Dopamine reuptake inhibitor

Dopamine

A dopamine reuptake inhibitor (DRI, DARI) is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). This in turn leads to increased extracellular concentrations of dopamine and therefore an increase in dopaminergic neurotransmission.

Indications

DRIs may be used in the clinical treatment of attention-deficit hyperactivity disorder (ADHD), narcolepsy, and fatigue or lethargy as stimulants, obesity as anorectics or appetite suppressants for weight loss purposes, as well as mood disorders such as major depressive disorder (MDD) usually of the treatment-resistant or atypical variants as antidepressants, social phobia (SP) also known as social anxiety disorder (SAD), and perhaps other anxiety disorders as anxiolytics, parkinsonism such as that seen in Parkinson's disease as antiparkinsonian agents, for palliative care of cancer related lethargy, drug addiction and/or dependence as anticraving agents, and both as augmentations and to offset some of the side effects of other drugs like the selective serotonin reuptake inhibitors (SSRIs), such as sexual dysfunction.^{[citation needed]}

Effects

General

DRIs can induce a wide range of psychological and physiological effects, including the following:

Psychological

• A general and subjective alteration in consciousness
• Stimulation, arousal, and hyperactivity
• Increased alertness, awareness, and wakefulness
• Increased energy and endurance
• Insomnia or inability to fall asleep
• Agitation or restlessness
• Enhanced attention, focus, and concentration
• Increased desire, drive, and motivation
• Improved cognition, memory, and learning
• Goal-oriented thoughts or organized behavior
• Rapid speech and/or racing thoughts
• Antidepressant benefits or mood lift
• Euphoria and/or rushes of pleasure
• Anxiolysis and/or stress reduction
• Sociability and/or talkativeness, as well as enhanced charisma and/or humor
• Increased self-confidence, arrogance, and/or egotism
• Feelings of power, grandiosity, and superiority
• Irritability, aggression, anger and/or rage
• Analgesia or pain relief
• Impulsivity or impetuousness
• Hypersexuality and aphrodisiac effects
• Anorexia or decreased appetite and subsequent weight loss

Physiological

• Dizziness, lightheadedness, or vertigo
• Mydriasis or pupil dilation
• Xerostomia or dry mouth
• Nausea and/or emesis or vomiting
• Gastrointestinal disturbances such as diarrhea and/or constipation
• Headache or migraine
• Trembling, shakiness, or muscle tremors
• Hypertension or increased blood pressure
• Tachycardia or increased heart rate
• Hyperthermia or increased body temperature
• Hyperhidrosis or increased perspiration or sweating

Miscellaneous

• Increased or decreased drug cravings and/or addiction (depending on the setting and usage)
• Drug tolerance with time and/or chronic administration, potentially resulting in dependence
• Drug interactions such as abolished effects from dopamine releasing agents like amphetamine

It should be noted, however, that many of these properties are dependent on whether the DRI in question is capable of crossing the blood-brain-barrier (BBB). Those that do not will only produce peripheral effects.

Overdose

At very high doses and/or with chronic administration characterized by overdose, stimulant psychosis may develop, the symptoms of which can include the following:

Psychological

• Disorientation and/or confusion
• Anxiety, severe paranoia, and/or panic attacks
• Hypervigilance or increased sensitivity to perceptual stimuli, accompanied by significantly increased threat detection
• Hypomania or full-blown mania
• Derealization and/or depersonalization
• Hallucinations and/or delusions
• Thought disorder or disorganized thinking
• Cognitive and memory impairment potentially to the point of retrograde or anterograde amnesia
• Temporary psychosis

Physiological

• Myoclonus or involuntary and intense muscle twitching
• Hyperreflexia or overresponsive/overreactive reflexes
• Syncope or fainting or loss of consciousness
• Seizures or convulsions
• Coma and/or death

Miscellaneous

• Neurotoxicity or brain damage

Additionally, potential incarceration, hospitalization, institutionalization, and/or death, on account of extreme erratic behavior which may include acts of crime, assault, accidental or intentional self-injury, and/or suicide, as well as illicit drug abuse, may ensue under such circumstances.

