A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a

reuptake inhibitor Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

of the

monoamine neurotransmitter 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. All monoamines ar ...

dopamine by blocking the action of the

dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dop ...

(DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the

postsynaptic Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

is blocked from re-entering the

presynaptic In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

neuron. This results in increased

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', '' number concentration'', ...

s of dopamine and increase in dopaminergic

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

. DRIs are used in the treatment of

attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappr ...

(ADHD) and

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...

for their psychostimulant effects, and in the treatment of

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

and

binge eating disorder Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFE ...

for their

appetite suppressant An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic. The term is (from the Greek ''ἀν-'' (an-) = "without" ...

effects. They are sometimes used as antidepressants in the treatment of

mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where a disturbance in the person's mood is the main underlying feature. The classification is in the '' Diagnostic and St ...

s, but their use as antidepressants is limited given that strong DRIs have a high abuse potential and legal restrictions on their use. Lack of dopamine reuptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior given increase in dopaminergic

. The

dopaminergic pathways Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. ...

are considered to be strong reward centers. Many DRIs such as

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

are drugs of abuse due to the rewarding effects evoked by elevated synaptic concentrations of dopamine in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

Society and culture

History of use

Until the 1950s, dopamine was thought to only contribute to the biosynthesis of

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

and epinephrine. It was not until dopamine was found in the brain in similar levels as norepinephrine that the possibility was considered that its biological role might be other than the synthesis of the

catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a su ...

Pharmacotherapeutic uses

The following drugs have DRI action and have been or are used clinically specifically for this property:

amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser ...

, dexmethylphenidate, difemetorex,

fencamfamine Fencamfamin ( INN), also known as fencamfamine or by the brand names Glucoenergan and Reactivan, is a stimulant which was developed by Merck in the 1960s. Medical uses Fencamfamin is still used, though rarely, for treating depressive day-time fa ...

, lefetamine, levophacetoperane, medifoxamine,

mesocarb Mesocarb (brand names Sidnocarb, Sydnocarb) is a drug that is currently being developed for Parkinson's disease. The drug was originally developed in the USSR in the 1970s for a variety of indications including asthenia, apathy, adynamia and ...

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser exten ...

nomifensine Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor, i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters ...

, pipradrol,

prolintane Prolintane (Catovit, Katovit, Promotil, Villescon) is a stimulant and norepinephrine-dopamine reuptake inhibitor developed in the 1950s. It is the member of amphetamine and derivatives. It is closely related in chemical structure to other drugs ...

, and pyrovalerone. The following drugs are or have been used clinically and possess only weak DRI action, which may or may not be clinically-relevant:

adrafinil Adrafinil, sold under the brand name Olmifon, is a wakefulness-promoting medication that was formerly used in France to improve alertness, attention, wakefulness, and mood, particularly in the elderly. It was also used off-label by individuals w ...

armodafinil Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (''R'')-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon In ...

, bupropion, mazindol, modafinil,

nefazodone Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...

sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...

, and

sibutramine Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor similar to a tricyclic antidepressant. Un ...

. The following drugs are or have been clinically used but only coincidentally have DRI properties:

benzatropine Benzatropine ( INN), known as benztropine in the United States and Japan, is a medication used to treat movement disorders like parkinsonism and dystonia, as well as extrapyramidal side effects of antipsychotics, including akathisia. It is not u ...

, diphenylpyraline,

etybenzatropine Etybenzatropine ( INN), also known as ethybenztropine (USAN, BAN) and tropethydrylin, is an anticholinergic/antihistamine marketed under the trade names Panolid, Ponalid, and Ponalide, which is used as an antiparkinsonian agent. Like its analog ...

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

, nefopam,

pethidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eis ...

(meperidine), and tripelennamine. The following are a selection of some particularly notably abused DRIs:

MDPV Methylenedioxypyrovalerone (MDPV) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It was first developed in the 1960s by a team at Boehringer Ingelheim. Its activity at the dopamine tra ...

naphyrone Naphyrone, also known as O-2482 and naphthylpyrovalerone, is a substituted cathinone drug derived from pyrovalerone that acts as a triple reuptake inhibitor, producing stimulant effects and has been reported as a novel designer drug. No safety ...

, and

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percept ...

(PCP). Amphetamines, including amphetamine, methamphetamine,

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desire ...

