Motivation-enhancing Drug

A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts.

There are limited clinical data on medications in treating motivational deficits and disorders. 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. Adenosine receptor antagonists, like caffeine and istradefylline, can also produce pro-motivational effects. Acetylcholinesterase inhibitors, like donepezil, have been used as well.

Some drugs do not appear to increase motivation and can actually have anti-motivational effects. Examples of these drugs include selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (NRIs), and antipsychotics (which are dopamine receptor antagonists or partial agonists). Cannabinoids, for instance those found in cannabis, have also been associated with motivational deficits.

Types of motivation-enhancing drugs

Dopaminergic agents

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

* Dopamine reuptake inhibitors (DRIs) like bupropion, CE-123, CE-158, CT-005404, JJC8-088, JJC8-089, methylphenidate, (''S'')-MK-26, modafinil, MRZ-9547 ((''R'')-phenylpiracetam), nomifensine, PRX-14040, pyrovalerone, RDS03-94, and vanoxerine (GBR-12909)
* Dopamine releasing agents (DRAs) like amphetamine, methamphetamine, and lisdexamfetamine
* Dopamine D₁ receptor agonists like razpipadon
* Dopamine precursors like levodopa (L-DOPA)
* Catecholaminergic activity enhancers (CAEs) like selegiline, PPAP, and BPAP

Other dopaminergic agents

Dopamine D₂-like receptor agonists, including pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, pergolide, and lisuride, have also been used to treat disorders of diminished motivation in humans. The clinical data on these agents for this use is very limited, but therapeutic successes have been reported. D₂-like receptor agonists are known to have sedative-like and non- rewarding effects in humans. In any case, dopamine D₂-like receptor antagonist and other antipsychotics, are known to produce anti-motivational effects in animals and humans. Bromocriptine has been reported to improve anergia and motivation in humans in very limited clinical reports. On the other hand, pergolide failed to show pro-motivational effects in animals.

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). Tolcapone, the only marketed COMT inhibitor that is centrally acting (as opposed to peripherally selective), shows antidepressant- and anti-anhedonia-like effects, stimulates exploratory behavior, and enhances the locomotor hyperactivity induced by psychostimulants like amphetamine and nomifensine in animals. 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, although clinical data are limited.

Mechanistic aspects of specific dopaminergic agents

Dopamine levels and signaling in the nucleus accumbens, part of the ventral striatum and the mesolimbic reward pathway, are thought to play a key role in mediating behavioral activation and motivation. Dopamine releasing agents like dextroamphetamine are able to rapidly increase striatal dopamine levels by 700 to 1,500% of baseline in rodents. These drugs show greater magnitudes of impact on dopamine levels than do dopamine reuptake inhibitors like methylphenidate. In addition, whereas dopamine reuptake inhibitors show a clear dose–effect ceiling in their effects on dopamine levels, dopamine releasing agents do not and have been found to maximally increase dopamine levels by more than 5,000%. Atypical dopamine reuptake inhibitors like modafinil can also increase dopamine levels in the striatum and nucleus accumbens in animals, but have further reduced impacts on dopamine levels compared to psychostimulants like amphetamine and methylphenidate.

Limitations of specific dopaminergic agents

A limitation of certain dopaminergic medications used to improve motivation, like psychostimulants, is development of tolerance to their effects. Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively short durations of action (~4hours for main desired effects) and their much longer elimination half-lives (~10hours) and durations in the body (~2days). It appears that continually increasing or ascending concentration–time curves are beneficial for prolonging effects, which has resulted in administration multiple times per day and development of delayed- and extended-release formulations. Drug holidays and breaks can be helpful in resetting tolerance.

Another possible limitation of amphetamine specifically is dopaminergic neurotoxicity, which might occur even at therapeutic doses.

A limitation of bupropion as a dopaminergic agent is that it achieves very limited clinical occupancy of the dopamine transporter (DAT).

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. Caffeine and theophylline act as non-selective antagonists of the adenosine receptors (including A₁, A_2A, A_2B, and A₃). Conversely, agents like istradefylline and preladenant are selective adenosine A_2A receptor antagonists. Adenosine A_2A 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. Adenosine A_2A 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 antagonist in animals. 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.

Cholinergic agents

Acetylcholinesterase inhibitors, like donepezil, rivastigmine, and galantamine, have been used in the treatment of disorders of diminished motivation. These drugs inhibit acetylcholinesterase, which metabolizes the neurotransmitter acetylcholine, thereby increasing acetylcholine levels in the brain and augmenting activation of the muscarinic acetylcholine and nicotinic acetylcholine receptors. They are approved and used in the treatment of Alzheimer's disease and provide modest cognitive improvements in people with the disease. 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. In addition, xanomeline, a muscarinic acetylcholine M₁ and M₄ receptor agonist, shows indirect antidopaminergic effects in the mesolimbic pathway in animals and, in combination with trospium, is approved as an antipsychotic in the treatment of schizophrenia. Furthermore, scopolamine has been found to reverse the anti-motivational effects of the dopamine D₂ receptor antagonist haloperidol in animals. 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.

Other agents

Serotonin 5-HT_2C receptor antagonist

HOME


Content is Copyleft
Website design, code, and AI is Copyrighted (c) 2014-2017 by Stephen Payne


Consider donating to Wikimedia



As an Amazon Associate I earn from qualifying purchases