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Motivation-enhancing drug

From Wikipedia, the free encyclopedia
Drug increasing motivation in humans
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 increasemotivation and treatdisorders of diminished motivation
Legal status
In Wikidata

Amotivation-enhancing drug,[2][3] also known as apro-motivational drug,[1] is adrug which increasesmotivation.[4][1] Drugs enhancing motivation can be used in the treatment ofmotivational deficits, for instance indepression,schizophrenia, andattention deficit hyperactivity disorder (ADHD).[5][4] They can also be used in the treatment ofdisorders of diminished motivation (DDMs), includingapathy,abulia, andakinetic mutism, disorders that can be caused by conditions likestroke,traumatic brain injury (TBI), andneurodegenerative diseases.[6][7] Motivation-enhancing drugs are usednon-medically by healthy people to increase motivation andproductivity as well, for instance ineducational 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 generallydopaminergic agents, for instancedopamine reuptake inhibitors (DRIs) likemethylphenidate andmodafinil,dopamine releasing agents (DRAs) likeamphetamine, and other dopaminergic medications.[4][1][13]Adenosine receptor antagonists, likecaffeine andistradefylline, can also produce pro-motivational effects.[13][14][15][16]Acetylcholinesterase inhibitors, likedonepezil, 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 includeselective serotonin reuptake inhibitors (SSRIs),[19][20][21]selectivenorepinephrine reuptake inhibitors (NRIs),[19] andantipsychotics (which aredopamine receptor antagonists orpartial agonists).[22][23][24][25]Cannabinoids, for instance those found incannabis, 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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DopamineD2-like receptor agonists, includingpramipexole,ropinirole,rotigotine,piribedil,bromocriptine,cabergoline,pergolide, andlisuride, 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 havesedative-like and non-rewarding effects in humans.[43][44][45] In any case, dopamine D2-like receptorantagonists, likehaloperidol and otherantipsychotics, 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 improveanergia 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 includerasagiline (aselectivemonoamine oxidase B (MAO-B)inhibitor; but see morebelow),tolcapone (acentrally-actingcatechol-O-methyltransferase (COMT)inhibitor), andamantadine (an indirectly acting dopaminergic agent that acts via unknown mechanisms).[12][18][53][17][54] Tolcapone, the only marketed COMT inhibitor that iscentrally acting (as opposed toperipherally selective), showsantidepressant- andanti-anhedonia-like effects, stimulatesexploratory behavior, and enhances thelocomotor hyperactivity induced bypsychostimulants likeamphetamine andnomifensine in animals.[55][56][57] Amantadine is widely used to treatmultiple sclerosis-relatedfatigue, among other fatigue- and motivation-related disorders, and is recommended by theUnited KingdomNational 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 thenucleus accumbens, part of theventral striatum and themesolimbic reward pathway, are thought to play a key role in mediating behavioral activation and motivation.[4][19][13][12] Dopamine releasing agents likedextroamphetamine are able to rapidly increasestriatal 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 likemethylphenidate.[62][63] In addition, whereas dopamine reuptake inhibitors show a cleardose–effectceiling 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 likemodafinil can also increase dopamine levels in the striatum and nucleus accumbens in animals, but have further reduced impacts on dopamine levels compared topsychostimulants 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 oftolerance to their effects.[66][67]Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively shortdurations of action (~4 hours for main desired effects) and their much longerelimination half-lives (~10 hours) and durations in the body (~2 days).[67][68][69][70][71][72][73] It appears that continually increasing or ascendingconcentration–time curves are beneficial for prolonging effects, which has resulted in administration multiple times per day and development ofdelayed- and extended-release formulations.[67][69][70] Drug holidays and breaks can be helpful in resetting tolerance.[66]

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

A limitation ofbupropion as a dopaminergic agent is that it achieves very limited clinical occupancy of thedopamine transporter (DAT).[80][81][82][83]

