Dopaminergic

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The chemical structure of the neurotransmitter dopamine Dopamine2.svg
The chemical structure of the neurotransmitter dopamine

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. [1] Dopaminergic substances or actions increase dopamine-related activity in the brain.

Contents

Dopaminergic brain pathways facilitate dopamine-related activity. 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 that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well.

Also, any endogenous or exogenous chemical substance that 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 some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

Dopaminergic agents

Dopamine precursors

Dopamine precursors including L-phenylalanine and L-tyrosine are used as dietary supplements. L-DOPA (Levodopa), another precursor, is used in the treatment of Parkinson's disease.

Dopamine receptor agonists

Dopamine receptor agonists such as apomorphine, bromocriptine, cabergoline, dihydrexidine (LS-186,899), dopamine, fenoldopam, piribedil, lisuride, pergolide, pramipexole, ropinirole, and rotigotine, are used in the treatment of Parkinson's disease and to treat depression and anxiety.

Dopamine receptor agonists can be divided into D1-like receptor agonists and D2-like receptor agonists.

Dopamine receptor positive allosteric modulators

Positive allosteric modulators of the dopamine D1 receptor like mevidalen and glovadalen are under development for the treatment of Lewy body disease and Parkinson's disease.

Dopamine receptor antagonists

Dopamine receptor antagonists including typical antipsychotics such as chlorpromazine (Thorazine), fluphenazine, haloperidol (Haldol), loxapine, molindone, perphenazine, pimozide, thioridazine, thiothixene, and trifluoperazine, the atypical antipsychotics such as amisulpride, clozapine, olanzapine, quetiapine (Seroquel), risperidone (Risperdal), sulpiride, and ziprasidone, and antiemetics like domperidone, metoclopramide, and prochlorperazine, among others, which are used in the treatment of schizophrenia and bipolar disorder as antipsychotics, and nausea and vomiting.

Dopamine receptor antagonists can be divided into D1-like receptor antagonists and D2-like receptor antagonists. Ecopipam is an example of a D1-like receptor antagonist.

Dopamine reuptake inhibitors

Dopamine reuptake inhibitors (DRIs) or dopamine transporter (DAT) inhibitors such as methylphenidate (Ritalin), amineptine, nomifensine, cocaine, bupropion, modafinil, and vanoxerine, 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, fatigue, drug addiction as anticraving agents, and sexual dysfunction, as well as illicit street drugs.

Dopamine depleting agents

Vesicular monoamine transporter 2 (VMAT2) inhibitors such as reserpine, tetrabenazine, valbenazine and deutetrabenazine act as dopamine depleting agents and are used as sympatholytics or antihypertensives, to treat tardive dyskinesia, and in the past as antipsychotics. They have been associated with side effects including depression, apathy, fatigue, amotivation, and suicidality.

Dopamine releasing agents

Dopamine releasing agents (DRAs) such as phenethylamine, amphetamine, lisdexamfetamine (Vyvanse), methamphetamine, methylenedioxymethamphetamine (MDMA), phenmetrazine, pemoline, 4-methylaminorex (4-MAR), and benzylpiperazine, among many others, which, like DRIs, 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 aphrodisiacs. Many of these compounds are also illicit street drugs.

Dopaminergic activity enhancers

Dopaminergic activity enhancers such as the prescription drug selegiline (deprenyl) and the research chemicals BPAP and PPAP enhance the action potential-mediated release of dopamine. [2] This is in contrast to dopamine releasing agents like amphetamine, which induce the uncontrolled release of dopamine regardless of electrical stimulation. [2] The effects of the activity enhancers may be mediated by intracellular TAAR1 agonism coupled with uptake into monoaminergic neurons by monoamine transporters. [3] [4] Dopaminergic activity enhancers are of interest in the potential treatment of a number of medical disorders, such as depression and Parkinson's disease. To date, only phenylethylamine, tryptamine, and tyramine have been identified as endogenous activity enhancers. [2]

Monoamine oxidase inhibitors

Monoamine oxidase (MAO) inhibitors (MAOIs) including non-selective agents such as phenelzine, tranylcypromine, isocarboxazid, and pargyline, MAOA selective agents like moclobemide and clorgyline, and MAOB selective agents such as selegiline and rasagiline, as well as the harmala alkaloids like harmine, harmaline, tetrahydroharmine, harmalol, harman, and norharman, which are found to varying degrees in Nicotiana tabacum (tobacco), Banisteriopsis caapi (ayahuasca, yage), Peganum harmala (Harmal, Syrian Rue), Passiflora incarnata (Passion Flower), and Tribulus terrestris , among others, which are used in the treatment of depression and anxiety as antidepressants and anxiolytics, respectively, in the treatment of Parkinson's disease and dementia, and for the recreational purpose of boosting the effects of certain drugs like phenethylamine (PEA) and psychedelics like dimethyltryptamine (DMT) via inhibiting their metabolism.

