[12][18][53][17][54] 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.
[55][56][57] 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.
[54][58][59][60][61] 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.
[67][68][69][70][71][72][73] 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.
[80][81][82][83] 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.
[13][14][15][90][91] 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.
[90] 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.
[90] 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.
[109] It has been found to increase norepinephrine and dopamine levels in the frontal cortex in rodents, though notably not in the striatum or nucleus accumbens (in contrast to other serotonin 5-HT2C receptor antagonists), and for this reason has sometimes been described as a "norepinephrine–dopamine disinhibitor" ("NDDI").
[109][110] Due to its indirect dopaminergic effects, the drug has been suggested as a possible treatment for disorders of diminished motivation like anhedonia and abulia.
[116][117] Zelatriazin was under development for the treatment of anhedonia in major depressive disorder and the negative symptoms of schizophrenia and reached phase 3 clinical trials.
[124][125][122] The serotonergic psychedelic 2,5-dimethoxy-4-propylamphetamine (DOPR), which acts as an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, has shown pro-motivational effects in rodents at sub-hallucinogenic doses or so-called "microdoses".
[7][17][136] However, SSRIs like fluoxetine and citalopram, NRIs like desipramine and atomoxetine, and MAO-A-inhibiting monoamine oxidase inhibitors (MAOIs) like moclobemide and pargyline, have all not shown pro-motivational effects in animals.
[102][103] 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.
[53] However, aripiprazole and cariprazine showed anti-motivational effects in animals and failed to reverse the motivational deficits induced by the dopamine depleting agent tetrabenazine.