Dopamine reuptake inhibitor

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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. 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[edit]

History of use[edit]

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 posibility was considered that its biological role might be other than the synthesis of the catecholamines.[2]

Pharmacotherapeutic uses[edit]

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, and potentially more potently as dopamine releasing agents (DRAs) (it should be noted that 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.[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 ]

DRIs have been explored as potential antiaddictive agents because of their ability to replace the reward effects received from other drugs. DRIs have been successfully used to serve as nicotine replacement in cases of smoking addiction and methadone replacement in the case of heroin 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 also shown effectiveness as therapy for excessive food intake and appetite control for obese patients. Most drugs marketed for this purpose have been withdrawn or discontinued because of adverse side effects such as increase in blood pressure, as well as high abuse potential.[11]

List of DRIs[edit]

3D structure of RTI-470, a high-affinity and selective DAT ligand[12]

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 ]

Selective dopamine reuptake inhibitors[edit]

DRIs with substantial activity at other sites[edit]

Other DRIs[edit]

See also[edit]

References[edit]

  1. ^ 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. doi:10.1073/pnas.1205297109. ISSN 0027-8424. 
  2. ^ Jack R. Cooper; Floyd E. Bloom; Robert H. Roth (1996). "9". The Biochemical Basis of Neuropharmacology (7th ed.). Oxford University Press, Inc. p. 293. 
  3. ^ Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000 ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Page 928 (4th of article) 1st paragraph. Lines 8—11. Mirror hotlink.
  4. ^ Bonnet, J.-J.; Benmansour, S.; Costenin, J.; Parker, E. M.; Cubeddu, L. X. J. Pharmacol. Exp. Ther. 1990, 253, 1206.
  5. ^ Mephedrone and Methylenedioxypyrovalerone (MDPV), Major Constituents of Bath Salts, Produce Opposite Effects at the Human Dopamine Transporter doi: 10.1007/s00213-013-2967-2.PMCID: PMC3881434. NIHMSID: NIHMS441214. Psychopharmacology (Berl). 2013 June; 227(3): 10.1007/s00213-013-2967-2.
  6. ^ Actions of cocaine on rat dopaminergic neurones in vitro. Br J Pharmacol. 1990 Apr;99(4):731-5. PMID 2361170. PMCID: PMC1917549
  7. ^ Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J (February 21, 2012). Alessi-Severini, Silvia, ed. "The prevalence and cost of unapproved uses of top-selling orphan drugs". PLoS ONE. 7 (2): e31894. doi:10.1371/journal.pone.0031894. PMC 3283698free to read. PMID 22363762. 
  8. ^ 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 3413742free to read. PMID 22537794. 
  9. ^ Wise RA (1996). "Neurobiology of addiction". Curr. Opin. Neurobiol. 6 (2): 243–51. doi:10.1016/S0959-4388(96)80079-1. PMID 8725967. 
  10. ^ 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 2751440free to read. PMID 16584128. 
  11. ^ Kintscher, U (2012). "Reuptake Inhibitors of Dopamine, Noradrenaline, and Seratonin". Handbook of Experimental Pharmacology. 209: 339–347. doi:10.1007/978-3-642-24716-3_15. 
  12. ^ doi:10.1208/aapsj080124 PMID 16584128
  13. ^ 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. PMID 18485464. 
  14. ^ 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. doi:10.1007/s12272-013-0009-6. ISSN 0253-6269.