Class of drug
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 .
[1]
DRIs are used in the treatment of
attention-deficit hyperactivity disorder (ADHD) and
narcolepsy for their
psychostimulant effects, and in the treatment of
obesity and
binge eating disorder for their
appetite suppressant effects. They are sometimes used as
antidepressants in the treatment of
mood disorders , 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
neurotransmission .[
citation needed ] The
dopaminergic pathways are considered to be strong reward centers.[
citation not found ] Many DRIs such as
cocaine are
drugs of abuse due to the
rewarding effects evoked by elevated
synaptic concentrations of
dopamine in the
brain .
Society and culture
History of use
Until the 1950s, dopamine was thought to only contribute to the
biosynthesis of
norepinephrine 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
catecholamines .
[2]
Pharmacotherapeutic uses
The following drugs have DRI action and have been or are used clinically specifically for this property:
amineptine ,
dexmethylphenidate ,
difemetorex ,
fencamfamine ,
lefetamine ,
levophacetoperane ,
medifoxamine ,
mesocarb ,
methylphenidate ,
nomifensine ,
pipradrol ,
prolintane , 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 ,
armodafinil ,
bupropion ,
mazindol ,
modafinil ,
nefazodone ,
sertraline , and
sibutramine .
The following drugs are or have been clinically used but only coincidentally have DRI properties:
benzatropine ,
diphenylpyraline ,
etybenzatropine ,
ketamine ,
nefopam ,
pethidine (meperidine), and
tripelennamine .
The following are a selection of some particularly notably abused DRIs:
cocaine ,
ketamine ,
MDPV ,
naphyrone , and
phencyclidine (PCP).
Amphetamines , including
amphetamine ,
methamphetamine ,
MDMA ,
cathinone ,
methcathinone ,
mephedrone , and
methylone , 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 -driven (i.e., relating to
hydrophobicity ) and the latter are
enthalpy -driven (i.e., relating
conformational change ).
[3]
[4] Reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon
oocytes that are naturally found on neurons, whereas releasing agents induce de-polarization of the neuron membrane.[
dubious –
discuss ]
[5]
[6]
The
wakefulness-promoting agent
modafinil and its
analogues (e.g.,
adrafinil ,
armodafinil ) have been approved to treat
narcolepsy and
shift work sleep disorder .
[7] These act as weak (
micromolar ) DRIs,
[8] 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.
[9] [
disputed –
discuss ]
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 replacement in the case of opioid addiction. DRIs have been explored as treatment for
cocaine addiction, and have shown to alleviate cravings and self-administration.
[10]
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.
[11]
List of DRIs
Only DRIs which are selective for the DAT over the other
monoamine transporters (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 .[
disputed –
discuss ]
Selective dopamine reuptake inhibitors
Neurotransmitter transporter inhibitors
DRIs with substantial activity at other sites
Other DRIs
See also
References
^ Song, R.; Zhang, H.-Y.; Li, X.; Bi, G.-H.; Gardner, E. L.; Xi, Z.-X. (2012).
"Increased vulnerability to cocaine in mice lacking dopamine D3 receptors" . Proceedings of the National Academy of Sciences . 109 (43): 17675–17680.
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2012PNAS..10917675S .
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10.1073/pnas.1205297109 .
ISSN
0027-8424 .
PMC
3491487 .
PMID
23045656 .
^ Jack R. Cooper; Floyd E. Bloom; Robert H. Roth (1996). "9". The Biochemical Basis of Neuropharmacology (7th ed.). Oxford University Press, Inc. p. 293.
^ Singh Satendra (2010).
"ChemInform Abstract: Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists" (PDF) . ChemInform . 31 (20): no.
doi :
10.1002/chin.200020238 . . Page 928 (4th of article) 1st paragraph. Lines 8—11.
Mirror hotlink.
^ Bonnet JJ, Benmansour S, Costentin J, Parker EM, Cubeddu LX (1990). "Thermodynamic analyses of the binding of substrates and uptake inhibitors on the neuronal carrier of dopamine labeled with [3H]GBR 12783 or [3H]mazindol". J. Pharmacol. Exp. Ther . 253 (3): 1206–14.
PMID
2141637 .
^ Cameron K, Kolanos R, Vekariya R, De Felice L, Glennon RA (2013).
"Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of "bath salts," produce opposite effects at the human dopamine transporter" . Psychopharmacology . 227 (3): 493–9.
doi :
10.1007/s00213-013-2967-2 .
PMC
3881434 .
PMID
23371489 .
^ Lacey MG, Mercuri NB, North RA (April 1990).
"Actions of cocaine on rat dopaminergic neurones in vitro" . Br. J. Pharmacol . 99 (4): 731–5.
doi :
10.1111/j.1476-5381.1990.tb12998.x .
PMC
1917549 .
PMID
2361170 .
^
^ Loland, C.J.; M. Mereu; O.M. Okunola; J. Cao; T.E. Prisinzano; T. Kopajtic; L. Shi; J.L. Katz; G. Tanda; A.H. Newman (1 September 2012).
"R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse" . Biol. Psychiatry . 72 (5): 405–13.
doi :
10.1016/j.biopsych.2012.03.022 .
PMC
3413742 .
PMID
22537794 .
^ Wise RA (1996). "Neurobiology of addiction". Curr. Opin. Neurobiol . 6 (2): 243–51.
doi :
10.1016/S0959-4388(96)80079-1 .