Adenosinergic agents

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Adenosine receptor antagonists, includingcaffeine,istradefylline (KW-6002),Lu AA47070,MSX-3,MSX-4,preladenant (SCH-420814), andtheophylline, have shown pro-motivational effects in animals and humans.[13][14][15][84][16][85] Caffeine and theophylline act asnon-selective antagonists of theadenosine receptors (includingA1,A2A,A2B, andA3).[13][86][87][88] Conversely, agents like istradefylline and preladenant are selective adenosineA2A 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, likeDPCPX andCPX, do not.[13][89] Adenosine A2A receptor antagonists appear to exert their pro-motivational effects in thenucleus accumbens core and can reverse the anti-motivational effects of dopamineD2 receptorantagonists likehaloperidol in animals.[13][14][15][90][91] Istradefylline is approved in the treatment ofParkinson's disease and has been found to improve symptoms of apathy,anhedonia, anddepression in people with the condition.[16][85]

Cholinergic agents

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Acetylcholinesterase inhibitors, likedonepezil,rivastigmine, andgalantamine, have been used in the treatment of disorders of diminished motivation.[17][18][6][11] These drugs inhibitacetylcholinesterase, whichmetabolizes theneurotransmitteracetylcholine, thereby increasing acetylcholine levels in the brain and augmenting activation of themuscarinic acetylcholine andnicotinic acetylcholine receptors.[92] They are approved and used in the treatment ofAlzheimer'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, themuscarinic acetylcholine receptor agonistpilocarpine has actually shown anti-motivational effects in animals that can be reversed by themuscarinic acetylcholine receptor antagonistscopolamine.[90] In addition,xanomeline, amuscarinic acetylcholineM1 andM4 receptor agonist, shows indirectantidopaminergic effects in themesolimbic pathway in animals and,in combination with trospium, is approved as anantipsychotic in the treatment ofschizophrenia.[95][96][97] Furthermore, scopolamine has been found to reverse the anti-motivational effects of thedopamineD2 receptor antagonisthaloperidol 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 indementia andParkinson's disease.[98][99][100]

Other agents

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Serotonin5-HT2C receptorantagonists, such asSB-242084, show pro-motivational effects in animals.[101][102][103][104][105] In addition, SB-242084 has shown modeststimulant-like andreinforcing effects in monkeys.[106] In accordance with the preceding, serotonin 5-HT2C receptor antagonists like SB-242084 andSB-206553 have been found to increasedopamine levels in thenucleus accumbens.[107][108]

Agomelatine is apotentmelatoninMT1 andMT2 receptoragonist and weak serotonin5-HT2B and 5-HT2C receptor antagonist that is marketed as anantidepressant.[109] It has been found to increasenorepinephrine and dopamine levels in thefrontal cortex in rodents, though notably not in thestriatum 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 likeanhedonia andabulia.[111] It has been found to be effective in the treatment of apathy in people withdementia[112][98][113][114] and was reported to reverseescitalopram-associated apathy in acase report.[111][115]

TheGPR139 agonistzelatriazin (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 inmajor depressive disorder and thenegative symptoms ofschizophrenia and reachedphase 3clinical trials.[118][119][120] However, its development was discontinued due to lack of clinical effectiveness.[118][121]

Thetumor necrosis factor α (TNF-α)monoclonal antibodyinfliximab has been found to increase motivation in people withdepression with highinflammation (as measured by highC-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]

TheDOxserotonergic psychedelic2,5-dimethoxy-4-propylamphetamine (DOPR), which acts as an agonist of the serotonin5-HT2A,5-HT2B, and5-HT2C receptors, has shown pro-motivational effects in rodents at sub-hallucinogenic doses or so-called "microdoses".[126][127] DOPR's closeanalogue2,5-dimethoxy-4-ethylamphetamine (DOET) has also been clinically studied at sub-hallucinogenic doses as a "psychic energizer".[128][129][130][131][132][133] The non-hallucinogenic4C analogueAriadne (4C-DOM) has indirect dopaminergic effects in rodents[134] and pro-motivational effects in monkeys as well.[135]ASR-2001 (2CB-5PrO), a non-hallucinogenicTWEETIO analogue of the related2C serotonergic psychedelic2C-B, is under development for use as astimulant-likemedication for the treatment ofpsychiatric disorders.[136][137][138][139][140]