Abuse

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 – discuss]}. DRIs such as cocaine, methylphenidate, and some tricyclic antidepressants, combination releasing agents such as amphetamine, cocaine, methamphetamine, and MDMA ("ecstasy") are widely abused throughout the world. It is estimated that there are approximately six million people addicted to cocaine in the United States (U.S.) alone.^[1]

Notably, some DRIs have a lower abuse potential than others. Those that have a slow onset and long duration of action such as bupropion (Wellbutrin, Zyban) are typically much less reinforcing than faster acting ones which produce a rush like cocaine.^[2] In fact, bupropion is often used as a maintenance therapy for treating stimulant addiction.^[3] However, depending on the route of administration (e.g., insufflation, inhalation, or injection), the pleasurable effects of the DRI in question can be dramatically enhanced, potentially rendering those with only mild rewarding effects to become far more reinforcing than they would be under normal circumstances.

List of DRIs

Pharmaceutical Drugs

• Amineptine (Survector, Maneon, Directim)
• Armodafinil (Nuvigil)
• Benzatropine/Benztropine (Cogentin)^[4]
• Bupropion (Wellbutrin, Zyban)
• Dexmethylphenidate (Focalin)
• Esketamine (Ketanest S)^[5]
• Etybenzatropine/Ethybenztropine (Panolid, Ponalid, Ponalide)
• Fencamfamine (Glucoenergan, Reactivan)
• Fencamine (Altimina, Sicoclor)
• Ketamine (Ketalar, Ketaset, Ketanest, Ketaject)^[5]
• Lefetamine (Santenol)
• Medifoxamine (Cledial)
• Mesocarb (Sidnocarb, Sydnocarb)
• Methylphenidate (Ritalin, Concerta)
• Modafinil (Provigil)
• Nefopam (Acupan)
• Nomifensine (Merital)
• Pipradrol (Meretran)
• Prolintane (Promotil, Katovit)
• Pyrovalerone (Centroton, Thymergix)
• Tiletamine (Telazol, Rompun)
• Tripelennamine (Pyribenzamine)^[6][7][8]

Street Drugs

• Cocaine (found in Erythroxylum coca (Coca))
• Desoxypipradrol (2-DPMP)
• Diphenylprolinol (D2PM)
• Eticyclidine (PCE)
• Methylenedioxypyrovalerone (MDPV)
• Phencyclidine (PCP)^[9]
• Rolicyclidine (PCPy)
• Tenocyclidine (TCP)

3D structure of RTI-470, a high-affinity and selective DAT ligand^[10]

Research Chemicals

• Altropane (IACFT; O-587)
• Amfonelic Acid (AFA; WIN-25,978)
• Benocyclidine (BTCP; GK-13)
• Brasofensine (NS-2214)
• Bromantane (ADK-709)
• DBL-583
• Dichloropane (RTI-111, O-401)
• Diclofensine (Ro-8-4650)
• Dieticyclidine
• Difemetorex
• Difluoropine (O-620)
• Gacyclidine (GK-11)
• GBR-12,935
• Indatraline (Lu-19-005)
• Ioflupane (β-CIT-FP)
• Iometopane (β-CIT, RTI-55)
• Manifaxine (GW-320,659
• Radafaxine (GW-353,162)
• Tametraline (CP-24,411)
• Tesofensine (NS-2330)
• Troparil (β-CPT; WIN-35,065-2)
• Vanoxerine (GBR-12,909)

Natural Sources

• Hypericum perforatum (St. John's Wort)
• Chaenomeles speciosa (Flowering Quince)^[11]
• Psoralea corylifolia (Babchi)^[12]

Of the above listed agents, altropane, amfonelic acid, benocyclidine, DBL-583, difluoropine, GBR-12,935, ioflupane, and vanoxerine are all highly selective, pure DRIs, with no known significant affinity for the serotonin or norepinephrine transporters or any other sites.

