Motivation-enhancing drug

See also: Disorders of diminished motivation § Treatment

Motivation-enhancing drug
Drug class
Dextroamphetamine, one of the most widely used motivation-enhancing drugs.
Class identifiers
Synonyms	Motivation-enhancing agent; Motivation-enhancing medication; Pro-motivational drug; [1] Pro-motivational agent; Pro-motivational medication
Use	To increase motivation and treat disorders of diminished motivation
Legal status
In Wikidata

A motivation-enhancing drug, ^{[2] [3]} also known as a pro-motivational drug, ^[1] is a drug which increases motivation. ^{[4] [1]} Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). ^{[5] [4]} 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. ^{[6] [7]} Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts. ^{[8] [1] [9] [10]}

There are limited clinical data on medications in treating motivational deficits and disorders. ^{[11] [12]} 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. ^{[4] [1] [13]} Adenosine receptor antagonists, like caffeine and istradefylline, can also produce pro-motivational effects. ^{[13] [14] [15] [16]} Acetylcholinesterase inhibitors, like donepezil, have been used as well. ^{[17] [18] [6] [11]}

Some drugs do not appear to increase motivation and can actually have anti-motivational effects. ^{[4] [13] [19]} Examples of these drugs include selective serotonin reuptake inhibitors (SSRIs), ^{[19] [20] [21]} selective norepinephrine reuptake inhibitors (NRIs), ^[19] and antipsychotics (which are dopamine receptor antagonists or partial agonists). ^{[22] [23] [24] [25]} Cannabinoids, for instance those found in cannabis, have also been associated with motivational deficits. ^{[26] [27] [28] [4] [29]}

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: ^{[4] [13]}

• 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) ^{[4] [13] [30]}
• Dopamine releasing agents (DRAs) like amphetamine and lisdexamfetamine ^{[4] [31]}
• Dopamine D₁ receptor agonists like razpipadon ^{[32] [33] [34]}
• Dopamine precursors like levodopa (L-DOPA) ^{[32] [17] [35]}
• Catecholaminergic activity enhancers (CAEs) like selegiline, PPAP, and BPAP ^{[36] [37] [38] [39]}

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. ^{[18] [6] [7] [12] [40] [41] [42]} The clinical data on these agents for this use is very limited, but therapeutic successes have been reported. ^{[12] [41]} D₂-like receptor agonists are known to have sedative-like and non-rewarding effects in humans. ^{[43] [44] [45]} In any case, dopamine D₂-like receptor antagonists, like haloperidol and other antipsychotics, are known to produce anti-motivational effects in animals ^{[4] [13] [12] [1]} and humans. ^{[22] [23] [46] [47] [48] [49]} Bromocriptine has been reported to improve anergia and motivation in humans in very limited clinical reports. ^{[40] [50] [51]} On the other hand, pergolide failed to show pro-motivational effects in animals. ^[52]

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). ^{[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]}

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. ^{[4] [19] [13] [12]} Dopamine releasing agents like dextroamphetamine are able to rapidly increase striatal dopamine levels by 700 to 1,500% of baseline in rodents. ^[62] These drugs show greater magnitudes of impact on dopamine levels than do dopamine reuptake inhibitors like methylphenidate. ^{[62] [63]} 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%. ^{[62] [64]} 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. ^[65]

Limitations of specific dopaminergic agents

A limitation of certain dopaminergic medications used to improve motivation, like psychostimulants, is development of tolerance to their effects. ^{[66] [67]} Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively short durations of action (~4 hours for main desired effects) and their much longer elimination half-lives (~10 hours) and durations in the body (~2 days). ^{[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. ^{[67] [69] [70]} Drug holidays and breaks can be helpful in resetting tolerance. ^[66]

Another possible limitation of amphetamine specifically is dopaminergic neurotoxicity, which might occur even at therapeutic doses. ^{[74] [75] [76] [77] [78] [79]}

A limitation of bupropion as a dopaminergic agent is that it achieves very limited clinical occupancy of the dopamine transporter (DAT). ^{[80] [81] [82] [83]}

