Pro-motivational agent

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A pro-motivational agent is a drug which increases motivation. [1] [2] They can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD), [3] [1] as well as in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, for instance due to stroke, traumatic brain injury, or neurodegenerative diseases. [4] [5] They are also used non-medically by healthy people to increase motivation and productivity, for instance in educational contexts. [6] [2] [7] [8]

Contents

There are limited clinical data on medications in treating motivational deficits and disorders. [9] [10] In any case, drugs used for pro-motivational purposes are generally dopaminergic agents, for instance dopamine reuptake inhibitors (DRIs) like methylphenidate and modafinil, dopamine releasing agents (DRAs) like amphetamine, and other dopaminergic medications. [1] [2] [11] Adenosine receptor antagonists, like caffeine and istradefylline, can also produce pro-motivational effects. [11] [12] [13] [14] Acetylcholinesterase inhibitors, like donepezil, have been used as well. [15] [16] [4] [9]

Some drugs do not appear to have pro-motivational effects and can actually produce anti-motivational effects. [1] [11] [17] Examples of these drugs include selective serotonin reuptake inhibitors (SSRIs), [17] [18] [19] selective norepinephrine reuptake inhibitors (NRIs), [17] and antipsychotics (which are dopamine receptor antagonists or partial agonists). [20] [21] [22] Cannabinoids have also been associated with motivational deficits. [23] [24] [25] [1] [26]

List of pro-motivational agents

Dopaminergic agents

Dopaminergic agents that have been found to produce pro-motivational effects in animals and/or humans include the following: [1] [11]

A limitation of bupropion as a dopaminergic agent is that it achieves very limited clinical occupancy of the dopamine transporter (DAT). [37] [38] [39] [40]

Dopamine D2-like receptor agonists, including pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, and pergolide, have also been used to treat disorders of diminished motivation in humans. [16] [4] [5] [10] [41] However, the quality of evidence on these agents for this use is very limited. [10] D2-like receptor agonists are known to have sedative-like and non-rewarding effects in humans. [42] [43] [44] In any case, dopamine D2-like receptor antagonists, like haloperidol and other antipsychotics, are known to produce anti-motivational effects in animals [1] [11] [10] [2] and humans. [20] [21] [45] [46] [47] [48]

Other dopaminergic drugs that have been used or suggested in the treatment of disorders of diminished motivation include rasagiline (a selective monoamine oxidase B (MAO-B) inhibitor; but see more below), tolcapone (a centrally-acting catechol-O-methyltransferase (COMT) inhibitor), and amantadine (an indirectly acting dopaminergic agent that acts via unknown mechanisms). [10] [16] [49] [15] [50] Amantadine is widely used to treat multiple sclerosis-related fatigue, among other fatigue- and motivation-related disorders, and is recommended by the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for this use. [50] [51] [52] [53] [54]

Adenosinergic agents

Adenosine receptor antagonists, including caffeine, istradefylline (KW-6002), Lu AA47070, MSX-3, MSX-4, preladenant (SCH-420814), and theophylline, have shown pro-motivational effects in animals and humans. [11] [12] [13] [55] [14] [56] Caffeine and theophylline act as non-selective antagonists of the adenosine receptors (including A1, A2A, A2B, and A3). [11] [57] [58] [59] Conversely, agents like istradefylline and preladenant are selective adenosine A2A receptor antagonists. [11] Adenosine A2A receptor antagonists, including the non-selective antagonists like caffeine, show pro-motivational effects in animals, whereas selective adenosine A1 receptor antagonists, like DPCPX and CPX, do not. [11] [60] Adenosine A2A receptor antagonists appear to exert their pro-motivational effects in the nucleus accumbens core and can reverse the anti-motivational effects of dopamine D2 receptor antagonists like haloperidol in animals. [11] [12] [13] [61] [62] Istradefylline is approved in the treatment of Parkinson's disease and has been found to improve symptoms of apathy, anhedonia, and depression in people with the condition. [14] [56]

