Dopaminergic (modern diseases)

Dopaminergic

Main article: Dopamine

The chemical structure of the neurotransmitter dopamine

Look up dopaminergic in Wiktionary, the free dictionary.

Dopaminergic means related to the neurotransmitter dopamine.^[1] For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT₂), and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes which regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylasemonoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Lastly, any endogenous or exogenous chemical substance which acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids which enhance dopamine release indirectly in the reward pathways, and amphetamines, which enhance dopamine release directly by binding to, and inhibiting VMAT₂. (DDC),

[edit] Supplements and drugs

A complete list of dopaminergic substances used as supplements and drugs includes:

• Dopamine (DA; Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc) itself, which is used in the treatment of severe hypotension, circulatory shock, and cardiac arrest as a vasopressor or antihypotensive agent.

• Precursors including L-phenylalanine (PHE), L-tyrosine (TYR), and L-DOPA (Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc; also found in Mucuna pruriens (Velvet Bean)), which are all used as dietary supplements, and the latter of which is also used in the treatment of Parkinson’s disease (PD).

• Cofactors including ferrous iron (Fe²⁺), tetrahydrobiopterin (THB, BH₄), vitamin B₃ (niacin, niacinamide) → NADPH, vitamin B₆ (pyridoxine, pyridoxamine, pyridoxal → pyridoxal phosphatevitamin B₉ (folic acid) → tetrahydrofolic acid (THFA, H₄FA), vitamin C (ascorbic acid), and zinc (Zn²⁺), which are used as dietary supplements. (PLP),

• Dopamine receptor agonists such as apomorphine (Apokyn, Uprima), bromocriptine (Parolodel), cabergoline (Dostinex), dihydrexidine (LS-186,899), dopamine (Intropin, Revivan), fenoldopampiribedil (Trivastal), lisuride (Dopergin), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and rotigotine (Neupro), which are used in the treatment of Parkinson’s diseaserestless legs syndrome (RLS), hyperprolactinemia (HPA), and sexual dysfunction (SD), as well as are being investigated in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively. (Corlopam), (PD),

• Dopamine receptor antagonists including typical antipsychotics such as chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), loxapine (Loxitane), molindone (Moban), perphenazinepimozide (Orap), thioridazine (Mellaril), thiothixene (Navane), and trifluoperazineatypical antipsychotics such as amisulpride (Solian), clozapine (Clozaril), olanzapinequetiapine (Seroquel), risperidone (Risperdal), sulpiride (Dogmatil), and ziprasidoneantiemetics like domperidone, metoclopramide (Reglan), and prochlorperazineschizophrenia (SCZ) and bipolar disorder (BD) as antipsychotics, and nausea and vomiting. (Trilafon), (Stelazine), the (Zyprexa), (Geodon), and (Compazine), among others, which are used in the treatment of schizophrenia (SCZ) and bipolar disorder (BD) as antipsychotics, and nausea and vomiting.

• Dopamine reuptake inhibitors (DRIs) or dopamine transporter (DAT) inhibitors such as methylphenidate (Ritalin, Focalin, Concerta), bupropion (Wellbutrin, Zyban), amineptine (Survector, Maneon, Directin), and nomifensine (Merital, Alival), as well as cocaine (“Coke”, “Crack”, etc), methylenedioxypyrovalerone (MDPV; “Sonic”), ketamine (K; Ketalar, Ketanest, Ketaset; “Special-K”, “Kit Kat”, etc), and phencyclidine (PCP; Sernyl; “Angel Dust”, “Rocket Fuel”, etc), among others, which are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy as psychostimulants, obesity as anorectics, depression and anxiety as antidepressants and anxiolytics, respectively, drug addiction as anticraving agents, and sexual dysfunction, as well as illicitstreet drugs.