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. ^{[13] [14] [15] [84] [16] [85]} Caffeine and theophylline act as non-selective antagonists of the adenosine receptors (including A₁, A_2A, A_2B, and A₃). ^{[13] [86] [87] [88]} Conversely, agents like istradefylline and preladenant are selective adenosine A_2A receptor antagonists. ^[13] 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. ^{[13] [89]} 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 antagonists like haloperidol in animals. ^{[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. ^{[16] [85]}

Cholinergic agents

Acetylcholinesterase inhibitors, like donepezil, rivastigmine, and galantamine, have been used in the treatment of disorders of diminished motivation. ^{[17] [18] [6] [11]} 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. ^[92] They are approved and used in the treatment of Alzheimer's disease and provide modest cognitive improvements in people with the disease. ^{[92] [93] [94]} 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. ^[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. ^{[95] [96] [97]} Furthermore, scopolamine has been found to reverse the anti-motivational effects of the dopamine D₂ receptor antagonist haloperidol in animals. ^[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. ^{[98] [99] [100]}

Other agents

Serotonin 5-HT_2C receptor antagonists, such as SB-242084, show pro-motivational effects in animals. ^{[101] [102] [103] [104] [105]} In addition, SB-242084 has shown modest stimulant-like and reinforcing effects in monkeys. ^[106] In accordance with the preceding, serotonin 5-HT_2C receptor antagonists like SB-242084 and SB-206553 have been found to increase dopamine levels in the nucleus accumbens. ^{[107] [108]}

Agomelatine is a potent melatonin MT₁ and MT₂ receptor agonist and weak serotonin 5-HT_2B and 5-HT_2C receptor antagonist that is marketed as an antidepressant. ^[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-HT_2C 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. ^[111] It has been found to be effective in the treatment of apathy in people with dementia ^{[112] [98] [113] [114]} and was reported to reverse escitalopram-associated apathy in a case report. ^{[111] [115]}

The GPR139 agonist zelatriazin (TAK-041; NBI-1065846) has shown pro-motivational effects in animals. ^{[116] [117]} On the basis of these findings, it has been speculated that the drug might be useful in the treatment of apathy in humans. ^{[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. ^{[118] [119] [120]} However, its development was discontinued due to lack of clinical effectiveness. ^{[118] [121]}

The tumor necrosis factor α (TNF-α) monoclonal antibody infliximab has been found to increase motivation in people with depression with high inflammation (as measured by high C-reactive protein levels). ^{[122] [123]} It has also been found to reduce symptoms of depression and anhedonia, for instance in people with high inflammation. ^{[124] [125] [122]}

Ineffective agents

Serotonergic and noradrenergic agents

Selective serotonin reuptake inhibitors (SSRIs) like escitalopram and norepinephrine reuptake inhibitors (NRIs) like atomoxetine have been used and recommended in the treatment of disorders of diminished motivation. ^{[7] [17] [126]} 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. ^{[4] [13] [30] [127] [39]} In fact, these drugs can produce further motivational deficits in animals. ^{[19] [127] [128] [39] [103]} Serotonergic antidepressants like SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) have also been implicated in inducing apathy and emotional blunting in humans. ^{[20] [21] [129]} Activation of the serotonin 5-HT_2C receptor by serotonergic agents like SSRIs may contribute to or mediate their anti-motivational effects, whereas co-administration of serotonin 5-HT_2C receptor antagonists may reverse the effects. ^{[102] [103]}

Selective MAO-B inhibitors

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. ^{[130] [131]}

Dopamine receptor antagonists and partial agonists

Antipsychotics, which classically act as dopamine receptor antagonists (mostly of the D₂-like receptors), are well-known as having robust and dose-dependent anti-motivational effects. ^{[4] [13] [22] [23] [46] [47] [49]} 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. ^{[22] [23] [46] [47] [49]}