Cholinergic agents

Acetylcholinesterase inhibitors, like donepezil, rivastigmine, and galantamine, have been used in the treatment of disorders of diminished motivation. [15] [16] [4] [9] These drugs inhibit acetylcholinesterase, which metabolizes the neurotransmitter acetylcholine, thereby increasing acetylcholine levels in the brain. [63] They are approved and used in the treatment of Alzheimer's disease and provide modest cognitive improvements in people with the disease. [63] [64] [65] Although acetylcholinesterase inhibitors have been used to treat disorders of diminished motivation, the muscarinic acetylcholine receptor agonist pilocarpine has actually shown anti-motivational effects in animals that can be reversed by the muscarinic acetylcholine receptor antagonist scopolamine. [61] In addition, scopolamine has been found to reverse the anti-motivational effects of the dopamine D2 receptor antagonist haloperidol in animals. [61] In any case, in spite of the preceding findings, acetylcholinesterase inhibitors have been found to be clinically effective, albeit modestly, for apathy in dementia and Parkinson's disease. [66] [67] [68]

Ineffective agents

Norepinephrine reuptake inhibitors (NRIs) like atomoxetine and selective serotonin reuptake inhibitors (SSRIs) like escitalopram have been used and recommended in the treatment of disorders of diminished motivation. [5] [15] [69] However, NRIs like desipramine and atomoxetine, SSRIs like fluoxetine and citalopram, and MAO-A-inhibiting monoamine oxidase inhibitors (MAOIs) like moclobemide and pargyline have all not shown pro-motivational effects in animals. [1] [11] [27] [70] [36] In fact, these drugs can produce further motivational deficits in animals. [17] [70] [71] [36] Serotonergic antidepressants like SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) have also been implicated in inducing apathy and emotional blunting in humans. [18] [19] [72]

In contrast to selegiline, selective MAO-B inhibitors without concomitant catecholaminergic activity enhancer (CAE) actions, like rasagiline, SU-11739, and lazabemide, are poorly effective in reversing behavioral deficits induced by the dopamine depleting agent tetrabenazine in animals. [73] [74]

Antipsychotics, which classically act as dopamine receptor antagonists (mostly of the D2-like receptors), are well-known as having anti-motivational effects. [1] [11] [20] [21] [45] [46] [48] In fact, these effects may play a key role in their effectiveness against the positive and psychotic symptoms of schizophrenia by blunting the emotions underlying delusions. [20] [21] [45] [46] [48] A novel class of antipsychotics, sometimes referred to as third-generation antipsychotics, act as dopamine receptor partial agonists instead of as pure antagonists and have mixed agonistic and antagonistic effects. [75] [76] These drugs include aripiprazole, brexpiprazole, and cariprazine. [76] Aripiprazole, a dopamine D2, D3, and D4 receptor partial agonist, has been suggested, at low doses, as a possible treatment for disorders of diminished motivation. [49] However, cariprazine, a D2 and D3 receptor partial agonist, has shown anti-motivational effects in animals. [22] Dopamine receptor partial agonists may differ in their intrinsic activities at the dopamine receptors and in their profiles of effects. [77]

Some atypical DRIs, like JJC8-091, in contrast to other DRIs, are not effective in producing pro-motivational effects in animals. [78]

Related Research Articles

<span class="mw-page-title-main">Adenosine receptor</span> Class of four receptor proteins to the molecule adenosine

The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.

<span class="mw-page-title-main">Tetrabenazine</span> Medication for hyperkinetic movement disorders

Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Nomifensine</span> Group of stereoisomers

Nomifensine, sold under the brand names Merital and Alival, is a norepinephrine–dopamine reuptake inhibitor (NDRI), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters. This is a mechanism of action shared by some recreational drugs like cocaine and the medication tametraline (see DRI). Research showed that the (S)-isomer is responsible for activity.

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

Adenosine A<sub>2A</sub> receptor Cell surface receptor found in humans

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.

<span class="mw-page-title-main">SCH-58261</span> Chemical compound

SCH-58261 is a drug which acts as a potent and selective antagonist for the adenosine receptor A2A, with more than 50x selectivity for A2A over other adenosine receptors. It has been used to investigate the mechanism of action of caffeine, which is a mixed A1 / A2A antagonist, and has shown that the A2A receptor is primarily responsible for the stimulant and ergogenic effects of caffeine, but blockade of both A1 and A2A receptors is required to accurately replicate caffeine's effects in animals. SCH-58261 has also shown antidepressant, nootropic and neuroprotective effects in a variety of animal models, and has been investigated as a possible treatment for Parkinson's disease.

