Dopamine reuptake inhibitor



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.

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. 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.

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. In fact, bupropion is often used as a maintenance therapy for treating stimulant addiction. 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)
 * Bupropion (Wellbutrin, Zyban)
 * Dexmethylphenidate (Focalin)
 * Esketamine (Ketanest S)
 * Etybenzatropine/Ethybenztropine (Panolid, Ponalid, Ponalide)
 * Fencamfamine (Glucoenergan, Reactivan)
 * Fencamine (Altimina, Sicoclor)
 * Ketamine (Ketalar, Ketaset, Ketanest, Ketaject)
 * 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)


 * Street Drugs
 * Cocaine (found in Erythroxylum coca (Coca))
 * Desoxypipradrol (2-DPMP)
 * Diphenylprolinol (D2PM)
 * Eticyclidine (PCE)
 * Methylenedioxypyrovalerone (MDPV)
 * Phencyclidine (PCP)
 * Rolicyclidine (PCPy)
 * Tenocyclidine (TCP)


 * 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)
 * Psoralea Corylifolia (Babchi)

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.