A novel class of antipsychotics, sometimes referred to as third-generation antipsychotics, act as dopamine D₂-like receptor partial agonists instead of as pure antagonists, and hence have mixed agonistic and antagonistic effects. ^{[132] [133]} These drugs include aripiprazole, brexpiprazole, and cariprazine. ^[133] Aripiprazole has been suggested, at low doses, as a possible treatment for disorders of diminished motivation. ^[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. ^{[25] [24]} Accordingly, aripiprazole reduced activation of the mesolimbic motivational pathway in humans similarly to but less robustly than haloperidol. ^{[134] [135]} On the other hand, another study found that aripiprazole reversed stress-induced motivational anhedonia in animals, an antidepressant-like effect. ^{[136] [137]} Different dopamine receptor partial agonists that are used in the treatment of schizophrenia are known to vary in their intrinsic activities at the dopamine receptors, so each drug may be expected to have a different profile of effects. ^[138]

Certain atypical dopamine reuptake inhibitors

Some atypical DRIs, like JJC8-091, in contrast to other DRIs, are not effective in producing pro-motivational effects in animals. ^[139] This has been attributed to binding to an occluded conformation of the dopamine transporter (DAT) that results in a diminished increase in dopamine levels. ^[139]

See also

• Tetrabenazine § Animal model of motivational dysfunction
• Conditioned avoidance response test § Test of other drug effects

