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Dopamine

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For other uses, see Dopamine (disambiguation).
Dopamine
Dopamine
General
Systematic name 4-(2-aminoethyl)benzene-1,2-diol
Other names 2-(3,4-dihydroxyphenyl)ethylamine;
3,4-dihydroxyphenethylamine;
3-hydroxytyramine; DA; Intropin
Revivan; Oxytyramine
Molecular formula C8H11NO2
SMILES NCCc1ccc(O)c(O)c1
Molar mass 153.178 g/mol
Appearance white powder with distinctive smell
CAS number [51-61-6]
Properties
Density and phase ? g/cm³, ?
Solubility in water 60.0 g/100 ml (? °C), solid
Melting point 128 °C (401 K)
Boiling point ? °C (? K)
Acidity (pKa) ?
Basicity (pKb) ?
Chiral rotation [α]D ?°
Viscosity ? cP at ? °C
Structure
Molecular shape ?
Coordination
geometry 		?
Crystal structure ?
Dipole moment ? D
Hazards
MSDS External MSDS
Main hazards ?
NFPA 704 ?
Flash point ? °C
R/S statement R: 36/37/38
S: 26-36
RTECS number UX1088000
Supplementary data page
Structure and
properties 		n, εr, etc.
Thermodynamic
data 		Phase behaviour
Solid, liquid, gas
Spectral data UV, IR, NMR, MS
Related compounds
Other anions ?
Other cations ?
Related Tyramine,
octopamine,
norepinephrine (noradrenaline)
Except where noted otherwise, data are given for
materials in their standard state (at 25 °C, 100 kPa)
Infobox disclaimer and references

Dopamine is a phenethylamine naturally produced by the human body. In the brain, dopamine functions as a neurotransmitter, activating the five types of dopamine receptor - D1, D2, D3, D4 and D5, and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra.

Dopamine is also a neurohormone released by the hypothalamus. Its main function as a hormone is to inhibit the release of prolactin from the anterior lobe of the pituitary.

Dopamine can be supplied as a medication that acts on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. However, since dopamine cannot cross the blood-brain barrier, dopamine given as a drug does not directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases such as Parkinson's disease and Dopa-Responsive Dystonia, L-DOPA (levodopa), which is the precursor of dopamine, can be given because it can cross the blood-brain barrier.

History

Dopamine was discovered by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden, in 1952. It was named Dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA).[1] Arvid Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not just a precursor of noradrenaline and adrenaline, but a neurotransmitter as well.

Biochemistry

Dopamine has the chemical formula (C6H3(OH)2-CH2-CH2-NH2). Its chemical name is 4-(2-aminoethyl)benzene-1,2-diol and it is abbreviated "DA."

As a member of the catecholamine family, dopamine is a precursor to epinephrine (adrenaline) and then norepinephrine (noradrenaline) in the biosynthetic pathways for these neurotransmitters.

Dopamine is biosynthesized in the body (mainly by nervous tissue and the medulla of the adrenal glands) first by the hydration of the amino acid L-tyrosine to L-DOPA via the enzyme tyrosine 3-monooxygenase, which is often known by its former name tyrosine hydroxylase, and then by the decarboxylation of DOPA by Aromatic L-amino acid decarboxylase (which is often referred to as dopa decarboxylase). In neurons, dopamine is packaged after synthesis into vesicles, which are then released in response to the presynaptic action potential. The inactivation mechanism of neurotransmission are 1) uptake via a specific transporter; 2) enzymatic breakdown; and 3) diffusion. Uptake back to the presynaptic neuron via the dopamine transporter is the major role in the inactivation of dopamine neurotransmission. The recycled dopamine will face either breakdown by an enzyme or be re-packaged into vesicles and reused.

