Dopamine Reuptake Inhibitors (DRIs) are drugs that function by preventing the reuptake of the neurotransmitter dopamine. The fact that they prevent dopamine reuptake leads to increased concentrations of dopamine between synapses. This increases stimulation of the central nervous system and tends to improve cognitive function, alertness, and performance.
Dopamine is an important monoamine neurotransmitter involved in the regulation of many important physiological functions of the brain such as reward, exercise, and emotion. Dopaminergic neurons in the brain release dopamine after signal stimulation, leading to increased levels of extracellular dopamine, which activates postsynaptic or presynaptic dopamine receptors, causing downstream cells or their own response. Most of the released dopamine is rapidly cleared within a few milliseconds. One of the main ways to produce this effect is dopamine transporter-mediated dopamine reuptake. The reuptake function of the dopamine transporter is regulated by a variety of factors, including the concentration of the substrate, post-translational modification of its own site, intracellular protein kinase activity, extracellular regulatory signals and so on.
Dopamine transporter (DAT)
The dopamine transporter (DAT) is one of the most relevant and investigated neurotransmitter transporters. DAT is a plasma membrane protein which plays a homeostatic role, controlling both extracellular and intracellular concentrations of dopamine. The dopamine transporter (DAT) is a member of the solute carrier 6 (SLC6) family which is composed of molecular machines that actively import their substrates into cells, using the transmembrane electro-chemical gradient. The DAT is worth special attention because it is a major regulator of DA neurotransmitter synaptic availability in mammals. On the one hand, it controls the extracellular concentration of dopamine and regulates the signal intensity of neurotransmitters. On the other hand, extracellular dopamine can be transported back to the cell to maintain dopamine balance. Disfunction of the dopamine transporter can cause a disturbance in the dopamine system, which in turn causes related neurological diseases such as depression, attention deficit hyperactivity disorder(ADHD), autism spectrum disorders, bipolar disorder schizophrenia and Parkinson's disease, etc. Clinically, drugs targeting the dopamine transporter are used to treat these diseases.
Dopamine reuptake inhibitor (DRI)
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). 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.
Classification of DRI
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.
1. Kristensen, A. S., Andersen, J., Jorgensen, T. N., Sorensen, L., Eriksen, J.,Loland, C. J., ... Gether, U. (2011). SLC6 neurotransmitter transporters:Structure, function, and regulation. Pharmacological Reviews, 63,585–640.
2. Lovell,P.V.,Kasimi,B.,Carleton,J.,Velho,T.A.,&Mello,C.V.(2015).Living Without DAT: Loss and compensation of the dopamine transporter gene in sauropsids (birds and reptiles). Scientific Reports, 5, 14093.
3. 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.