References

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62. Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". J Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . PMID   23539642.
63. Hodgkins P, Shaw M, Coghill D, Hechtman L (September 2012). "Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options". Eur Child Adolesc Psychiatry. 21 (9): 477–492. doi:10.1007/s00787-012-0286-5. PMC   3432777 . PMID   22763750. Intraperitoneal administration of dl-threo-MPH 10 mg/kg to spontaneously hypertensive rats elicits a rapid 3–4-fold increase in extracellular concentrations of noradrenaline in the prefrontal cortex and dopamine in the striatum, peaking within 45 min of dosing, and remaining above control levels for at least 3 h [48]. [...] Intraperitoneal administration of d-AMF 1 mg/kg to spontaneously hypertensive rats elicits a 15-fold increase in striatal dopamine concentrations 30 min post-dose that return to control levels within 90 min, and a fourfold increase in noradrenaline concentrations in the prefrontal cortex within 45 min of dosing that remain above control levels for at least 3 h.
64. Cheetham SC, Kulkarni RS, Rowley HL, Heal DJ (2007). The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine's enantiomers compared with Sprague-Dawleys. Neuroscience 2007, San Diego, CA, Nov 3-7, 2007. Society for Neuroscience. Archived from the original on 27 July 2024. Both d- and l-[amphetamine (AMP)] evoked rapid increases in extraneuronal concentrations of [noradrenaline (NA)] and [dopamine (DA)] that reached a maximum 30 or 60 min after administration. However, the [spontaneously hypertensive rats (SHRs)] were much more responsive to AMP's enantiomers than the [Sprague-Dawleys (SDs)]. Thus, 3 mg/kg d-AMP produced a peak increase in [prefrontal cortex (PFC)] NA of 649 ± 87% (p<0.001) in SHRs compared with 198 ± 39% (p<0.05) in SDs; the corresponding figures for [striatal (STR)] DA were 4898 ± 1912% (p<0.001) versus 1606 ± 391% (p<0.001). At 9 mg/kg, l-AMP maximally increased NA efflux by 1069 ± 105% (p<0.001) in SHRs compared with 157 ± 24% (p<0.01) in SDs; the DA figures were 3294 ± 691% (p<0.001) versus 459 ± 107% (p<0.001).
65. Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G (2021). "Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?". Front Neurosci. 15: 656475. doi: 10.3389/fnins.2021.656475 . PMC   8187604 . PMID   34121988. MOD binding to DAT differs from that of other typical, cocaine-like, DAT blockers (Schmitt and Reith, 2011). In contrast to cocaine, MOD prefers to bind to, or stabilize the DAT protein in a more inward-facing occluded conformation (Schmitt and Reith, 2011; Loland et al., 2012) that still inhibits uptake and results in increases in extracellular DA in the NAcc (Ferraro et al., 1996c; Zolkowska et al., 2009), the NAcc shell (NAS) (Loland et al., 2012; Mereu et al., 2020), and the striatum (Rowley et al., 2014). MOD also increases electrically evoked DA in the DS and VS (Bobak et al., 2016) (summarized in Table 2) like abused psychostimulants (Nisell et al., 1994; Pontieri et al., 1996; Munzar et al., 2004; Kohut et al., 2014). However, while acute administration of MOD (Mereu et al., 2017, 2020) or its enantiomers (Loland et al., 2012; Keighron et al., 2019a, b) increases extracellular NAcc DA levels in rodents, these effects, even at very high doses, elicited a limited stimulation of DA in striatal areas compared to the stimulation elicited by abused psychostimulants (Loland et al., 2012; Mereu et al., 2017, 2020). This limited efficacy of MOD to increase DA levels, as compared to abused psychostimulants, also predicts a limited potential for abuse.
66. Handelman K, Sumiya F (July 2022). "Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report". Brain Sciences. 12 (8): 959. doi: 10.3390/brainsci12080959 . PMC   9332474 . PMID   35892400.
67. Ermer JC, Pennick M, Frick G (May 2016). "Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy". Clinical Drug Investigation. 36 (5): 341–356. doi:10.1007/s40261-015-0354-y. PMC   4823324 . PMID   27021968.
68. Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID   19426289. Metabolism does not appear to be altered by chronic exposure, thus dose escalation appears to arise from pharmacodynamic rather than pharmacokinetic tolerance [24]. [...] The terminal plasma half-life of methamphetamine of approximately 10 hours is similar across administration routes, but with substantial inter-individual variability. Acute effects persist for up to 8 hours following a single moderate dose of 30 mg [30]. [...] peak plasma methamphetamine concentration occurs after 4 hours [35]. Nevertheless, peak cardiovascular and subjective effects occur rapidly (within 5–15 minutes). The dissociation between peak plasma concentration and clinical effects indicates acute tolerance, which may reflect rapid molecular processes such as redistribution of vesicular monoamines and internalization of monoamine receptors and transporters [6,36]. Acute subjective effects diminish over 4 hours, while cardiovascular effects tend to remain elevated. This is important, as the marked acute tachyphylaxis to subjective effects may drive repeated use within intervals of 4 hours, while cardiovascular risks may increase [11,35].