Dopamine releasing agents (DRAs) such as amphetamine and methamphetamine also function as DRIs secondary to their releasing action. To distinguish between DRIs and DRAs, the latter are not included in the above list. For a list of DRAs, see the releasing agent article. In correspondence with the previous paragraph, notably, to date, there are no known selective DRAs, as dissociating affinity between the dopamine and norepinephrine transporters has so far proven to be virtually impossible to achieve, likely on account of the very similar structure of the respective proteins.^[13]

See also

• Dopaminergic
• Reuptake inhibitor
• Serotonin reuptake inhibitor (SRI)
• Selective serotonin reuptake inhibitor (SSRI)
• Norepinephrine reuptake inhibitor (NRI)
• Serotonin-norepinephrine reuptake inhibitor (SNRI)
• Norepinephrine-dopamine reuptake inhibitor (NDRI)
• Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)
• Discovery and development of dual serotonin and norepinephrine reuptake inhibitors

References

1. ^ http://www.drugabuse.gov/STRC/Forms.html#Cocaine
2. ^ Gardner EL, Liu X, Paredes W, et al. (October 2006). "A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: effects in laboratory rat models relating to addiction". Neuropharmacology 51 (5): 993–1003. doi:10.1016/j.neuropharm.2006.06.009. PMID 16901516. 
3. ^ Elkashef, A.M. 2005. Bupropion for the Treatment of Methamphetamine Dependence. Pages 1162–1170, in Neuropsychopharmacology (2008) 33
4. ^ Schmitt KC, Zhen J, Kharkar P, et al. (November 2008). "Interaction of cocaine-, benztropine-, and GBR12909-like compounds with wild-type and mutant human dopamine transporters: molecular features that differentially determine antagonist-binding properties". Journal of Neurochemistry 107 (4): 928–40. doi:10.1111/j.1471-4159.2008.05667.x. PMC 2728472. PMID 18786172. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2728472. 
5. ^ ^{a b} Nishimura M, Sato K, Okada T, et al. (March 1998). "Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells". Anesthesiology 88 (3): 768–74. doi:10.1097/00000542-199803000-00029. PMID 9523822. 
6. ^ Oishi R, Shishido S, Yamori M, Saeki K (February 1994). "Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain". Naunyn-Schmiedeberg's Archives of Pharmacology 349 (2): 140–4. PMID 7513381. 
7. ^ Sato T, Suemaru K, Matsunaga K, Hamaoka S, Gomita Y, Oishi R (May 1996). "Potentiation of L-dopa-induced behavioral excitement by histamine H1-receptor antagonists in mice". Japanese Journal of Pharmacology 71 (1): 81–4. doi:10.1254/jjp.71.81. PMID 8791174. 
8. ^ Yeh SY, Dersch C, Rothman R, Cadet JL (September 1999). "Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats". Synapse 33 (3): 207–17. doi:10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8. PMID 10420168. 
9. ^ Pechnick RN, Bresee CJ, Poland RE (March 2006). "The role of antagonism of NMDA receptor-mediated neurotransmission and inhibition of the dopamine reuptake in the neuroendocrine effects of phencyclidine". Life Sciences 78 (17): 2006–11. doi:10.1016/j.lfs.2005.09.018. PMID 16288927. 
10. ^ doi:10.1208/aapsj080124 PMID 16584128
11. ^ 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. 
12. ^ Zhao G, Li S, Qin GW, Fei J, Guo LH (July 2007). "Inhibitive effects of Fructus Psoraleae extract on dopamine transporter and noradrenaline transporter". Journal of Ethnopharmacology 112 (3): 498–506. doi:10.1016/j.jep.2007.04.013. PMID 17555897. 
13. ^ Rothman RB, Blough BE, Baumann MH (2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal 9 (1): E1–10. doi:10.1208/aapsj0901001. PMC 2751297. PMID 17408232. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2751297.