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Motivation-enhancing drug

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See also: Disorders of diminished motivation § Treatment
Motivation-enhancing drug
Drug class
Dextroamphetamine, one of the most widely used motivation-enhancing drugs.
Class identifiers
SynonymsMotivation-enhancing agent; Motivation-enhancing medication; Pro-motivational drug;[1] Pro-motivational agent; Pro-motivational medication
UseTo 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

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Dopaminergic agents

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Dopaminergic agents that have been found to produce pro-motivational effects in animals and/or humans include the following:[4][13]

Other dopaminergic agents

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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

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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

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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

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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, A2A, A2B, and A3).[13][86][87][88] Conversely, agents like istradefylline and preladenant are selective adenosine A2A receptor antagonists.[13] 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.[13][89] 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.[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

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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

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Agomelatine, a serotonin 5-HT2C receptor antagonist and melatonin MT1 and MT2 receptor agonist that has sometimes been described as a "norepinephrine–dopamine disinhibitor" ("NDDI") (in the prefrontal cortex),[101] has indirect dopaminergic actions and has been suggested as a possible treatment for disorders of diminished motivation like anhedonia and abulia.[102] It has been found to be effective in the treatment of apathy in people with dementia.[103][98][104][105] The drug was also reported to reverse escitalopram-associated apathy in a case report.[102][106]

The GPR139 agonist zelatriazin (TAK-041; NBI-1065846) has shown pro-motivational effects in animals.[107][108] On the basis of these findings, it has been speculated that the drug might be useful in the treatment of apathy in humans.[107][108] 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.[109][110][111] However, its development was discontinued due to lack of clinical effectiveness.[109][112]

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).[113][114] The drug has also been found to reduce symptoms of depression and anhedonia, for instance in people with high inflammation.[115][116][113]

Ineffective agents

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Serotonergic and noradrenergic agents

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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][117] 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][118][39] In fact, these drugs can produce further motivational deficits in animals.[19][118][119][39] Serotonergic antidepressants like SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) have also been implicated in inducing apathy and emotional blunting in humans.[20][21][120]

Selective MAO-B inhibitors

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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.[121][122]

Dopamine receptor antagonists and partial agonists

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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.[123][124] These drugs include aripiprazole, brexpiprazole, and cariprazine.[124] 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.[125][126] On the other hand, another study found that aripiprazole reversed stress-induced motivational anhedonia in animals, an antidepressant-like effect.[127][128] 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.[129]

Certain atypical dopamine reuptake inhibitors

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Some atypical DRIs, like JJC8-091, in contrast to other DRIs, are not effective in producing pro-motivational effects in animals.[130] This has been attributed to binding to an occluded conformation of the dopamine transporter (DAT) that results in a diminished increase in dopamine levels.[130]

