Dopaminergic means "related todopamine" (literally, "working on dopamine"), a commonneurotransmitter.[1] Dopaminergic substances or actions increase dopamine-related activity in the brain.
Dopaminergic brain pathways facilitate dopamine-related activity. For example, certainproteins such as thedopamine transporter (DAT),vesicular monoamine transporter 2 (VMAT2), anddopamine receptors can be classified as dopaminergic, andneurons thatsynthesize or contain dopamine andsynapses with dopamine receptors in them may also be labeled asdopaminergic.Enzymes that regulate thebiosynthesis ormetabolism of dopamine such asaromatic L-amino acid decarboxylase orDOPA decarboxylase,monoamine oxidase (MAO), andcatecholO-methyl transferase (COMT) may be referred to asdopaminergic as well.
Also, anyendogenous orexogenouschemical 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 havedopaminergic effects, two prominent examples beingopioids, which enhance dopamine release indirectly in thereward pathways, and somesubstituted amphetamines, which enhance dopamine release directly by binding to and inhibitingVMAT2.
Dopamineprecursors includingL-phenylalanine andL-tyrosine are used asdietary supplements.L-DOPA (Levodopa), another precursor, is used in the treatment ofParkinson's disease.Prodrugs of levodopa, includingmelevodopa,etilevodopa,foslevodopa, andXP-21279 also exist. They are inactive themselves but are converted into dopamine and hence act as non-selective dopamine receptor agonists.
Dopamine receptor agonists can be divided intonon-selective dopamine receptor agonists,D1-like receptor agonists, andD2-like receptor agonists.
Non-selective dopamine receptor agonists includedopamine,deoxyepinephrine (epinine),dinoxyline, anddopexamine. They are mostlyperipherally selective drugs, are often alsoadrenergic receptor agonists, and are used to treat certaincardiovascular conditions.
D2-like receptor agonists include theergolinesbromocriptine,cabergoline,dihydroergocryptine,ergoloid,lisuride,metergoline,pergolide,quinagolide, andterguride; themorphine analogueapomorphine; and the structurally distinct agentspiribedil,pramipexole,ropinirole,rotigotine, andtalipexole. Some of these agents also have weak affinity for the D1-like receptors. They are used to treatParkinson's disease,restless legs syndrome,hyperprolactinemia,prolactinomas,acromegaly,erectile dysfunction, and forlactation suppression. They are also being studied in the treatment ofdepression and are sometimes used in the treatment ofdisorders of diminished motivation likeapathy,abulia, andakinetic mutism.
D1-like receptor agonists include6-Br-APB,A-68930,A-77636,A-86929,adrogolide,dihydrexidine,dinapsoline,doxanthrine,fenoldopam,razpipadon,SKF-81,297,SKF-82,958,SKF-89,145,tavapadon, andtrepipam. They have been researched for and are under development for the treatment ofParkinson's disease anddementia-related apathy. Peripherally selective D1-like receptor agonists like fenoldopam are used to treathypertensive crisis.
Positive allosteric modulators of the dopamineD1 receptor likemevidalen andglovadalen are under development for the treatment ofLewy body disease andParkinson's disease.
Dopamine receptor antagonists includingtypical antipsychotics such aschlorpromazine (Thorazine),fluphenazine,haloperidol (Haldol),loxapine,molindone,perphenazine,pimozide,thioridazine,thiothixene, andtrifluoperazine, theatypical antipsychotics such asamisulpride,clozapine,olanzapine,quetiapine (Seroquel),risperidone (Risperdal),sulpiride, andziprasidone, andantiemetics likedomperidone,metoclopramide, andprochlorperazine, among others, which are used in the treatment ofschizophrenia andbipolar disorder asantipsychotics, andnausea andvomiting.
Dopamine receptor antagonists can be divided intoD1-like receptor antagonists andD2-like receptor antagonists.Ecopipam is an example of a D1-like receptor antagonist.
At low doses, dopamineD2 andD3 receptor antagonists can preferentially blockpresynaptic dopamine D2 and D3autoreceptors and thereby increase dopamine levels and enhance dopaminergic neurotransmission.[2][3][4] Examples of dopamine D2 and D3 receptor antagonists which have been used in this way includeamisulpride,[3][5][6]sulpiride,[7][8][9][10] andENX-104.[11][12]
Negative allosteric modulators of the dopamine receptors, such asSB269652, have been identified and are being researched.[13][14][15][16]
Dopamine reuptake inhibitors (DRIs) ordopamine transporter (DAT) inhibitors such asmethylphenidate (Ritalin),amineptine,nomifensine,cocaine,bupropion,modafinil,armodafinil,phenylpiracetam,mesocarb, andvanoxerine, among others. They are used in the treatment ofattention-deficit hyperactivity disorder (ADHD) aspsychostimulants,narcolepsy aswakefulness-promoting agents,obesity andbinge eating disorder asappetite suppressants,depression asantidepressants, andfatigue aspro-motivational agents. They are also used asillicitstreet andrecreational drugs due to their potentiallyeuphoriant and psychostimulant effects.
Dopamine releasing agents (DRAs) such asphenethylamine,amphetamine,lisdexamfetamine (Vyvanse),methamphetamine,methylenedioxymethamphetamine (MDMA),phenmetrazine,pemoline,4-methylaminorex (4-MAR),phentermine, andbenzylpiperazine, among many others, which, like DRIs, are used in the treatment ofattention-deficit hyperactivity disorder (ADHD) andnarcolepsy aspsychostimulants,obesity asanorectics,depression andanxiety asantidepressants andanxiolytics respectively,drug addiction asanticraving agents, andsexual dysfunction asaphrodisiacs. Many of these compounds are alsoillicitstreet orrecreational drugs.