69. Abbas K, Barnhardt EW, Nash PL, Streng M, Coury DL (April 2024). "A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder". Expert Review of Neurotherapeutics. 24 (4): 421–432. doi: 10.1080/14737175.2024.2321921 . PMID   38391788. For several decades, clinical benefits of amphetamines have been limited by the pharmacologic half-life of around 4 hours. Although higher doses can produce higher maximum concentrations, they do not affect the half-life of the dose. Therefore, to achieve longer durations of effect, stimulants had to be dosed at least twice daily. Further, these immediate-release doses were found to have their greatest effect shortly after administration, with a rapid decline in effect after reaching peak blood concentrations. The clinical correlation of this was found in comparing math problems attempted and solved between a mixed amphetamine salts preparation (MAS) 10 mg once at 8 am vs 8 am followed by 12 pm [14]. The study also demonstrated the phenomenon of acute tolerance, where even if blood concentrations were maintained over the course of the day, clinical efficacy in the form of math problems attempted and solved would diminish over the course of the day. These findings eventually led to the development of a once daily preparation (MAS XR) [15], which is a composition of 50% immediate-release beads and 50% delayed release beads intended to mimic this twice-daily dosing with only a single administration.
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74. Baumeister AA (2021). "Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?". Harvard Review of Psychiatry. 29 (2): 142–158. doi:10.1097/HRP.0000000000000283. PMID   33560690. It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.
75. Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". Journal of Attention Disorders. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID   17606768. Recently, however, new data from Ricaurte et al. (2005) indicate that primates may be much more susceptible than rats to AMPH-induced neurotoxicity. They examined the effect of the drug in adult baboons and squirrel monkeys, as clinically used to treat ADHD. In the first two studies, baboons were trained to orally selfadminister a mixture of AMPH salts (a 3:1 ratio of dextro [S(+)] and levo [R(-)] AMPH, which simulated a common formulation for ADHD treatment). AMPH was administered twice daily for approximately 4 weeks at escalating doses of 2.5 to 20 mg (0.67 to 1.00 mg/kg). During the second study, plasma AMPH concentrations were determined at the end of each week. In the third study, AMPH was administered by orogastric gavage to squirrel monkeys and doses were adjusted (to 0.58-0.68 mg/kg) so that for approximately the last 3 weeks plasma drug concentrations were comparable to those reported in clinical populations of children receiving chronic AMPH treatment—100 to 150 ng/ml (McGough et al., 2003). Measurements in all three investigations were taken 2 to 4 weeks after drug treatment. Results from the first two studies showed significant reductions in striatal dopamine concentration, dopamine transporter density, and vesicular monoamine transporter sites. Plasma AMPH concentration at the end of the 4 week treatment period was 168 ± 25 ng/ml. In squirrel monkeys, brain dopamine concentrations and vesicular transporter sites were also significantly reduced although dopamine transporter decreases were not statistically significant. These results raise obvious concerns about clinical drug treatment of ADHD, although extrapolation to human populations may be premature until possible species differences in mechanism of action, developmental variables, or metabolism are determined.
76. Asser A, Taba P (2015). "Psychostimulants and movement disorders". Frontiers in Neurology. 6: 75. doi: 10.3389/fneur.2015.00075 . PMC   4403511 . PMID   25941511. Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57).
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101. Olivetti PR, Balsam PD, Simpson EH, Kellendonk C (June 2020). "Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders". Basic Clin Pharmacol Toxicol. 126 Suppl 6 (Suppl 6): 47–55. doi:10.1111/bcpt.13271. PMC   7057665 . PMID   31188541. Serotonin 2C receptor antagonism: Enhancement of dopamine release and motivation [...]
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108. De Deurwaerdère P, Navailles S, Berg KA, Clarke WP, Spampinato U (March 2004). "Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens". J Neurosci. 24 (13): 3235–3241. doi:10.1523/JNEUROSCI.0112-04.2004. PMC   6730027 . PMID   15056702.
109. Norman TR, Olver JS (April 2019). "Agomelatine for depression: expanding the horizons?". Expert Opin Pharmacother. 20 (6): 647–656. doi:10.1080/14656566.2019.1574747. PMID   30759026. Binding studies show that [agomelatine] has a high affinity for human melatonin MT1- and MT2-receptors (Ki: 0.1nM; 0.12nM respectively) and acts as an agonist at these receptors [7]. It has little affinity (Ki > 10μM) for most other receptors, [...] [Agomelatine] binds to the 5-HT2C receptor (Ki = 631nM) as well as cloned, human 5-HT2B receptors (Ki = 660nM), but has negligible affinity at 5-HT2A receptors [7]. At 5-HT2B and 5-HT2C receptors agomelatine acts as an antagonist. The interaction with 5-HT2C receptors may be more nuanced than simple antagonism since this receptor is subject to RNA editing, which can generate multiple isoforms of the receptor with various properties (e.g., affinity, coupling and constitutive activity) [9]. Blockade of the 5-HT2C receptor is believed to be responsible for the dose dependent increase in the extracellular concentrations of both noradrenaline and dopamine observed in the prefrontal cortex following acute drug administration [7]. By contrast dopamine concentrations in the nucleus accumbens or the striatum were not affected by agomelatine [7]. Furthermore, there was no change in extracellular concentrations of serotonin.