See also

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References

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  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.
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  100. ^ Reilly S, Dhaliwal S, Arshad U, Macerollo A, Husain N, Costa AD (February 2024). "The effects of rivastigmine on neuropsychiatric symptoms in the early stages of Parkinson's disease: A systematic review". Eur J Neurol. 31 (2): e16142. doi:10.1111/ene.16142. PMC 11236000. PMID 37975761.
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  103. ^ Harrison F, Aerts L, Brodaty H (November 2016). "Apathy in Dementia: Systematic Review of Recent Evidence on Pharmacological Treatments". Curr Psychiatry Rep. 18 (11): 103. doi:10.1007/s11920-016-0737-7. PMID 27726067.
  104. ^ Theleritis C, Siarkos K, Politis A, Smyrnis N, Papageorgiou C, Politis AM (July 2023). "A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders". Brain Sci. 13 (7): 1061. doi:10.3390/brainsci13071061. PMC 10377475. PMID 37508993.
  105. ^ Callegari I, Mattei C, Benassi F, Krueger F, Grafman J, Yaldizli Ö, Sassos D, Massucco D, Scialò C, Nobili F, Serrati C, Amore M, Cocito L, Emberti Gialloreti L, Pardini M (2016). "Agomelatine Improves Apathy in Frontotemporal Dementia". Neurodegener Dis. 16 (5–6): 352–356. doi:10.1159/000445873. PMID 27229348.
  106. ^ De Berardis D, Valchera A, Fornaro M, Serroni N, Marini S, Moschetta FS, Martinotti G, Di Giannantonio M (April 2013). "Agomelatine reversal of escitalopram-induced apathy: a case report". Psychiatry Clin Neurosci. 67 (3): 190–191. doi:10.1111/pcn.12032. PMID 23581873.
  107. ^ a b Zhang R, Chen J (December 2023). "Research progress on the role of orphan receptor GPR139 in neuropsychiatric behaviours". Eur J Pharmacol. 960: 176150. doi:10.1016/j.ejphar.2023.176150. PMID 38059447. In 2021, Reichard et al., (2021) developed the GPR139 agonist TAK041, also known as NBI-1065846. TAK-041 has good physical and chemical properties, can cross the blood–brain barrier, and shows potential in preclinical studies to treat schizophrenia symptoms. Several clinical trials indicate that TAK-041 is safe and metabolically stable (Kamel et al., 2021; Reichard et al., 2021; Yin et al., 2022). Apathy is a condition characterised by a lack of motivation, emotion, or interest and is a common symptom of many psychiatric and neurological disorders. Munster et al. (2022) provided preclinical evidence supporting GPR139 agonism (using TAK-041) as a molecular mechanism for treating apathy. The research and development of TAK-041 have effectively promoted the process of de-orphaning GPR139 and its clinical application value.
  108. ^ a b 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". Neuropharmacology. 213: 109078. doi:10.1016/j.neuropharm.2022.109078. PMID 35561791.
  109. ^ a b "TAK 041". AdisInsight. 26 September 2023. Retrieved 26 September 2024.
  110. ^ Lu Y, Hatzipantelis CJ, Langmead CJ, Stewart GD (July 2024). "Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia". Br J Pharmacol. 181 (14): 2095–2113. doi:10.1111/bph.16221. PMID 37605621.
  111. ^ 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.
  112. ^ "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.
  113. ^ a b 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.
  114. ^ Treadway MT, Etuk SM, Cooper JA, Hossein S, Hahn E, Betters SA, Liu S, Arulpragasam AR, DeVries BA, Irfan N, Nuutinen MR, Wommack EC, Woolwine BJ, Bekhbat M, Kragel PA, Felger JC, Haroon E, Miller AH (September 2024). "A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation". Mol Psychiatry. doi:10.1038/s41380-024-02751-x. PMID 39289477.
  115. ^ Rahmati-Dehkordi F, Birang N, Jalalian MN, Tamtaji Z, Dadgostar E, Aschner M, Shafiee Ardestani M, Jafarpour H, Mirzaei H, Nabavizadeh F, Tamtaji OR (September 2024). "Can infliximab serve as a new therapy for neuropsychiatric symptoms?". Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-024-03397-w. PMID 39225829.
  116. ^ Rizk MM, Bolton L, Cathomas F, He H, Russo SJ, Guttman-Yassky E, Mann JJ, Murrough J (June 2024). "Immune-Targeted Therapies for Depression: Current Evidence for Antidepressant Effects of Monoclonal Antibodies". J Clin Psychiatry. 85 (3). doi:10.4088/JCP.23nr15243. PMID 38959503.
  117. ^ Tay J, Morris RG, Markus HS (July 2021). "Apathy after stroke: Diagnosis, mechanisms, consequences, and treatment". Int J Stroke. 16 (5): 510–518. doi:10.1177/1747493021990906. PMC 8267086. PMID 33527880.
  118. ^ a b Yohn SE, Collins SL, Contreras-Mora HM, Errante EL, Rowland MA, Correa M, Salamone JD (February 2016). "Not All Antidepressants Are Created Equal: Differential Effects of Monoamine Uptake Inhibitors on Effort-Related Choice Behavior". Neuropsychopharmacology. 41 (3): 686–694. doi:10.1038/npp.2015.188. PMC 4707815. PMID 26105139.
  119. ^ Yohn SE, Errante EE, Rosenbloom-Snow A, Somerville M, Rowland M, Tokarski K, Zafar N, Correa M, Salamone JD (October 2016). "Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology". Neuropharmacology. 109: 270–280. doi:10.1016/j.neuropharm.2016.06.018. PMID 27329556.
  120. ^ Camino S, Strejilevich SA, Godoy A, Smith J, Szmulewicz A (July 2023). "Are all antidepressants the same? The consumer has a point". Psychological Medicine. 53 (9): 4004–4011. doi:10.1017/S0033291722000678. PMID 35346413.
  121. ^ Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". Int J Mol Sci. 24 (17): 13334. doi:10.3390/ijms241713334. PMC 10487936. PMID 37686140.
  122. ^ Miklya I (June 2014). "Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline". Pharmacol Rep. 66 (3): 453–458. doi:10.1016/j.pharep.2013.11.003. PMID 24905523.
  123. ^ Lieberman JA (2004). "Dopamine partial agonists: a new class of antipsychotic". CNS Drugs. 18 (4): 251–267. doi:10.2165/00023210-200418040-00005. PMID 15015905.
  124. ^ a b Taylor D, Chithiramohan R, Grewal J, Gupta A, Hansen L, Reynolds GP, Pappa S (September 2023). "Dopamine partial agonists: a discrete class of antipsychotics". Int J Psychiatry Clin Pract. 27 (3): 272–284. doi:10.1080/13651501.2022.2151473. PMID 36495086.
  125. ^ 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]. [...]
  126. ^ 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.
  127. ^ 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.
  128. ^ Scheggi S, Pelliccia T, Gambarana C, De Montis MG (February 2018). "Aripiprazole relieves motivational anhedonia in rats". J Affect Disord. 227: 192–197. doi:10.1016/j.jad.2017.10.032. PMID 29100151.
  129. ^ Keks N, Hope J, Schwartz D, McLennan H, Copolov D, Meadows G (May 2020). "Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia". CNS Drugs. 34 (5): 473–507. doi:10.1007/s40263-020-00718-4. PMID 32246399.
  130. ^ a b Ecevitoglu A, Meka N, Rotolo RA, Edelstein GA, Srinath S, Beard KR, Carratala-Ros C, Presby RE, Cao J, Okorom A, Newman AH, Correa M, Salamone JD (July 2024). "Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors". Neuropsychopharmacology. 49 (8): 1309–1317. doi:10.1038/s41386-024-01826-1. PMC 11224370. PMID 38429498.


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