, cathinone,

methcathinone Methcathinone (α-methylamino- propiophenone or ephedrone) (sometimes called "cat" or "jeff" or "catnip" or "M-Kat" or "kat" or "intash" ) is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone. It is used as a recreationa ...

, mephedrone, and

methylone Methylone (also known as "3,4-methylenedioxy-''N''-methylcathinone", "MDMC", "βk-MDMA" and by the slang term "M1") is an empathogen and stimulant psychoactive drug. It is a member of the substituted amphetamine, substituted cathinone and s ...

, are all DRIs as well, but are distinct in that they also behave, potentially more potently, as dopamine releasing agents (DRAs) (due to Yerkes–Dodson's law, 'more potently stimulated' may not equal more optimally functionally stimulated). There are very distinct differences in the mode of action between dopamine releasers/substrates & dopamine re-uptake inhibitors; the former are functionally

entropy Entropy is a scientific concept, as well as a measurable physical property, that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynam ...

-driven (''i.e.'' relating to

hydrophobicity In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...

) and the latter are

enthalpy Enthalpy , a property of a thermodynamic system, is the sum of the system's internal energy and the product of its pressure and volume. It is a state function used in many measurements in chemical, biological, and physical systems at a constant ...

-driven (''i.e.'' relating conformational change). Reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon

oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The femal ...

s that are naturally found on neurons, whereas releasing agents induce de-polarization of the neuron membrane. The

wakefulness-promoting agent Eugeroics (originally "eugrégorique" or "eugregoric"), also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of cer ...

modafinil and its analogues (e.g.,

) have been approved to treat

and shift work sleep disorder. These act as weak ( micromolar) DRIs, but this effect does not correlate with wakefulness-promoting effects, suggesting the effect is too weak to be of clinical significance. The conclusion is these drugs promote wakefulness via some other mechanism. DRIs have been explored as potential antiaddictive agents in the context of replacement therapy strategies, analogous to nicotine replacement for treating tobacco addiction and

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroi ...

replacement in the case of opioid addiction. DRIs have been explored as treatment for

addiction, and have shown to alleviate cravings and self-administration. Monoamine reuptake inhibitors, including DRIs, have shown effectiveness as therapy for excessive food intake and appetite control for obese patients. Though such pharmacotherapy is still available, the majority of stimulant anorectics marketed for this purpose have been withdrawn or discontinued due to adverse side effects such as hypertension, valvulopathy, and drug dependence.

List of DRIs

Only DRIs which are selective for the DAT over the other

monoamine transporter Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible fo ...

s (MATs) are listed below. For a list of DRIs that act at multiple MATs, see other monoamine reuptake inhibitor pages such as NDRI and SNDRI.

Selective dopamine reuptake inhibitors

Neurotransmitter transporters inhibitors

* 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone * Altropane (O-587) * Amfonelic acid (WIN 25978) *

Amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser ...

(has a reasonable degree of selectivity for dopamine over norepinephrine reuptake inhibition) * BTCP (GK-13), same acronym as for breakthrough cancer pain. * 3C-PEP *

DBL-583 DBL-583 is a selective dopamine reuptake inhibitor of the piperazine chemical class. It is the decanoate ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is re ...

* Difluoropine (O-620) *

GBR-12783 GBR-12783 is a psychostimulant which acts as a selective dopamine reuptake inhibitor 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 t ...

GBR-12935 GBR-12935 is a piperazine derivative which is a potent and selective dopamine reuptake inhibitor. It was originally developed in its 3H radiolabelled form for the purpose of mapping the distribution of dopaminergic neurons in the brain by selec ...

GBR-13069 GBR-13069 is a psychostimulant and selective dopamine reuptake inhibitor 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 ...

GBR-13098 GBR-13098 is a psychostimulant and selective dopamine uptake inhibitor. Blocking the endogenous striatal dopamine (DA) transporter with GBR-13098 in mice has been shown to prevent damage to the DA nerve terminals caused by malonate The conjugat ...

* GYKI-52895 * Iometopane (β-CIT, RTI-55) *

Ethylphenidate Ethylphenidate (EPH), also known as Baxtercaine in the United Kingdom is a psychostimulant and a close analog of methylphenidate. Ethylphenidate acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effecti ...