• Dopamine releasing agents (DRAs) such as amphetamine (Adderall, Dexedrine; “Speed”), lisdexamfetamine (Vyvanse), methamphetamine (Desoxyn; “Meth”, “Crank”, “Crystal”, etc), methylenedioxymethamphetamine (MDMA; “Ecstasy”, “E”, “X”, “XTC”, etc), phenmetrazine (Preludin; “Prellies”), pemoline (Cylert), 4-methylaminorex (4-MAR; “Ice”, “Euphoria”, etc), and benzylpiperazineattention-deficit hyperactivity disorder (ADHD) and narcolepsy as psychostimulants, obesity as anorectics, depression and anxiety as antidepressants and anxiolytics, respectively, drug addiction as anticraving agents, and sexual dysfunction, as well as illicit street drugs. (BZP; “Bennies”, “A2”, “Sunrise”, “Frenzy”, etc), among many others, which, like DRIs, are used in the treatment of

• Dopamine activity enhancers such as BPAP and PPAP, which are currently only research chemicals, but are being investigated for clinical development in the treatment of a number of medical disorders.

• Vesicular monoamine transporter 2 (VMAT₂) inhibitors such as reserpine (Serpasil), tetrabenazinedeserpidine (Harmonyl), which are used as sympatholytics or antihypertensives, and in the past as antipsychotics. (Nitoman, Xenazine), and

• Monoamine oxidase (MAO) inhibitors (MAOIs) including nonselective agents such as phenelzinetranylcypromine (Parnate), and isocarboxazid (Marplan), MAO_A selective agents like moclobemide (Aurorix, Manerix), and MAO_B selective agents such as selegiline (Eldepryl, Zelapar, Emsam), rasagiline (Azilect), and pargyline (Eutonyl), as well as the harmala alkaloids like harmine, harmaline, tetrahydroharmine, harmalol, harman, and norharman, which are found to varying degrees in Nicotiana tabacum (Tobacco; also cigarettes, cigars, chew, hookah, etc), Banisteriopsis caapiPeganum harmala (Harmal, Syrian Rue), Passiflora incarnata (Passion Flower), and Tribulus terrestris (Puncture Vine), among others, which are used in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively, in the treatment of Parkinson’s disease (PD) and dementia, and for the recreational purpose of boosting the effects of certain drugsphenethylamine (PEA) and psychedelics like dimethyltryptamine (DMT) via inhibiting their metabolism. (Nardil), (Ayahausca, Caapi, Yage), like

• Catechol O-methyl transferase (COMT) inhibitors such as entacapone (Comtan, Stalevo) and tolcapone (Tasmar), which are used in the treatment of Parkinson’s disease (PD).

• Dopamine β-hydroxylase (DBH) inhibitors like disulfiram (Antabuse), which is used in the treatment of drug addiction as an anticraving agent.

• Phenylalanine hydroxylase (PAH) inhibitors like 3,4-dihydroxystyrene (DHS) which is currently only a research chemical with no suitable therapeutic indications, likely on account of the fact that such drugs would induce the potentially highly dangerous hyperphenylalaninemia (HPA) and/or phenylketonuria (PKU).

• Tyrosine hydroxylase (TH) inhibitors like metirosine (Demser), which is used in the treatment of pheochromocytoma (PCC) as a sympatholytic or antihypertensive agent.

• Aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylase (DDC) inhibitors including benserazide (Prolopa, Madopar, etc), carbidopa (Lodosyn, Atamet, Parcopa, Sinemet, Stalevo, etc), and methyldopa (Aldomet, Aldoril, Dopamet, Dopegyt, etc), which are used in the treatment of Parkinson’s disease (PD) in augmentation of L-DOPA ((Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc)) to block the peripheral conversion of dopamine thereby inhibiting undesirable side effects, and as sympatholytic or antihypertensive agents.

Others such as hyperforin and adhyperforin (both found in Hypericum perforatum (St. John’s Wort (SJW))), L-theanine (found in Camellia sinensis (Tea Plant, also known as Black, White, Oolong, Pu-erh, or Green Tea)), and S-adenosyl-L-methionine (SAMe), which are all dietary supplements used mainly  for the remedification of depression and anxietyantidepressants and anxiolytics, respectively.