Catechol O-methyltransferase inhibitors

Catechol O-methyl transferase (COMT) inhibitors such as entacapone, opicapone, and tolcapone, which are used in the treatment of Parkinson's disease. Entacapone and opicapone are peripherally selective, but tolcapone significantly crosses the blood–brain barrier. Tolcapone is under study for potential treatment of certain psychiatric disorders such as obsessive–compulsive disorder and schizophrenia. [5] [6] [7]

Other enzyme inhibitors

Dopamine β-hydroxylase inhibitors like disulfiram (Antabuse), which can be used in the treatment of addiction to cocaine and similar dopaminergic drugs as a deterrent drug. The excess dopamine resulting from inhibition of the dopamine β-hydroxylase enzyme increases unpleasant symptoms such as anxiety, higher blood pressure, and restlessness. Disulfiram is not an anticraving agent, because it does not decrease craving for drugs. Instead, positive punishment from its unpleasant effects deters drug consumption. [8]

Phenylalanine hydroxylase inhibitors like 3,4-dihydroxystyrene), which is currently only a research chemical with no suitable therapeutic indications, likely because such drugs would induce the potentially highly dangerous hyperphenylalaninemia or phenylketonuria.

Tyrosine hydroxylase inhibitors like metirosine, which is used in the treatment of pheochromocytoma as a sympatholytic or antihypertensive agent.

Aromatic L-amino acid decarboxylase (AAAD) or DOPA decarboxylase inhibitors including benserazide, carbidopa, and methyldopa, which are used in the treatment of Parkinson's disease in augmentation of L-DOPA to block the peripheral conversion of dopamine, thereby inhibiting undesirable side-effects, and as sympatholytic or antihypertensive agents.

Miscellaneous agents

Tyrosine hydroxylase (TH) upregulators such as bromantane and low-dose aspirin through an unknown mechanism of action. [9] [10] Bromantane's upregulation of TH may persist for a time (up to at least one month) after its discontinuation based on data related to its efficacy in treating asthenic disorders in Russia. [11]

Amantadine has dopaminergic effects through uncertain mechanisms of action. [12] [13] It is structurally related to other adamantanes like bromantane and rimantadine, which also have dopaminergic actions. [14] Like bromantane, amantadine can upregulate tyrosine hydroxylase, but it is unclear whether this is involved in or responsible for its dopaminergic actions. [12]

Others such as hyperforin and adhyperforin (both found in Hypericum perforatum St. John's Wort), L-theanine (found in Camellia sinensis , the tea plant), and S-adenosyl-L-methionine (SAMe)

See also

Related Research Articles

<span class="mw-page-title-main">Substantia nigra</span> Structure in the basal ganglia of the brain

The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. In some plant families, l-DOPA is the central precursor of a biosynthetic pathway that produces a class of pigments called betalains. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.

α-Methyl-<i>p</i>-tyrosine Chemical compound

α-Methyl-p-tyrosine (AMPT), or simply α-methyltyrosine, also known in its chiral 2-(S) form as metirosine, is a tyrosine hydroxylase enzyme inhibitor and is therefore a drug involved in inhibiting the catecholamine biosynthetic pathway. AMPT inhibits tyrosine hydroxylase whose enzymatic activity is normally regulated through the phosphorylation of different serine residues in regulatory domain sites. Catecholamine biosynthesis starts with dietary tyrosine, which is hydroxylated by tyrosine hydroxylase and it is hypothesized that AMPT competes with tyrosine at the tyrosine-binding site, causing inhibition of tyrosine hydroxylase.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">Vesicular monoamine transporter 2</span> Mammalian protein found in Homo sapiens

The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene. SLC18A2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase(COMT) inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">Benzofuranylpropylaminopentane</span> Chemical compound

(–)-Benzofuranylpropylaminopentane is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals.