Ineffective agents

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Serotonergic and noradrenergic agents

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Selective serotonin reuptake inhibitors (SSRIs) likeescitalopram andnorepinephrine reuptake inhibitors (NRIs) likeatomoxetine have been used and recommended in the treatment of disorders of diminished motivation.[7][17][141] However, SSRIs likefluoxetine andcitalopram, NRIs likedesipramine and atomoxetine, andMAO-A-inhibitingmonoamine oxidase inhibitors (MAOIs) likemoclobemide andpargyline, have all not shown pro-motivational effects in animals.[4][13][30][142][39] In fact, these drugs can produce further motivational deficits in animals.[19][142][143][39][103]Serotonergicantidepressants like SSRIs andserotonin–norepinephrine reuptake inhibitors (SNRIs) have also been implicated in inducing apathy andemotional blunting in humans.[20][21][144] Activation of the serotonin5-HT2C receptor by serotonergic agents like SSRIs may contribute to or mediate their anti-motivational effects, whereas co-administration of serotonin 5-HT2C receptor antagonists may reverse the effects.[102][103]

Selective MAO-B inhibitors

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In contrast toselegiline,selectiveMAO-B inhibitors without concomitantcatecholaminergic activity enhancer (CAE) actions, likerasagiline,SU-11739, andlazabemide, are poorly effective in reversing behavioral deficits induced by thedopamine depleting agenttetrabenazine in animals.[145][146]

Dopamine receptor antagonists and partial agonists

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Antipsychotics, which classically act asdopamine receptor antagonists (mostly of theD2-like receptors), are well-known as having robust anddose-dependent anti-motivational effects.[4][13][22][23][46][47][49] In fact, these effects may play a key role in their effectiveness against thepositive andpsychoticsymptoms ofschizophrenia byblunting the emotions underlyingdelusions.[22][23][46][47][49]

A novel class of antipsychotics, sometimes referred to asthird-generation antipsychotics, act as dopamine D2-like receptorpartial agonists instead of aspure antagonists, and hence have mixed agonistic and antagonistic effects.[147][148] These drugs includearipiprazole,brexpiprazole, andcariprazine.[148] 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 thedopamine depleting agenttetrabenazine.[25][24] Accordingly, aripiprazole reduced activation of themesolimbic motivational pathway in humans similarly to but less robustly thanhaloperidol.[149][150] On the other hand, another study found that aripiprazole reversedstress-induced motivational anhedonia in animals, anantidepressant-like effect.[151][152] Different dopamine receptor partial agonists that are used in the treatment of schizophrenia are known to vary in theirintrinsic activities at the dopamine receptors, so each drug may be expected to have a different profile of effects.[153]

Certain atypical dopamine reuptake inhibitors

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Some atypical DRIs, likeJJC8-091, in contrast to other DRIs, are not effective in producing pro-motivational effects in animals.[154] This has been attributed to binding to an occludedconformation of thedopamine transporter (DAT) that results in a diminished increase in dopamine levels.[154]