(more selective for DA vs NE reuptake inhibition compared to methylphenidate, but still has a marked effect on both) * Modafinil (relatively weak but very selective for the

, with little to no effect on the

or serotonin transporters) *

Armodafinil Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (''R'')-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon In ...

(R-enantiomer of modafinil; somewhat more potent at inhibiting DAT than racemic modafinil, with equally negligible action on

NET Net or net may refer to: Mathematics and physics * Net (mathematics), a filter-like topological generalization of a sequence * Net, a linear system of divisors of dimension 2 * Net (polyhedron), an arrangement of polygons that can be folded up ...

and SERT) *

RTI-229 RTI-229, also known as (–)-3β-(4-iodophenyl)tropane-2β-pyrrolidine carboxamide and RTI-''4229''-229, is a potent and long-lasting stimulant drug which was developed in the 1990s as part of a large group of related analogues from the phenylt ...

Vanoxerine Vanoxerine is a piperazine derivative which is a potent and selective dopamine reuptake inhibitor (DRI). Vanoxerine binds to the target site on the dopamine transporter (DAT) ~ 50 times more strongly than cocaine, but simultaneously inhibits the ...

(GBR-12909)

DRIs with substantial activity at other sites

Adrafinil Adrafinil, sold under the brand name Olmifon, is a wakefulness-promoting medication that was formerly used in France to improve alertness, attention, wakefulness, and mood, particularly in the elderly. It was also used off-label by individuals w ...

(weak, possibly stressful on liver) *

Amantadine 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 due to wi ...

(also a weak

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

) *

Benztropine Benzatropine ( INN), known as benztropine in the United States and Japan, is a medication used to treat movement disorders like parkinsonism and dystonia, as well as extrapyramidal side effects of antipsychotics, including akathisia. It is not u ...

(also muscarinic antagonist) * Bupropion (also a more potent NRI and likely NRA due to bupropion's major metabolite

hydroxybupropion Hydroxybupropion (code name BW 306U), or 6-hydroxybupropion, is the major active metabolite of the antidepressant and smoking cessation drug bupropion. It is formed from bupropion by the liver enzyme CYP2B6 during first-pass metabolism. With ora ...

) *

Cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

Fluorenol Fluorenol, also known as hydrafinil, is an alcohol derivative of fluorene. In the most significant isomer, fluoren-9-ol or 9-hydroxyfluorene, the hydroxy group is located on the bridging carbon between the two benzene rings. Hydroxyfluorene can be ...

(extremely weak) * Medifoxamine (relatively weak) *

Metaphit Metaphit (1- -(3-Isothiocyanato)phenylyclohexylpiperidine) is a research chemical that acts as an acylator of NMDARAn, sigma and DAT binding sites in the CNS. It is the ''m''-isothiocyanate derivative of phencyclidine (PCP) and binds irreversi ...

(irreversible; depletes dopamine) *

Methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser exten ...

(has a mild degree of selectivity for dopamine over norepinephrine reuptake inhibition, although it significantly affects both) *

Nomifensine Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor, i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters ...

(Dual selective 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. *

Isopropylphenidate Isopropylphenidate (also known as IPH and IPPD) is a piperidine based stimulant drug, closely related to methylphenidate, but with the methyl ester replaced by an isopropyl ester. It has similar effects to methylphenidate but with a longer dura ...

Rimcazole Rimcazole is an antagonist of the sigma receptor as well as a dopamine reuptake inhibitor. Sigma receptors are thought to be involved in the drug psychosis that can be induced by some drugs such as phencyclidine and cocaine, and rimcazole was ori ...

Venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic ...

(weak) *

Solriamfetol Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth. Common side effects of solriamfetol include heada ...

(also norepinephrine reuptake inhibitor)

Other DRIs

* ''

Chaenomeles speciosa ''Chaenomeles speciosa'', the flowering quince, Chinese quince, or Japanese quinceBailey, L.H.; Bailey, E.Z.; the staff of the Liberty Hyde Bailey Hortorium. 1976. ''Hortus third: A concise dictionary of plants cultivated in the United States ...

'' (Flowering quince) * Oroxylin A (found in '' Oroxylum indicum'' and '' Scutellaria baicalensis'' (Skullcap))

References

{{DEFAULTSORT:Dopamine Reuptake Inhibitor