PMID
8725967 .
S2CID
25378856 .
^ Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (2006).
"Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse" . AAPS J . 8 (1): E196–203.
doi :
10.1208/aapsj080124 .
PMC
2751440 .
PMID
16584128 .
^ Kintscher, U (2012). "Reuptake Inhibitors of Dopamine, Noradrenaline, and Serotonin". Appetite Control . Handbook of Experimental Pharmacology. Vol. 209. pp. 339–347.
doi :
10.1007/978-3-642-24716-3_15 .
ISBN
978-3-642-24715-6 .
PMID
22249822 .
^ Markowitz, JS; Patrick, KS (June 2008).
"Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?" . Journal of Clinical Psychopharmacology . 28 (3 Suppl 2): S54-61.
doi :
10.1097/JCP.0b013e3181733560 .
PMID
18480678 . Retrieved 28 May 2024 .
^ Markowitz, John S.; Zhu, Hao-Jie; Patrick, Kennerly S. (18 December 2013).
"Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability" . Journal of Child and Adolescent Psychopharmacology . 23 (10): 648–654.
doi :
10.1089/cap.2013.0074 .
hdl :
2027.42/140321 .
ISSN
1044-5463 .
PMID
24261661 .
^ Zhao G, Jiang ZH, Zheng XW, Zang SY, Guo LH (September 2008). "Dopamine transporter inhibitory and antiparkinsonian effect of common flowering quince extract". Pharmacology Biochemistry and Behavior . 90 (3): 363–71.
doi :
10.1016/j.pbb.2008.03.014 .
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S2CID
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^ Yoon, Seo Young; dela Peña, Ike; Kim, Sung Mok; Woo, Tae Sun; Shin, Chan Young; Son, Kun Ho; Park, Haeil; Lee, Yong Soo; Ryu, Jong Hoon; Jin, Mingli; Kim, Kyeong-Man; Cheong, Jae Hoon (2013). "Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro". Archives of Pharmacal Research . 36 (1): 134–140.
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S2CID
23927252 .
μ-Opioid receptor
agonists (
opioids ) (e.g.,
morphine ,
heroin ,
hydrocodone ,
oxycodone ,
opium ,
kratom )
α2 δ subunit -containing
voltage-dependent calcium channels
blockers (
gabapentinoids ) (e.g.,
gabapentin ,
pregabalin ,
phenibut )
AMPA receptor
antagonists (e.g.,
perampanel )
CB1 receptor
agonists (
cannabinoids ) (e.g.,
THC ,
cannabis )
Dopamine receptor agonists (e.g.,
levodopa )
Dopamine releasing agents (e.g.,
amphetamine ,
methamphetamine ,
MDMA ,
mephedrone )
Dopamine reuptake inhibitors (e.g.,
cocaine ,
methylphenidate )
GABAA receptor
positive allosteric modulators (e.g.,
barbiturates ,
benzodiazepines ,
carbamates ,
ethanol (alcohol) (
alcoholic drink ),
inhalants ,
nonbenzodiazepines ,
quinazolinones )
GHB (
sodium oxybate ) and
analogues
Glucocorticoids (corticosteroids) (e.g.,
dexamethasone ,
prednisone )
nACh receptor agonists (e.g.,
nicotine ,
tobacco ,
arecoline ,
areca nut )
Nitric oxide prodrugs (e.g.,
alkyl nitrites (
poppers ))
NMDA receptor antagonists (e.g.,
DXM ,
ketamine ,
methoxetamine ,
nitrous oxide ,
phencyclidine ,
inhalants )
Orexin receptor antagonists (e.g.,
suvorexant )
DAT Tooltip Dopamine transporter (
DRIs Tooltip Dopamine reuptake inhibitors )
NET Tooltip Norepinephrine transporter (
NRIs Tooltip Norepinephrine reuptake inhibitors )
Others:
Antihistamines (e.g.,
brompheniramine ,
chlorphenamine ,
pheniramine ,
tripelennamine )
Antipsychotics (e.g.,
loxapine ,
ziprasidone )
Arylcyclohexylamines (e.g.,
ketamine ,
phencyclidine )
Dopexamine
Ephenidine
Ginkgo biloba
Indeloxazine
Nefazodone
Opioids (e.g.,
desmetramadol ,
methadone ,
pethidine (meperidine) ,
tapentadol ,
tramadol ,
levorphanol )
SERT Tooltip Serotonin transporter (
SRIs Tooltip Serotonin reuptake inhibitors )
Others:
A-80426
Amoxapine
Antihistamines (e.g.,
brompheniramine ,
chlorphenamine ,
dimenhydrinate ,
diphenhydramine ,
mepyramine (pyrilamine) ,
pheniramine ,
tripelennamine )
Antipsychotics (e.g.,
loxapine ,
ziprasidone )
Arylcyclohexylamines (e.g.,
3-MeO-PCP ,
esketamine ,
ketamine ,
methoxetamine ,
phencyclidine )
Cyclobenzaprine
Delucemine
Dextromethorphan
Dextrorphan
Efavirenz
Hypidone
Medifoxamine
Mesembrine
Mifepristone
MIN-117 (WF-516)
N-Me-5-HT
Opioids (e.g.,
dextropropoxyphene ,
methadone ,
pethidine (meperidine) ,
levorphanol ,
tapentadol ,
tramadol )
Roxindole
VMATs Tooltip Vesicular monoamine transporters Others