See also

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References

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  39. ^abcContreras-Mora H, Rowland MA, Yohn SE, Correa M, Salamone JD (March 2018). "Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions".Pharmacol Biochem Behav.166:13–20.doi:10.1016/j.pbb.2018.01.001.PMID 29309800.
  40. ^abSalamone JD, Koychev I, Correa M, McGuire P (August 2015). "Neurobiological basis of motivational deficits in psychopathology".Eur Neuropsychopharmacol.25 (8):1225–1238.doi:10.1016/j.euroneuro.2014.08.014.PMID 25435083.
  41. ^abSami MB, Faruqui R (December 2015). "The effectiveness of dopamine agonists for treatment of neuropsychiatric symptoms post brain injury and stroke".Acta Neuropsychiatr.27 (6):317–326.doi:10.1017/neu.2015.17.PMID 25850757.Dopamine agonists have been reported to have positive effects in treating the neuropsychiatric sequalae of brain injury. One case series reported 19 out of 30 patients with severe head injury and aggression to respond to amantadine over the course of a year (15). Other case series have also shown positive response of cognitive function, attention and motivation in persons with head injury in the rehabilitative setting (16–18). Open label trials have shown improved neuropsychiatric outcomes in braininjured patients with bromocriptine and amantadine (19,20). Case studies have also reported improvement with the use of dopaminergic therapy in patients with neuropsychiatric sequalae of stroke. A combination of carbidopa/levodopa and pergolide has been reported to substantially improve the outcome of post-infarct akinetic mutism (21). Ropinirole has been reported to have had a dramatic effect on post-stroke apathy (22). However most of the reported associations to date have been limited by considerable methodological shortcomings. Case studies are anecdotal evidence, whereas larger case series may report improvement but are uncontrolled. This is critical in studies of neurological injury, where a degree of improvement may be expected by neuronal recovery over time. Similarly trials to date which have reported positive results have been open-label and consequently susceptible to placebo effect. Thus a systematic review of rigorous double-blind randomised controlled trials (RCTs) is needed.
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  43. ^Rothman RB (1994). "A Review of the Effects of Dopaminergic Agents in Humans: Implications for Medication Development". In Erinoff L, Brown RM (eds.).Neurobiological Models for Evaluating Mechanisms Underlying Cocaine Addiction (NIDA Research Monograph 145)(PDF). U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute on Drug Abuse. pp. 67–87. Retrieved4 August 2024.
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  45. ^Singer C (January 2002). "Adverse effects in the treatment of Parkinson's disease".Expert Rev Neurother.2 (1):105–118.doi:10.1586/14737175.2.1.105.PMID 19811020.
  46. ^abcMoncrieff, Joanna (2007). "What Do Neuroleptics Really Do? A Drug-Centred Account".The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment. Palgrave Macmillan London. pp. 100–117.doi:10.1007/978-0-230-58944-5_7 (inactive 1 November 2024).ISBN 978-0-230-57431-1.{{cite book}}: CS1 maint: DOI inactive as of November 2024 (link)
  47. ^abcMoncrieff, Joanna (2013). "The Patient's Dilemma: Other Evidence on the Effects of Antipsychotics".The Bitterest Pills. London: Palgrave Macmillan UK. pp. 113–131.doi:10.1057/9781137277442_7.ISBN 978-1-137-27743-5.
  48. ^Moncrieff J, Cohen D, Mason JP (August 2009). "The subjective experience of taking antipsychotic medication: a content analysis of Internet data".Acta Psychiatr Scand.120 (2):102–111.doi:10.1111/j.1600-0447.2009.01356.x.PMID 19222405.
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  51. ^Powell JH, al-Adawi S, Morgan J, Greenwood RJ (April 1996)."Motivational deficits after brain injury: effects of bromocriptine in 11 patients".J Neurol Neurosurg Psychiatry.60 (4):416–421.doi:10.1136/jnnp.60.4.416.PMC 1073895.PMID 8774407.
  52. ^Marciano, Theresa (24 July 2023)."Assessing the effects of Pergolide on the motivational aspects of depression in rats using operant conditioning".Honors Scholar Theses. Retrieved26 September 2024.
  53. ^abCostello H, Husain M, Roiser JP (January 2024)."Apathy and Motivation: Biological Basis and Drug Treatment".Annu Rev Pharmacol Toxicol.64:313–338.doi:10.1146/annurev-pharmtox-022423-014645.PMID 37585659.