Legal liability (Intentional creation of)

Legal liability 

Legal liability is the legal bound obligation to pay debts.^[1]

• In law a person is said to be legally liable when they are financially and legally responsible for something. Legal liability concerns both civil law and criminal law. See Strict liability. Under English law, with the passing of the Theft Act 1978, it is an offense to evade a liability dishonestly. Payment of damages usually resolved the liability. Vicarious liability arises under the common law doctrine of agency – respondeat superior – the responsibility of the superior for the acts of their subordinate.
• In commercial law, limited liability is a form of business ownership in which business owners are legally responsible for no more than the amount that they have contributed to a venture. If for example, a business goes bankrupt an owner with limited liability will not lose unrelated assets such as a personal residence (assuming they do not give personal guarantees). This is the standard model for larger businesses, in which a shareholder will only lose the amount invested (in the form of stock value decreasing). For an explanation see business entity.
• Manufacturer’s liability is a legal concept in most countries that reflects the fact that producers have a responsibility not to sell a defective product. See product liability.

Phenethylamine (neurochemistry)(misinformation included)

Phenethylamine

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Phenethylamine

Systematic (IUPAC) name
phenylethan-2-amine
Identifiers
CAS number	64-04-0
ATC code	?
PubChem	CID 1001
ChemSpider	13856352
Chemical data
Formula	C8H11N
Mol. mass	121.18 g/mol
SMILES	eMolecules & PubChem
Synonyms	2-phenylethylamine, β-phenylethylamine, 1-amino-2-phenylethane
Pharmacokinetic data
Metabolism	MAO-A, MAO-B, ALDH, DBH, CYP2D6
Half-life	~5-10 minutes
Therapeutic considerations
Pregnancy cat.	?
Legal status	Uncontrolled
Routes	Oral

Phenethylamine (PEA) is a natural monoamine alkaloid, trace amine, and psychoactive drug with stimulantmammalian central nervous system, phenethylamine is believed to function as a neuromodulatorneurotransmitter. It is biosynthesized from the amino acid phenylalanine by enzymatic decarboxylation. Besides mammals, phenethylamine is found in many other organisms and foods such as chocolate, especially after microbial fermentation. It is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, orally ingested phenethylamine is usually inactive on account of extensive first-pass metabolism by monoamine oxidase (MAO) into phenylacetic acid, preventing significant concentrations from reaching the brain.^[1][2] effects. In the or

The group of phenethylamine derivatives is referred to as the phenethylamines. Substituted phenethylamines, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include stimulants, psychedelics, and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others.

Contents [show] 1 Chemistry 2 Pharmacology 3 Pharmacokinetics 4 Chocolate theory of love 5 See also 6 References 7 External links

[edit] Chemistry

Phenethylamine is an amine, consisting of a benzene ring and an aminoethyl group. It is a colorless liquid at room temperature. Phenethylamine is soluble in water, ethanol, and ether. Similar to other low-molecular-weight amines, it has a fishy odor. Upon exposure to air, it forms a solid carbonate salt with carbon dioxide. Phenethylamine is strongly basic and forms a stable crystalline hydrochloride salt with a melting point of 217 °C. Phenethylamine is also a skin irritant and possible sensitizer.

Phenethylamine has an inactive constitutional isomer 1-phenylethylamine, which itself has two stereoisomers: (R)-(+)-1-phenylethylamine and (S)-(-)-1-phenylethylamine.

[edit] Pharmacology

Phenethylamine, similarly to amphetamine, acts as a releasing agent of norepinephrine and dopamine.^[3][4][5][6] For this reason, it has been called the “body’s endogenous amphetamine”. However when taken orally it is rapidly metabolized.

Low concentrations of endogenous phenethylamine are found in those suffering from attention-deficit hyperactivity disorder (ADHD)^[7] and often in clinical depression, while levels are elevated in schizophrenia.^[8]

Dopamine Dopaminergic system (misinformation included)

 Dopamine

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For other uses, see Dopamine (disambiguation).