Dopaminergic activity enhancers such as theprescription drugselegiline (deprenyl) and theresearch chemicalsBPAP andPPAP enhance theaction potential-mediated release of dopamine.[17] This is in contrast to dopamine releasing agents like amphetamine, which induce the uncontrolled release of dopamine regardless of electrical stimulation.[17] The effects of the activity enhancers may be mediated byintracellularTAAR1agonism coupled with uptake into monoaminergic neurons bymonoamine transporters.[18][19] Dopaminergic activity enhancers are of interest in the potential treatment of a number ofmedical disorders, such asdepression andParkinson's disease. To date, onlyphenylethylamine,tryptamine, andtyramine have been identified as endogenous activity enhancers.[17]
Vesicular monoamine transporter 2 (VMAT2) inhibitors such asreserpine,tetrabenazine,valbenazine, anddeutetrabenazine act asdopamine depleting agents and are used assympatholytics orantihypertensives, to treattardive dyskinesia, and in the past asantipsychotics. They have been associated with side effects includingdepression,apathy,fatigue,amotivation, andsuicidality.
Monoamine oxidase (MAO)inhibitors (MAOIs) includingnon-selective agents such asphenelzine,tranylcypromine,isocarboxazid, andpargyline,MAOAselective agents likemoclobemide andclorgyline, andMAOBselective agents such asselegiline andrasagiline, as well as theharmala alkaloids likeharmine,harmaline,tetrahydroharmine,harmalol,harman, andnorharman, which are found to varying degrees inNicotiana tabacum (tobacco),Banisteriopsis caapi (ayahuasca, yage),Peganum harmala (Harmal, Syrian Rue),Passiflora incarnata (Passion Flower), andTribulus terrestris, among others, which are used in the treatment ofdepression andanxiety asantidepressants andanxiolytics, respectively, in the treatment ofParkinson's disease anddementia, and for therecreational purpose of boosting the effects of certaindrugs likephenethylamine (PEA) andpsychedelics likedimethyltryptamine (DMT) via inhibiting theirmetabolism.
CatecholO-methyl transferase (COMT)inhibitors such asentacapone,opicapone, andtolcapone, which are used in the treatment ofParkinson's disease. Entacapone and opicapone areperipherally selective, but tolcapone significantly crosses theblood–brain barrier. Tolcapone is under study for potential treatment of certainpsychiatric disorders such asobsessive–compulsive disorder andschizophrenia.[20][21][22]
Aromatic L-amino acid decarboxylase (AAAD) orDOPA decarboxylase inhibitors includingbenserazide,carbidopa, andmethyldopa, which are used in the treatment ofParkinson's disease inaugmentation ofL-DOPA to block theperipheral conversion ofdopamine, thereby inhibiting undesirableside-effects, and assympatholytic orantihypertensive agents.
Dopamine β-hydroxylase inhibitors likedisulfiram (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 ananticraving agent, because it does not decrease craving for drugs. Instead,positive punishment from its unpleasant effects deters drug consumption.[23] Other dopamine β-hydroxylase inhibitors include the centrally activenepicastat and theperipherally selectiveetamicastat andzamicastat.
Phenylalanine hydroxylase inhibitors like3,4-dihydroxystyrene), which is currently only aresearch chemical with no suitable therapeutic indications, likely because such drugs would induce the potentially highly dangeroushyperphenylalaninemia orphenylketonuria.
Tyrosine hydroxylase inhibitors likemetirosine, which is used in the treatment ofpheochromocytoma as asympatholytic orantihypertensive agent.
Dopaminergic neurotoxins like6-hydroxydopamine (6-OHDA) andMPTP are used inscientific research tolesion the dopamine system and study the biological role of dopamine.
Amantadine has dopaminergic effects through uncertainmechanisms of action.[24][25] It is structurally related to otheradamantanes likebromantane andrimantadine, which also have dopaminergic actions.[26] Bromantane can upregulatetyrosine hydroxylase (TH) and thereby increase dopamine production and this might be involved in its dopaminergic effects.[27][28] Amantadine can upregulate TH similarly, but as with bromantane, it is unclear whether this is involved in or responsible for its dopaminergic actions.[24] Amantadine is used in the treatment ofParkinson's disease,levodopa-induced dyskinesia, andfatigue inmultiple sclerosis. It has also been used in the treatment ofdisorders of consciousness,disorders of diminished motivation, andbrain injuries. The drug is being studied in the treatment ofdepression andattention deficit hyperactivity disorder (ADHD) as well.
4,4-Diphenylpiperidines includingbudipine andprodipine are effective in the treatment ofParkinson's disease.[29][30][31] Theirmechanism of action is unknown but they act as indirect dopaminergic agents.[30][29][31] They have distinct effects from other antiparkinsonian agents and dopaminergic drugs.[30][29][31]
Aspirin upregulatestyrosine hydroxylase and increases dopamine production.[32]
Others such ashyperforin andadhyperforin (both found inHypericum perforatum St. John's Wort),L-theanine (found inCamellia sinensis, the tea plant), andS-adenosyl-L-methionine (SAMe).