  54. ^abDanysz W, Dekundy A, Scheschonka A, Riederer P (February 2021)."Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials".J Neural Transm (Vienna).128 (2):127–169.doi:10.1007/s00702-021-02306-2.PMC 7901515.PMID 33624170.
  55. ^Guay DR (January 1999). "Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease".Pharmacotherapy.19 (1):6–20.doi:10.1592/phco.19.1.6.30516.PMID 9917075.It also enhances locomotor hyperactivity induced by amphetamine and nomifensine and stereotypy induced by amphetamine, and stimulates exploratory activity in the open field test in rats and mice.14 Tolcapone potentiates levodopa antagonism of haloperidol-induced catalepsy in MPP+-lesioned mice (murine model of Parkinson's disease) and potentiates and prolongs levodopa-induced circling behavior in rats with 6-hydroxydopamine-induced nigrostriatal pathway lesions (another animal model of Parkinson's disease).23, 24 [...] The effect of tolcapone on animal models of depression was evaluated in two studies. In rats with chronic mild stress-induced anhedonia, tolcapone 10 or 30 mg/kg twice/day by intraperitoneal injection prevented the stress-induced anhedonic state compared with vehicle-treated controls.28 Another rat study using the forced swimming test and learned helplessness paradigm, found no significant antidepressant activity of the agent.29 The relevance of these findings to the management of depression in humans with both parkinsonian and nonparkinsonian disease is unknown.
  56. ^Maj J, Rogóz Z, Skuza G, Sowińska H, Superata J (1990). "Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease".J Neural Transm Park Dis Dement Sect.2 (2):101–112.doi:10.1007/BF02260898.PMID 1977408.
  57. ^Parada A, Soares-da-Silva P (October 2000)."POSTER COMMUNICATIONS: 49P. BIA 3-202 does not potentiate locomotor hyperactivity during increased dopaminergic stimulation".British Journal of Pharmacology.131 (Suppl). Wiley:38P –129P.PMC 1910551.Tolcapone administered 6 h before amphetamine challenge was found to significantly increase locomotor activity in rats treated with 0.5 and 2.0 mg kg-1 amphetamine. In rats given 4.0 mg kg-1 amphetamine, tolcapone produced a marked decrease in locomotor activity and increased two-fold the duration of the stereotyped behaviour.
  58. ^"Recommendations | Multiple sclerosis in adults: management | Guidance | NICE".www.nice.org.uk. June 22, 2022.Archived from the original on January 7, 2023. RetrievedJanuary 7, 2023.
  59. ^Zimek D, Miklusova M, Mares J (2023)."Overview of the Current Pathophysiology of Fatigue in Multiple Sclerosis, Its Diagnosis and Treatment Options - Review Article".Neuropsychiatr Dis Treat.19:2485–2497.doi:10.2147/NDT.S429862.PMC 10674653.PMID 38029042.Currently, different pharmacological agents are used for the treatment for fatigue in patients with MS, including amantadine, modafinil and pemoline.99,100 Of these, the most commonly used is amantadine. Its main mechanism of action is not yet fully understood, although its effects on fatigue seem to be related to its dopaminergic effects, supporting the dopamine imbalance theory for MS-related fatigue.101 In general, all trials that compared amantadine with placebo showed a significant effect of amantadine on fatigue. However, the results of these trials need to be interpreted with caution because of the low number of participants included in the trials and the short duration of the interventions.8 The daily dose of amantadine used in all published studies was 200 mg, which is the standard amount administered today. Amantadine is the only oral treatment that is currently recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of MS-related fatigue.102
  60. ^Yang TT, Wang L, Deng XY, Yu G (September 2017). "Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis".J Neurol Sci.380:256–261.doi:10.1016/j.jns.2017.07.042.PMID 28870581.
  61. ^Dobryakova E, Genova HM, DeLuca J, Wylie GR (2015)."The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders".Front Neurol.6: 52.doi:10.3389/fneur.2015.00052.PMC 4357260.PMID 25814977.
  62. ^abcHeal 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 fromthe 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. ^abHandelman 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. ^abcErmer 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. ^abAbbas 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.
  70. ^abSwanson JM, Volkow ND (January 2009)."Psychopharmacology: concepts and opinions about the use of stimulant medications".Journal of Child Psychology and Psychiatry, and Allied Disciplines.50 (1–2):180–193.doi:10.1111/j.1469-7610.2008.02062.x.PMC 2681087.PMID 19220601.