Dopamine
IUPAC name[hide] 4-(2-aminoethyl)benzene-1,2-diol
Other names[hide] 2-(3,4-dihydroxyphenyl)ethylamine; 3,4-dihydroxyphenethylamine; 3-hydroxytyramine; DA; Intropin; Revivan; Oxytyramine
Identifiers
CAS number	51-61-6 Y, 62-31-7 (hydrochloride)
PubChem	681
ChemSpider	661
UNII	VTD58H1Z2X Y
SMILES	[show] c1cc(c(cc1CCN)O)O
InChI	[show] 1/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2
InChI key	[show] VYFYYTLLBUKUHU-UHFFFAOYAA
Properties
Molecular formula	C8H11NO2
Molar mass	153.18 g/mol
Density	1.26 g/cm3
Melting point	128 °C, 401 K, 262 °F
Boiling point	decomposes
Solubility in water	60.0 g/100 ml
Hazards
R-phrases	R36/37/38
S-phrases	S26 S36
(what is this?)  (verify) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)Y
Infobox references

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors—D₁, D₂, D₃, D₄, and D₅—and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area.^[1] Dopamine is also a neurohormonehypothalamus. Its main function as a hormone is to inhibit the release of prolactin from the anterior lobe of the pituitary. released by the

Dopamine is available as an intravenous medication acting on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. However, because 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, which is the precursor of dopamine, can be given because it can cross the blood-brain barrier.

Contents [show] 1 History 2 Biochemistry 2.1 Name and family 2.2 Biosynthesis 2.3 Inactivation and degradation 3 Functions in the brain 3.1 Anatomy 3.2 Tonic and phasic activity 3.3 Movement 3.4 Cognition and frontal cortex 3.5 Regulating prolactin secretion 3.6 Motivation and pleasure 3.6.1 Reinforcement 3.6.2 Reuptake inhibition, expulsion 3.6.3 Incentive salience 3.6.4 Dopamine, learning, and reward-seeking behavior 3.6.5 Animal studies 3.6.6 The effects of drugs that reduce dopamine activity 3.6.7 Opioid and cannabinoid transmission 3.6.8 Sociability 3.6.9 Processing of pain 3.6.10 Salience 3.6.11 Behavior disorders 3.7 Latent inhibition and creative drive 3.8 Chemoreceptor trigger zone 3.9 Dopaminergic mind hypothesis 4 Links to psychosis 5 Therapeutic use 6 Nonneural functions 6.1 Immunoregulatory 6.2 Peripheral effects 6.3 Renal effects 7 Dopamine and fruit browning 8 See also 9 References 10 External links

[edit] History

Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England.^[2] It was named dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). Dopamine’s function as a neurotransmitter was first recognized in 1958 by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden.^[3] Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not just a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but a neurotransmitter as well.

[edit] Biochemistry

Biosynthesis of dopamine

[edit] Name and family

Dopamine has the chemical formula C₆H₃(OH)₂-CH₂-CH₂-NH₂. Its chemical name is “4-(2-aminoethyl)benzene-1,2-diol” and its abbreviation is “DA.”
As a member of the catecholamine family, dopamine is a precursor to norepinephrine (noradrenaline) and then epinephrine (adrenaline) in the biosynthetic pathways for these neurotransmitters.

The effects of drugs that reduce dopamine activity

In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have been shown to reduce motivation, cause anhedonia (inability to experience pleasure), and long-term use has been associated with the irreversible movement disorder, tardive dyskinesia.^[26] Furthermore, antipsychotic drugs are associated with weight gain, diabetes, lactation, gynecomastia, drooling, dysphoria, fatigue, sexual dysfunction, and heart rhythm problems. Selective D2/D3 agonists pramipexole and ropinirole, used to treat restless legs syndrome^[27] (RLS), have limited anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

[edit] Opioid and cannabinoid transmission

Opioid and cannabinoid transmission instead of dopamine may modulate consummatory pleasure and food palatability (liking).^[28] 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.^[29] Libido can be increased by drugs that affect dopamine, but not by drugs that affect opioid peptides or other neurotransmitters.