Functions in the Brain

Dopamine has many functions in the brain. Most importantly, dopamine is central to the reward system.[2] Dopamine neurons in the primate brain are found in Substantia nigra and Ventral tegmental area (VTA). The phasic responses of dopamine neurons are observed when an unexpected reward is presented. These responses transfer to the onset of a conditioned stimulus after repeated pairings with the reward. Further, dopamine neurons are depressed when the expected reward is omitted. Thus, dopamine neurons seem to encode the prediction error of rewarding outcomes. In nature, we learn to repeat behaviors that lead to maximize rewards. Dopamine is therefore believed by many to provide a teaching signal to parts of the brain responsible for acquiring new behavior. Temporal difference learning provides a computational model describing how the prediction error of dopamine neurons is used as a teaching signal.

In insects, a similar reward system exists, using octopamine, a chemical relative of dopamine.[3].

Movement

Via the dopamine receptors D1, D2, D3, D4 and D5, dopamine reduces the influence of the indirect pathway, and increases the actions of the direct pathway within the basal ganglia. Insufficient dopamine biosynthesis in the dopaminergic neurons can cause Parkinson's disease, in which a person loses the ability to execute smooth, controlled movements. The phasic dopaminergic activation seems to be crucial with respect to a lasting internal encoding of motor skills (Beck, 2005).

Cognition and frontal cortex

In the frontal lobes, dopamine controls the flow of information from other areas of the brain. Dopamine disorders in this region of the brain can cause a decline in neurocognitive functions, especially memory, attention, and problem-solving. Reduced dopamine concentrations in the prefrontal cortex are thought to contribute to attention deficit disorder. Conversely, anti-psychotic medications act as dopamine antagonists and are used in the treatment of positive symptoms in schizophrenia.

Regulating prolactin secretion

Dopamine is the primary neuroendocrine regulator of the secretion of prolactin from the anterior pituitary gland. Dopamine produced by neurons in the arcuate nucleus of the hypothalamus is secreted into the hypothalamo-hypophysial blood vessels of the median eminence, which supply the pituitary gland. The lactotrope cells that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion.

Motivation and pleasure

Dopamine is commonly associated with the pleasure system of the brain, providing feelings of enjoyment and reinforcement to motivate a person proactively to perform certain activities. Dopamine is released (particularly in areas such as the nucleus accumbens and striatum) by naturally rewarding experiences such as food, sex,[4][5] use of certain drugs and neutral stimuli that become associated with them. This theory is often discussed in terms of drugs such as cocaine and amphetamines, which seem to directly or indirectly lead to the increase of dopamine in these areas, and in relation to neurobiological theories of chemical addiction, arguing that these dopamine pathways are pathologically altered in addicted persons.

However, cocaine and amphetamine influence separate mechanisms of action. Cocaine is a dopamine transporter blocker that competitively inhibits dopamine uptake to increase the lifetime of dopamine and augments an overabundance of dopamine (an increase of up to 150%) within the parameters of the dopamine neurotransmitters. Like cocaine, amphetamines increase the concentration of dopamine in the synaptic gap, but by a different mechanism. Amphetamines are similar in structure to dopamine, and so can enter the terminal button of the presynaptic neuron via its dopamine transporters as well as by diffusing through the neural membrane directly. When entering inside the presynaptic neuron, amphetamines force the dopamine molecules out of their storage vesicles and expel them into the synaptic gap by making the dopamine transporters work in reverse. Dopamine's role in experiencing pleasure has been questioned by several researchers. It has been argued that dopamine is more associated with anticipatory desire and motivation (commonly referred to as "wanting") as opposed to actual consummatory pleasure (commonly referred to as "liking"). Dopamine is not released when unpleasant or aversive stimuli are encountered, and so motivates towards the pleasure of avoiding or removing the unpleasant stimuli.

Recent research suggests that the firing of dopamine neurons is a motivational chemical as a result of reward-anticipation. This is based on evidence[citation needed] that, when a reward is perceived to be greater than expected, the firing of certain dopamine neurons increases, which correspondingly increases desire or motivation toward the reward.

