Dopamine receptor
Dopamine receptors are a class of
Dopamine receptors are implicated in many neurological processes, including motivational and incentive salience, cognition, memory, learning, and fine motor control, as well as modulation of
Subtypes
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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 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.[5]
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.[6]
D1-like family
The
- D1 is encoded by the Dopamine receptor D1 gene (DRD1).
- D5 is encoded by the Dopamine receptor D5 gene (DRD5).
D2-like family
The
- D2 is encoded by the Dopamine receptor D2 gene (DRD2), of which there are two forms: D2Sh (short) and D2Lh (long):
- The synaptic cleft).[9]
- 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.[9]
- The
- 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.[10]
- D4 is encoded by the
Receptor heteromers
Dopamine receptors have been shown to heteromerize with a number of other
- D1–D2
- D1–D3
- D2–D3
- D2–D4
- D2–D5
Non-isoreceptors
- D1–adenosine A1
- D2–adenosine A2A
- D2–ghrelin receptor
- D2sh–TAAR1 (an autoreceptorheteromer)
- D4–adrenoceptor α1B
- D4–adrenoceptor β1
Signaling mechanism
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.[7]
cAMP independent
D1 receptor agonism and D2 receptor blockade also increases mRNA translation by phosphorylating
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 of
Role in the central nervous system
Dopamine receptors control neural signaling that modulates many important behaviors, such as
Non-CNS dopamine receptors
Cardio-pulmonary system
In humans, the
D4 receptors have been identified in the
Renal system
Dopamine receptors are present along the
The Pancreas
The role of the pancreas[26] is to secrete digestive enzymes via exocrine glands and hormones via endocrine glands. Pancreatic endocrine glands, composed of dense clusters of cells called the Islets of Langerhans, secrete insulin, glucagon, and other hormones essential for metabolism and glycemic control. Insulin secreting beta cells have been intensely researched due to their role in diabetes.[27]
Recent studies have found that beta cells, as well as other endocrine and exocrine pancreatic cells, express D2 receptors[28] and that beta cells co-secrete dopamine along with insulin.[29] Dopamine has been purported to be a negative regulator of insulin,[30][31] 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 certain antipsychotic medications.[32][33] Traditional/typical antipsychotic medications function by altering the dopamine pathway in the brain, such as blocking D2 receptors.[34] Common side effects of these medications include rapid weight gain and glycemic dysregulation, among others.[35] 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.[36]
In disease
Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including
Attention-deficit hyperactivity disorder
Dopamine receptors have been recognized as important components in the mechanism 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.[43] 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.[43]
The D4.7 allele has suppressed gene expression compared to other variants.[44]
Addictive drugs
Dopamine is the primary neurotransmitter involved in the
Pathological gambling
Pathological gambling is classified as a mental health disorder that has been linked to obsessive-compulsive spectrum disorder and behavioral addiction. Dopamine has been associated with reward and reinforcement in relation to behaviors and drug addiction.[50] The role between dopamine and pathological gambling may be a link between cerebrospinal fluid measures of dopamine and dopamine metabolites in pathological gambling.[51] 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.[50]
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, 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.
Genetic hypertension
Dopamine receptor
Parkinson's disease
Parkinson's disease is associated with the loss of cells responsible for dopamine synthesis and other neurodegenerative events.[50] Parkinson's disease patients are treated with medications which help to replenish dopamine availability, allowing relatively normal brain function and neurotransmission.[53] 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.[54]
Dopamine regulation
Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors.[55]
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).[56] Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.