<span class="mw-page-title-main">Istradefylline</span> Chemical compound

Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.

<span class="mw-page-title-main">Preladenant</span> Chemical compound

Preladenant is a drug that was developed by Schering-Plough which acted as a potent and selective antagonist of the adenosine A2A receptor. It was being researched as a potential treatment for Parkinson's disease. Positive results were reported in Phase II clinical trials in humans, but it did not prove itself to be more effective than a placebo during Phase III trials, and so was discontinued in May 2013.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

Adenosine A2A receptor antagonists are a class of drugs that blocks adenosine at the adenosine A2A receptor. Notable adenosine A2A receptor antagonists include caffeine, theophylline and istradefylline.

<span class="mw-page-title-main">Monoamine-depleting agent</span> Drug class

Monoamine-depleting agents are a group of drugs which reversibly deplete one or more of the monoamine neurotransmitters, serotonin, dopamine, and norepinephrine. One mechanism by which these agents act is by inhibiting reuptake by the vesicular monoamine transporters, VMAT1 and VMAT2. Examples of monoamine-depleting agents include deutetrabenazine, oxypertine, reserpine, tetrabenazine, and valbenazine. Tetrabenazine selectively depletes dopamine at low doses and is used as an animal model of amotivation.

Disorders of diminished motivation (DDM) are a group of disorders involving diminished motivation and associated emotions. Many different terms have been used to refer to diminished motivation. Often however, a spectrum is defined encompassing apathy, abulia, and akinetic mutism, with apathy the least severe and akinetic mutism the most extreme.

<span class="mw-page-title-main">PRX-14040</span> Dopamine reuptake inhibitor

PRX-14040 is a selective dopamine reuptake inhibitor that was developed by Prexa Pharmaceuticals. It has 28-fold selectivity for the dopamine transporter over the norepinephrine transporter. Similarly to various other dopamine reuptake inhibitors, the drug has been found to reverse motivational deficits induced by the dopamine depleting agent tetrabenazine in animals.

<span class="mw-page-title-main">MRZ-9547</span> Dopamine reuptake inhibitor that was under development for fatigue in Parkinsons disease

MRZ-9547, also known as (R)-phenylpiracetam, (R)-phenotropil, or (R)-fonturacetam, is a selective dopamine reuptake inhibitor (IC50Tooltip half-maximal inhibitory concentration = 14.5 μM) that was developed by Merz Pharma. It is the (R)-enantiomer of the racetam and nootropic phenylpiracetam (phenotropil; fonturacetam).

CT-005404, or CT-5404, is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It shows pro-motivational effects in animals and reverses motivational deficits induced by tetrabenazine and interleukin-1β. CT-005404 is described as being orally active in animals and having a long duration of action. It is under development by Chronos Therapeutics for treatment of motivational disorders. The drug was first described by 2018.

<span class="mw-page-title-main">CE-158</span> Chemical compound

CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead.

<span class="mw-page-title-main">Lu AA47070</span> An adenosine A2A receptor antagonist for Parkinsons disease that was abandoned

Lu AA47070 is a selective adenosine A2A receptor antagonist that was under development for the treatment of Parkinson's disease but was never marketed. It has been found to reverse some of the effects of dopamine D2 receptor antagonists like pimozide and haloperidol, for instance tremulous jaw movements, catalepsy, locomotor suppression, and other anti-motivational effects, in animals. The drug is a prodrug of Lu AA41063. It was discontinued in phase 1 clinical trials because it lacked the intended pharmacological properties in humans. Lu AA47070 was first described by 2008.

<span class="mw-page-title-main">MSX-3</span> Selective adenosine A2A receptor antagonist used in scientific research

MSX-3 is a selective adenosine A2A receptor antagonist used in scientific research. Similarly to MSX-4, it is a water-soluble ester prodrug of MSX-2.

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