Clues to dopamine's role in motivation, desire, and pleasure have come from studies performed on animals. In one such study rats were depleted of dopamine by up to 99% in the nucleus accumbens and neostriatum using 6-hydroxydopamine.[6] With this large reduction in dopamine, the rats would no longer eat by their own volition. The researchers then force fed the rats food and noted whether they had the proper facial expressions indicating whether they liked or disliked it. The researchers of this study concluded that the reduction in dopamine did not reduce the rat's consummatory pleasure, only the desire to actually eat. In another study, mutant hyperdopaminergic (increased dopamine) mice show higher "wanting" but not "liking" of sweet rewards.[7]

In humans, though, drugs that reduce dopamine activity (neuroleptics, eg. some antipsychotics) have been shown to reduce motivation as well as cause anhedonia (the inability to experience pleasure).[8] Conversely the selective D2/D3 agonists pramipexole and ropinirole have anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale.[9] (The Snaith-Hamilton-Pleasure-Scale (SHAPS), introduced in English in 1995, assesses self-reported anhedonia in psychiatric patients.)

Opioid and cannabinoid transmission instead of dopamine may modulate consummatory pleasure and food palatability (liking).[10] This could explain why animals' "liking" of food is independent of brain dopamine concentration. Other consummatory pleasures, however, may be more associated with dopamine. One study found that both anticipatory and consummatory measures of sexual behavior (male rats) were disrupted by DA receptor antagonists.[11] Libido can be increased by drugs that affect dopamine but not by drugs that affect opioid peptides or other neurotransmitters.

Sociability is also closely tied to dopamine neurotransmission. Low D2 receptor binding is found in people with social anxiety. Traits common to negative schizophrenia (social withdrawal, apathy, anhedonia) are thought to be related to a hypodopaminergic state in certain areas of the brain. In instances of bipolar, manic subjects can become hypersocial as well as hypersexual. This is also credited to an increase in dopamine, because mania alleviates from dopamine blocking antipsychotics.

Dopamine may also have a role in the salience ('noticeableness') of perceived objects and events, with potentially important stimuli such as: 1) rewarding things or 2) dangerous or threatening things seeming more noticeable or important.[12] This hypothesis argues that dopamine assists decision-making by influencing the priority, or level of desire, of such stimuli to the person concerned.

Pharmacological blockade of brain dopamine receptors increases rather than decreases drug-taking behavior. Since blocking dopamine decreases desire, the increase in drug taking behavior may be seen as not a chemical desire but as a deeply psychological desire to just 'feel something'.

Deficits in dopamine levels are implicated in Attention-deficit hyperactivity disorder(ADHD), and stimulant medications used to successfully treat the disorder increase dopamine neurotransmitter levels, leading to decreased symptoms.

Latent inhibition and creative drive

Dopamine in the mesolimbic pathway increases general arousal and goal directed behaviors and decreases latent inhibition; all three effects increase the creative drive of idea generation. This has led to a three-factor model of creativity involving the frontal lobes, the temporal lobes, and mesolimbic dopamine.[13]

Main article: Dopamine hypothesis of psychosis

Disruption to the dopamine system has also been strongly linked to psychosis and schizophrenia,[14] with abnormally high dopamine action apparently leading to these conditions. Dopamine neurons in the mesolimbic pathway are particularly associated with these conditions. Evidence comes partly from the discovery of a class of drugs called the phenothiazines (which block D2 dopamine receptors) that can reduce psychotic symptoms, and partly from the finding that drugs such as amphetamine and cocaine (which are known to greatly increase dopamine levels) can cause psychosis. Because of this, most modern antipsychotic medications are designed to block dopamine function to varying degrees.

Depression

Low levels of the neurotransmitter dopamine may lead to depression. Amphetamines and dopamine reuptake inhibitors (such as bupropion (Zyban/Wellbutrin)) have potent anti-depressant effects but these drugs quickly lose their benefit after they deplete dopamine levels in the brain. [citation needed]

Antidepressants appear to primarily enhance serotonergic neurotransmission during preliminary drug administration.[citation needed] However it takes several weeks for the antidepressant effect to be noticed. This late effect of antidepressants is thought [citation needed] to result from the indirect serotonergic modulation of dopaminergic neurotransmission.