110. Fasipe, OlumuyiwaJohn (2018). "Neuropharmacological classification of antidepressant agents based on their mechanisms of action". Archives of Medicine and Health Sciences. 6 (1). Medknow: 81. doi: 10.4103/amhs.amhs_7_18 . ISSN   2321-4848.
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117. Münster A, Sommer S, Kúkeľová D, Sigrist H, Koros E, Deiana S, Klinder K, Baader-Pagler T, Mayer-Wrangowski S, Ferger B, Bretschneider T, Pryce CR, Hauber W, von Heimendahl M (August 2022). "Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions" (PDF). Neuropharmacology. 213: 109078. doi:10.1016/j.neuropharm.2022.109078. PMID   35561791.
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120. Reichard HA, Schiffer HH, Monenschein H, Atienza JM, Corbett G, Skaggs AW, Collia DR, Ray WJ, Serrats J, Bliesath J, Kaushal N, Lam BP, Amador-Arjona A, Rahbaek L, McConn DJ, Mulligan VJ, Brice N, Gaskin PL, Cilia J, Hitchcock S (August 2021). "Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia". J Med Chem. 64 (15): 11527–11542. doi:10.1021/acs.jmedchem.1c00820. PMID   34260228.
121. "Neurocrine Biosciences Provides Development Pipeline Update". Neurocrine Biosciences. 9 November 2023. Retrieved 26 September 2024. The investigational NBI-1065846, as part of the collaboration with Takeda Pharmaceutical Company Limited (Takeda), did not meet its primary endpoint in the Phase 2 TERPSIS™ study evaluating its efficacy compared to placebo in patients with anhedonia in major depressive disorder. No further development with NBI-1065846 is planned at this time.
122. Lee Y, Subramaniapillai M, Brietzke E, Mansur RB, Ho RC, Yim SJ, McIntyre RS (December 2018). "Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression". Ther Adv Psychopharmacol. 8 (12): 337–348. doi:10.1177/2045125318791944. PMC   6278744 . PMID   30524702.
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134. de Bartolomeis A, Barone A, Begni V, Riva MA (February 2022). "Present and future antipsychotic drugs: A systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective". Pharmacol Res. 176: 106078. doi:10.1016/j.phrs.2022.106078. hdl: 2434/909466 . PMID   35026403. Aripiprazole, brexpiprazole, and cariprazine are representative of a new class of APs that act as "dopamine stabilizers", namely partial agonists at D2R/D3R [16]. Partial agonists may act as functional agonists or antagonists, depending on the surrounding levels of endogenous ligand. According to this view, D2R partial agonists may act as functional antagonists within the mesolimbic system, where a hyperdopaminergic state may contribute to positive symptoms; on the other hand, they act as functional agonists in the mesocortical pathway, where extracellular dopamine levels are low, thus mitigating, or at least not worsening, negative and cognitive symptoms [17], [18]. [...]
135. Bolstad I, Andreassen OA, Groote I, Server A, Sjaastad I, Kapur S, Jensen J (December 2015). "Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study". Eur Neuropsychopharmacol. 25 (12): 2252–2261. doi:10.1016/j.euroneuro.2015.09.016. hdl: 10852/50193 . PMID   26476705. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups.
136. Scheggi S, De Montis MG, Gambarana C (November 2018). "Making Sense of Rodent Models of Anhedonia". Int J Neuropsychopharmacol. 21 (11): 1049–1065. doi:10.1093/ijnp/pyy083. PMC   6209858 . PMID   30239762. In self-administration protocols, the schedule used to assess the motivation to work for a natural (or a drug) reward is commonly the progressive ratio (PR) schedule (Hodos, 1961) where increasing effort is required to obtain the reward as the ratio requirement progressively increases, and the last ratio completed is the breaking point. The breaking point measures the effort the animal is willing to exert to obtain the reinforcing stimulus and is then considered an index of motivation, or of the perceived reinforcing value of the stimulus. Thus, a decrease in breaking point may be regarded as a core symptom in animal models of anhedonia, although this decrease is not reliably observed in all the models. Reductions in breakpoints for sucrose have been reported in a genetic animal model of depression, the congenital learned helpless rat (Vollmayr et al., 2004), in a chronic unavoidable stress protocol in rats (Marchese et al., 2013; Scheggi et al., 2016), and in rats and mice exposed to chronic social defeat (Bergamini et al., 2016; Spierling et al., 2017). This index of reduced motivation for a natural reward can be restored to control values by treatments endowed with antidepressant and/or promotivational activity, for example, lithium, clozapine, aripiprazole, and lamotrigine (Marchese et al., 2013; Scheggi et al., 2015, 2017b; Scheggi, Pelliccia, De Montis and Gambarana, unpublished data). Conversely, exposure to the CMS model does not usually affect sucrose breaking point.
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