituted amphetamines, inhibit thedopamine transporter (DAT), the protein responsible for removing dopamine from the neuralsynapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signalling. When this occurs, particularly in thenucleus accumbens,[54] increased D1[47] and decreased D2[54] receptor signalling mediates the "incentive salience" factor and can significantly increase positive associations with the drug in the brain.[53]
Pathological gambling is classified as a mental health disorder that has been linked to obsessive-compulsive spectrum disorder and behavioural addiction. Dopamine has been associated with reward and reinforcement in relation to behaviors and drug addiction.[55] The role between dopamine and pathological gambling may be a link between cerebrospinal fluid measures of dopamine and dopamine metabolites in pathological gambling.[56] Molecular genetic study shows that pathological gambling is associated with the TaqA1 allele of the Dopamine Receptor D2 (DRD2) dopamine receptor. Furthermore, TaqA1 allele is associated with other reward and reinforcement disorders, such as substance abuse and other psychiatric disorders. Reviews of these studies suggest that pathological gambling and dopamine are linked; however, the studies that succeed in controlling for race or ethnicity, and obtain DSM-IV diagnoses do not show a relationship between TaqA1 allelic frequencies and the diagnostic of pathological gambling.[55]
While there is evidence that the dopamine system is involved inschizophrenia, the theory that hyperactive dopaminergicsignal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, indirectly increase dopamine signalling; large doses and prolonged use can induce symptoms that resemble schizophrenia. Additionally, manyantipsychotic drugs target dopamine receptors, especially D2 receptors.
Dopamine receptormutations can cause genetichypertension in humans.[57] This can occur inanimal models and humans with defective dopamine receptor activity, particularly D1.[25]
Parkinson's disease is associated with the loss of cells responsible for dopamine synthesis and other neurodegenerative events.[55] Parkinson's disease patients are treated with medications which help to replenish dopamine availability, allowing relatively normal brain function and neurotransmission.[58] Research shows that Parkinson's disease is linked to the class of dopamine agonists instead of specific agents. Reviews touch upon the need to control and regulate dopamine doses for Parkinson's patients with a history of addiction, and those with variable tolerance or sensitivity to dopamine.[59]
Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels candownregulate (reduce the numbers of) orupregulate (increase the numbers of) dopamine receptors.[60]
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).[61] Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.
Addictive stimuli have variable effects on dopamine receptors, depending on the particular stimulus.[62] According to one study,[63] cocaine,opioids likeheroin, amphetamine, alcohol, andnicotine 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.[64][65] A recent news article[66] summarized a U.S.DOE Brookhaven National Laboratory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days. Cocaine upregulates D3 receptors in thenucleus accumbens, further reinforcing drug seeking behaviour.[67] andCaffeine increases striatal dopamine D2/D3 receptor availability in the human brain,[68] Caffeine, or other more selectiveadenosine A2A receptor antagonists, causes significantly less motor stimulation in dopamine D2 receptor.[69]
Certain stimulants will enhance cognition in the general population (e.g., direct or indirectmesocorticalDRD1 agonists as a class), but only when used at low (therapeutic) concentrations.[70][71][72] Relatively high doses of dopaminergic stimulants will result in cognitive deficits.[71][72]
{{cite book}}:|journal= ignored (help)Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1"
The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition. ... Earlier research has failed to distinguish whether stimulants' effects are small or whether they are nonexistent (Ilieva et al., 2013; Smith & Farah, 2011). The present findings supported generally small effects of amphetamine and methylphenidate on executive function and memory. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ...
The results of this meta-analysis cannot address the important issues of individual differences in stimulant effects or the role of motivational enhancement in helping perform academic or occupational tasks. However, they do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
Mild dopaminergic stimulation of the prefrontal cortex enhances working memory. ...
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spatial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.