Therapeutic use

Main article: L-DOPA

Levodopa is a dopamine precursor used in various forms to treat Parkinson's disease. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, dopa decarboxylase), such as carbidopa or benserazide. Inhibitors of alternative metabolic route for dopamine by catechol-O-methyl transferase are also used. These include entacapone and tolcapone.

Dopamine is also used as an inotropic drug in patients with shock to increase cardiac output and blood pressure.

Major pathways

Dopamine and fruit browning

Polyphenol oxidases (PPOs) are a family of enzymes responsible for the browning of fresh fruits and vegetables when they are cut or bruised. These enzymes use molecular oxygen (O2) to oxidise various 1,2-diphenols to their corresponding quinones. The natural substrate for PPOs in bananas is dopamine. The product of their oxidation, dopamine quinone, spontaneously oxidises to other quinones. The quinones then polymerise and condense with amino acids and proteins to form brown pigments known as melanins. The quinones and melanins derived from dopamine may help protect damaged fruit and vegetables against growth of bacteria and fungi.[15]

References

  1. ^ Benes, F.M. Carlsson and the discovery of dopamine. Trends in Pharmacological Sciences, Volume 22, Issue 1, 1 January 2001, Pages 46-47.
  2. ^ Schultz, Cambridge university, UK
  3. ^ Barron AB, Maleszka R, Vander Meer RK, Robinson GE (2007): "Octopamine modulates honey bee dance behavior." Proc Natl Acad Sci U S A. 104 (5): 1703-7 PMID 17237217 (PDF)
  4. ^ Giuliano, F. (2001). "Dopamine and male sexual function". Eur Urol. 40: 601–608. PMID 11805404. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Giuliano, F. (2001). "Dopamine and sexual function". Int J Impot Res. 13 (Suppl 3): S18–S28. doi:10.1038/sj.ijir.3900719. PMID 11477488. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Berridge K, Robinson T (1998). "What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?". Brain Res Brain Res Rev. 28 (3): 309–69. PMID 9858756.
  7. ^ Peciña S, Cagniard B, Berridge K, Aldridge J, Zhuang X (2003). "Hyperdopaminergic mutant mice have higher "wanting" but not "liking" for sweet rewards". J Neurosci. 23 (28): 9395–402. PMID 14561867.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Lambert M, Schimmelmann B, Karow A, Naber D (2003). "Subjective well-being and initial dysphoric reaction under antipsychotic drugs - concepts, measurement and clinical relevance". Pharmacopsychiatry. 36 (Suppl 3): S181-90. PMID 14677077.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Lemke M, Brecht H, Koester J, Kraus P, Reichmann H (2005). "Anhedonia, depression, and motor functioning in Parkinson's disease during treatment with pramipexole". J Neuropsychiatry Clin Neurosci. 17 (2): 214–20. PMID 15939976.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Peciña S, Berridge K (2005). "Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?". J Neurosci. 25 (50): 11777–86. PMID 16354936.
  11. ^ Pfaus J, Phillips A (1991). "Role of dopamine in anticipatory and consummatory aspects of sexual behavior in the male rat". Behav Neurosci. 105 (5): 727–43. PMID 1840012.
  12. ^ Schultz W (2002). "Getting formal with dopamine and reward". Neuron. 36 (2): 241–263. PMID 12383780.
  13. ^ Flaherty, A.W, (2005). "Frontotemporal and dopaminergic control of idea generation and creative drive". Journal of Comparative Neurology. 493 (1): 147–153. PMID 16254989.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  14. ^ "Disruption of gene interaction linked to schizophrenia". St. Jude Children's Research Hospital. Retrieved 2006-07-06.
  15. ^ Mayer, AM (2006). "Polyphenol oxidases in plants and fungi: Going places? A review". Phytochemistry. 67: 2318–2331. PMID 16973188.

See also

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