Certain stimulants will enhance cognition in the general population (e.g., direct or indirect
Form of neuroplasticity or behavioral plasticity |
Type of reinforcer | Sources | |||||
---|---|---|---|---|---|---|---|
Opiates | Psychostimulants | High fat or sugar food | Sexual intercourse | Physical exercise (aerobic) |
Environmental enrichment | ||
MSNs
|
↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [57] |
Behavioral plasticity | |||||||
Escalation of intake | Yes | Yes | Yes | [57] | |||
Psychostimulant cross-sensitization |
Yes | Not applicable | Yes | Yes | Attenuated | Attenuated | [57] |
Psychostimulant self-administration |
↑ | ↑ | ↓ | ↓ | ↓ | [57] | |
Psychostimulant conditioned place preference |
↑ | ↑ | ↓ | ↑ | ↓ | ↑ | [57] |
Reinstatement of drug-seeking behavior
|
↑ | ↑ | ↓ | ↓ | [57] | ||
Neurochemical plasticity | |||||||
CREBphosphorylation in the nucleus accumbens |
↓ | ↓ | ↓ | ↓ | ↓ | [57] | |
Sensitized dopamine response in the nucleus accumbens |
No | Yes | No | Yes | [57] | ||
Altered striatal dopamine signaling | ↓ DRD3 |
↑ DRD3 |
↑ DRD3 |
↑ DRD2 |
↑ DRD2 |
[57] | |
Altered striatal opioid signaling | No change or ↑μ-opioid receptors |
↑μ-opioid receptors ↑κ-opioid receptors |
↑μ-opioid receptors | ↑μ-opioid receptors | No change | No change | [57] |
Changes in striatal opioid peptides | ↑dynorphin No change: enkephalin |
↑dynorphin | ↓enkephalin | ↑dynorphin | ↑dynorphin | [57] | |
Mesocorticolimbic synaptic plasticity | |||||||
Number of dendrites in the nucleus accumbens | ↓ | ↑ | ↑ | [57] | |||
Dendritic spine density in the nucleus accumbens |
↓ | ↑ | ↑ | [57] |
See also
- D2 short(presynaptic)
- Category:Dopamine agonists
- Category:Dopamine antagonists
References
- S2CID 21432517.
- PMID 15148138.
- S2CID 40366909.
- PMID 24770629.
- ^ PMID 11986886.
- PMID 16458973.
- ^ S2CID 12407397.
- S2CID 20136388.
- ^ a b "Introduction to Neuroscience".
- S2CID 46096849.
- ^ NCBI Database
- PMID 12192625.
- S2CID 25892078.
- PMID 14699430.
- PMID 25671228.
- PMID 24830558.
- PMID 26418645.
- ^ PMID 25671228.
- PMID 21922001.
- S2CID 20906770.
- ISBN 978-0-471-97819-0.
- PMID 16968475.
- S2CID 36507640.
- ^ S2CID 10896819.
- PMID 9730266.
- PMID 20700834, retrieved 12 April 2024
- PMID 30641727.
- PMID 16129680.
- PMID 16129680.
- PMID 32318020.
- PMID 33589583.
- PMID 31299229.
- PMID 20187598.
- PMID 11607043.
- PMID 20923620.
- PMID 29692257.
- PMID 10698826.
- ^ PMID 16613557.
- )
- S2CID 44866985.
- PMID 16961425.
- ^ S2CID 40444893.
- ^ S2CID 25065281.
- PMID 14581929.
- S2CID 11959878.
- PMID 22238577.
- PMID 29503841.
- ^ a b "Drugs and the Brain". National Institute on Drug Abuse. 22 March 2022. Retrieved 21 August 2022.
- ^ S2CID 25983940.
- ^ PMID 18640909.
- S2CID 20594850.
- S2CID 28595227.
- S2CID 6551470.
- S2CID 11266116.
- S2CID 9353254.
- S2CID 20804595.
- ^ PMID 21459101."
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 - PMID 18316420.
- ^ Park P (9 August 2007). "Food Addiction: From Drugs to Donuts, Brain Activity May be the Key".
- PMID 20348917.
- ^ "Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol". 18 April 2008.
- PMID 8815892.
- PMID 25871974.
- PMID 27057246.
- S2CID 15788121.
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. - ^ ISBN 978-0-07-148127-4.
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. - ^ PMID 24344115.
External links
- "Dopamine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 1 February 2017. Retrieved 20 July 2006.
- Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)
- Scholarpedia article on Dopamine anatomy