Dopamine reuptake inhibitor

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A dopamine reuptake inhibitor (DRI) is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the post-synaptic neuron is blocked from re-entering the pre-synaptic neuron. This, in turn, leads to increased extracellular concentrations of dopamine and therefore an increase in dopaminergic neurotransmission.[1]

DRIs are frequently used in the treatment of conditions like ADHD and narcolepsy on account of their psychostimulant effects and in the treatment of obesity due to their appetite suppressant properties. They have also been used as antidepressants in the treatment of mood disorders, but their use for this indication has been limited on account of their abuse potential and legal restriction. Lack of dopamine uptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior due to the increase in dopaminergic neurotransmission. The dopaminergic pathways are considered to be strong reward centers. In addition, many DRIs such as cocaine are drugs of abuse due to the rewarding effects evoked by elevated synaptic concentrations of dopamine in the brain.

Due to their strong rewarding and reinforcing properties, DRIs are notorious for their high abuse potential and liability to cause cravings, addiction, and dependence.[dubious ] DRIs such as cocaine and methylphenidate and combination releasing agents such as amphetamine, methamphetamine, and MDMA ("ecstasy") are widely used recreationally throughout the world.

Society and culture[edit]

History of use[edit]

Until the 1950s, dopamine was thought to be nothing but part of the synthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain in same levels as norepinephrine that it was considered that dopamine might have a biological role other than the synthesis of the catecholamines.[2]

Pharmacotherapeutic uses[edit]

Norepinephrine-dopamine reuptake inhibition is used as an antidepressant in the form of bupropion, the only norepinephrine-dopamine reuptake inhibitor (NDRI) approved by the Food and Drug Administration for this purpose. Dopamine supplementation is also utilized as a means to counter act depression. Though no supplement exists that contains dopamine, certain supplements contain nutrients known to aid in dopamine production such as tyrosine, ginkgo biloba, and certain B-vitamins.[3]

Recently the FDA approved wakefulness-promoter and potential anti-apathy medication Modafinil and its derivatives - approved to treat narcolepsy and shift work sleep disorder[4] - were revealed to function through the DRI mechanism.[5] It is used off-label as a method of counteracting the apathy component of depression, Alzheimer's disease, Chagas' disease, Creutzfeldt-Jakob disease, dementia, Korsakoff's syndrome, excessive vitamin D; hypothyroidism and other conditions.

DRIs have been explored as potential pharmacotherapeutics because of their ability to replace rewards received from other drugs. DRIs have been successfully used to serve as nicotine replacements in cases of smoking addictions well as methadone replacements in the case of heroin addiction. DRIs have been explored as potential substitutes for cocaine addiction, and have been shown to alleviate cravings and self-administration.[6]

Monoamine reuptake inhibitors, including DRIs, have also been shown to be effective as therapy for food intake and appetite control for obese subjects. Most marketed drugs for this purpose have been withdrawn due to adverse side-effects such as increase in blood pressure and high abuse potential.[7]

Bupropion[edit]

Preclinical and clinical data demonstrate that bupropion acts via dual inhibition of norepinephrine and dopamine reuptake, which constitutes a novel mechanism of antidepressant action. As such, bupropion is associated with a unique clinical profile with efficacy comparable to that of other antidepressants. Devoid of clinically significant serotonergic effects or direct effects on postsynaptic receptors, bupropion—the only currently available NDRI—is as effective as other antidepressants but does not cause common antidepressant-associated side-effects such as sexual dysfunction, weight gain, and sedation. Data supports the use of bupropion as a first-line antidepressant as well as its possible utility as augmentation therapy.[8]

List of DRIs[edit]

3D structure of RTI-470, a high-affinity and selective DAT ligand[9]

Many DRIs exist, including the following:

Selective dopamine reuptake inhibitors[edit]

  • Amineptine (has a reasonable degree of selectivity for dopamine reuptake inhibition over norepinephrine reuptake inhibition)
  • Altropane (O-587)
  • Amfonelic acid (WIN 25978)

DRIs with activity at other sites[edit]

Other DRIs[edit]

  • Chaenomeles speciosa (Flowering Quince)[10]
  • Hyperforin, Adhyperforin (Two of the chief active constituents of St. John's wort act as a reuptake inhibitors of various other neurotransmitters including the other monoamine neurotransmitters, serotonin and norepinephrine, with approximately equal affinity)

Note: Only DRIs selective for the DAT over the other monoamine transporters (MATs) are listed here. For a list of DRIs that act at multiple MATs, see the other monoamine reuptake inhibitor pages such as NDRI and SNDRI.

Additional note: Dopamine releasing agents (DRAs) such as psychostimulants of the amphetamine class also act as DRIs secondarily to their releasing action. To distinguish between DRIs and DRAs, however, the latter are not included in the above list. For a list of DRAs, see the releasing agent article.

See also[edit]

References[edit]

  1. ^ Rui Song; Hai-Ying Zhang, Xia Li, Guo-Hua Bi, Eliot L. Gardner, Zheng-Xiong Xi (5 September 2012). "Increased vulnerability to cocaine in mice lacking dopamine D3 receptors". PNAS. 
  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. ^ Stephen B. Dunnett; A. Bjorklund, T. Hokfelt (2005). Dopamine. Elsevier Science Ltd. pp. 588. ISBN 9780444517784.
  4. ^ Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J (February 21, 2012). "The prevalence and cost of unapproved uses of top-selling orphan drugs". In Alessi-Severini, Silvia. PLoS ONE 7 (2): e31894. doi:10.1371/journal.pone.0031894. PMC 3283698. PMID 22363762. 
  5. ^ 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. PMID 22537794. 
  6. ^ Carroll, F. Ivy; James L. Howard; Leonard L. Howell; Barbara S. Fox; Michael J. Kuhar (24 March 2006). "Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse". The AAPS Journal. 1 8. Retrieved 11-12-2012. 
  7. ^ Kintscher, U (2012). "Reuptake Inhibitors of Dopamine, Noradrenaline, and Seratonin". Handbook of Experimental Pharmocology 209: 339–347. 
  8. ^ Stahl, Stephen; Pradko, James. Haight, Barbara. Modell, Jack. Rockett, Carol. Learned-Coughlin, Susan (27 May 2004). "A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor". Prime Care Companian J Clinical Psychiatry 6 (4): 159–166. 
  9. ^ doi:10.1208/aapsj080124 PMID 16584128
  10. ^ 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.