[edit] Sociability

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 disorder, manic subjects can become hypersocial, as well as hypersexual.^{[citation needed]} This is credited to an increase in dopamine, because mania can be reduced by dopamine-blocking anti-psychotics.^[30]

[edit] Processing of pain

Dopamine has been demonstrated to play a role in pain processing in multiple levels of the central nervous system including the spinal cord,^[31] periaqueductal gray (PAG),^[32] thalamus,^[33] basal ganglia,^[34][35] insular cortex,^[36][37] and cingulate cortex.^[38] Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson’s disease.^[39] Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including burning mouth syndrome,^[40] fibromyalgia,^[41][42] and restless legs syndrome.^[43] In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumably via activation of neurons involved in descending inhibition.^[44] In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.

[edit] Salience

Dopamine may also have a role in the salience of potentially important stimuli, such as sources of reward or of danger.^[45] This hypothesis argues that dopamine assists decision-making by influencing the priority, or level of desire, of such stimuli to the person concerned.

[edit] Behavior disorders

Deficient dopamine neurotransmission is implicated in attention-deficit hyperactivity disorder, and stimulant medications used to successfully treat the disorder increase dopamine neurotransmission, leading to decreased symptoms.^[46] Consistent with this hypothesis, dopaminergic pathways have a role in inhibitory action control and the inhibition of the tendency to make unwanted actions.^[47]

The long term use of levodopa in Parkinson’s disease has been linked to dopamine dysregulation syndrome.^[48]

[edit] 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.^[49]

[edit] Chemoreceptor trigger zone

Dopamine is one of the neurotransmitters implicated in the control of nausea and vomiting via interactions in the chemoreceptor trigger zone. Metoclopramide is a D2-receptor antagonist that functions as a prokinetic/antiemetic.

[edit] Dopaminergic mind hypothesis

The dopaminergic mind hypothesis seeks to explain the differences between modern humans and their hominid relatives by focusing on changes in dopamine.^[50] It theorizes that increased levels of dopamine were part of a general physiological adaptation due to an increased consumption of meat around two million years ago in Homo habilis, and later enhanced by changes in diet and other environmental and social factors beginning approximately 80,000 years ago. Under this theory, the “high-dopamine” personality is characterized by high intelligence, a sense of personal destiny, a religious/cosmic preoccupation, an obsession with achieving goals and conquests, an emotional detachment that in many cases leads to ruthlessness, and a risk-taking mentality. High levels of dopamine are proposed to underlie increased psychological disorders in industrialized societies. According to this hypothesis, a “dopaminergic society” is an extremely goal-oriented, fast-paced, and even manic society, “given that dopamine is known to increase activity levels, speed up our internal clocks and create a preference for novel over unchanging environments.”^[50] In the same way that high-dopamine individuals lack empathy and exhibit a more masculine behavioral style, dopaminergic societies are “typified by more conquest, competition, and aggression than nurturance and communality.”^[50] Although behavioral evidence and some indirect anatomical evidence (e.g., enlargement of the dopamine-rich striatum in humans)^[51] support a dopaminergic expansion in humans, there is still no direct evidence that dopamine levels are markedly higher in humans relative to other apes.^[52] However, recent discoveries about the sea-side settlements of early man may provide evidence of dietary changes consistent with this hypothesis.^[53]

[edit] Links to psychosis

Main article: Dopamine hypothesis of schizophrenia

Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia.^[54] Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals. Anti-psychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level, and thereby blocking the effects of the neurochemical in a dose-dependant manner. The older, so-called typical antipsychotics most commonly act on D2 receptors,^[55] while the atypical drugs also act on D1, D3 and D4 receptors.^[56][57] The finding that drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold,^[58] can temporarily cause psychosis, provides further evidence for this link.^[5

Therapeutic use

Main article: L-DOPA

Levodopa is a dopamine precursor used in various forms to treat Parkinson’s disease and dopa-responsive dystonia. 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.