<span class="mw-page-title-main">Bromantane</span> Stimulant drug

Bromantane, sold under the brand name Ladasten, is an atypical central nervous system (CNS) stimulant and anxiolytic drug of the adamantane family that is related to amantadine and memantine. Medically, it is approved in Russia for the treatment of neurasthenia. Although the effects of bromantane have been determined to be dependent on the dopaminergic and possibly serotonergic neurotransmitter systems, its exact mechanism of action is unknown, and is distinct in its properties relative to typical stimulants such as amphetamine. Bromantane has sometimes been described as an actoprotector.

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

<span class="mw-page-title-main">Monoaminergic activity enhancer</span> Class of compounds in the nervous system

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of compounds that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.

<span class="mw-page-title-main">Pharmacology of selegiline</span> Pharmacology of the antiparkinsonian and antidepressant selegiline

The pharmacology of selegiline is the study of the pharmacodynamic and pharmacokinetic properties of the antiparkinsonian and antidepressant selegiline (L-deprenyl). Selegiline is available in a few different forms, including oral tablets and capsules, orally disintegrating tablets (ODTs), and transdermal patches. These forms have differing pharmacological properties.

References

  1. Melinosky C (27 November 2022). "Parkinson's Disease: Glossary of Terms". WebMD.
  2. 1 2 3 Shimazu S, Miklya I (May 2004). "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 28 (3): 421–427. doi:10.1016/j.pnpbp.2003.11.016. PMID   15093948. S2CID   37564231.
  3. Harsing LG, Knoll J, Miklya I (August 2022). "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". Int J Mol Sci. 23 (15): 8543. doi: 10.3390/ijms23158543 . PMC   9369307 . PMID   35955676.
  4. Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". Int J Mol Sci. 24 (17): 13334. doi: 10.3390/ijms241713334 . PMC   10487936 . PMID   37686140.
  5. Kings E, Ioannidis K, Grant JE, Chamberlain SR (June 2024). "A systematic review of the cognitive effects of the COMT inhibitor, tolcapone, in adult humans". CNS Spectr. 29 (3): 166–175. doi:10.1017/S1092852924000130. PMID   38487834.
  6. Grant JE, Hook R, Valle S, Chesivoir E, Chamberlain SR (September 2021). "Tolcapone in obsessive-compulsive disorder: a randomized double-blind placebo-controlled crossover trial". Int Clin Psychopharmacol. 36 (5): 225–229. doi:10.1097/YIC.0000000000000368. PMC   7611531 . PMID   34310432.
  7. Apud JA, Weinberger DR (2007). "Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors". CNS Drugs. 21 (7): 535–557. doi:10.2165/00023210-200721070-00002. PMID   17579498.
  8. Krampe H, Stawicki S, Wagner T, Bartels C, Aust C, Rüther E, Poser W, Ehrenreich H (January 2006). "Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome". Alcoholism: Clinical and Experimental Research. 30 (1): 86–95. doi:10.1111/j.1530-0277.2006.00013.x. PMID   16433735.
  9. Rangasamy SB, Dasarathi S, Pahan P, Jana M, Pahan K (June 2019). "Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson's Disease". Journal of Neuroimmune Pharmacology. 14 (2): 173–187. doi:10.1007/s11481-018-9808-3. PMC   6401361 . PMID   30187283.
  10. Mikhaylova M, Vakhitova JV, Yamidanov RS, Salimgareeva MK, Seredenin SB, Behnisch T (October 2007). "The effects of ladasten on dopaminergic neurotransmission and hippocampal synaptic plasticity in rats". Neuropharmacology. 53 (5): 601–608. doi:10.1016/j.neuropharm.2007.07.001. PMID   17854844. S2CID   43661752.
  11. Voznesenskaia TG, Fokina NM, Iakhno NN (2010). "[Treatment of asthenic disorders in patients with psychoautonomic syndrome: results of a multicenter study on efficacy and safety of ladasten]". Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova. 110 (5 Pt 1): 17–26. PMID   21322821.
  12. 1 2 Huber TJ, Dietrich DE, Emrich HM (March 1999). "Possible use of amantadine in depression". Pharmacopsychiatry. 32 (2): 47–55. doi:10.1055/s-2007-979191. PMID   10333162.
  13. Danysz W, Dekundy A, Scheschonka A, Riederer P (February 2021). "Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials". J Neural Transm (Vienna). 128 (2): 127–169. doi:10.1007/s00702-021-02306-2. PMC   7901515 . PMID   33624170.
  14. Ragshaniya A, Kumar V, Tittal RK, Lal K (March 2024). "Nascent pharmacological advancement in adamantane derivatives". Arch Pharm (Weinheim). 357 (3): e2300595. doi:10.1002/ardp.202300595. PMID   38128028.