  71. ^Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME (2017)."Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects".Frontiers in Pharmacology.8: 617.doi:10.3389/fphar.2017.00617.PMC 5594082.PMID 28936175.
  72. ^Folgering JH, Choi M, Schlumbohm C, van Gaalen MM, Stratford RE (April 2019)."Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response".Journal of Neuroscience Methods.317:71–81.doi:10.1016/j.jneumeth.2019.02.005.PMID 30768951.
  73. ^van Gaalen MM, Schlumbohm C, Folgering JH, Adhikari S, Bhattacharya C, Steinbach D, Stratford RE (April 2019)."Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine".The Journal of Pharmacology and Experimental Therapeutics.369 (1):107–120.doi:10.1124/jpet.118.254508.PMID 30733244.
  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).
  77. ^Courtney KE, Ray LA (2016). "Clinical neuroscience of amphetamine-type stimulants".Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development. Progress in Brain Research. Vol. 223. pp. 295–310.doi:10.1016/bs.pbr.2015.07.010.ISBN 978-0-444-63545-7.PMID 26806782.Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005).
  78. ^Berman SM, Kuczenski R, McCracken JT, London ED (February 2009)."Potential adverse effects of amphetamine treatment on brain and behavior: a review".Molecular Psychiatry.14 (2):123–142.doi:10.1038/mp.2008.90.PMC 2670101.PMID 18698321.Though the paradigm used by Ricaurte et al. 53 arguably still incorporates amphetamine exposure at a level above much clinical use,14,55 it raises important unanswered questions. Is there a threshold of amphetamine exposure above which persistent changes in the dopamine system are induced? [...]
  79. ^Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH, McCann UD (October 2005). "Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates".The Journal of Pharmacology and Experimental Therapeutics.315 (1):91–98.doi:10.1124/jpet.105.087916.PMID 16014752.
  80. ^Hart XM, Spangemacher M, Defert J, Uchida H, Gründer G (April 2024). "Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants".Ther Drug Monit.46 (2):155–169.doi:10.1097/FTD.0000000000001142.PMID 38287888.
  81. ^Eap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C (October 2021)."Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants"(PDF).The World Journal of Biological Psychiatry.22 (8):561–628.doi:10.1080/15622975.2021.1878427.PMID 33977870.S2CID 234472488.Archived(PDF) from the original on 5 May 2022. Retrieved10 April 2022.
  82. ^Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders".Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. Academic Press. pp. 177–216.doi:10.1016/B978-0-12-420118-7.00005-6.ISBN 978-0-12-420118-7.PMID 24484978.
  83. ^Verbeeck W, Bekkering GE, Van den Noortgate W, Kramers C (October 2017)."Bupropion for attention deficit hyperactivity disorder (ADHD) in adults".The Cochrane Database of Systematic Reviews.2017 (10): CD009504.doi:10.1002/14651858.CD009504.pub2.PMC 6485546.PMID 28965364.
  84. ^Jenner P, Mori A, Kanda T (November 2020)."Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?".Parkinsonism Relat Disord. 80 Suppl 1:S28 –S36.doi:10.1016/j.parkreldis.2020.09.022.PMID 33349577.
  85. ^abTurner V, Husain M (2022). "Anhedonia in Neurodegenerative Diseases".Anhedonia: Preclinical, Translational, and Clinical Integration. Current Topics in Behavioral Neurosciences. Vol. 58. pp. 255–277.doi:10.1007/7854_2022_352.ISBN 978-3-031-09682-2.PMID 35435648.Recently, PD patients have been treated with istradefylline, an adenosine A2A receptor antagonist used for treatment of motor symptoms. The drug was given to 14 PD patients for 12 weeks, measuring anhedonia, apathy and depression using the SHAPS, Apathy Scale and BDI. On istradefylline, SHAPS, Apathy Scale and BDI scores significantly reduced from baseline scores at 4-, 8- and 12-weeks, with mean SHAPS scores at week 12 about 50% reduced from baseline scores, indicating that istradefylline reduces anhedonia (Nagayama et al. 2019). As apathy and depression rates dropped as well as anhedonia, this trial also provided evidence for the overlapping relationship between the three symptoms. [...] Taken together, there is some evidence that dopamine agonists such as pramipexole and piribedil, or the adenosine A2A receptor antagonist istradefylline can improve anhedonia and apathy in PD.
  86. ^Ribeiro JA, Sebastião AM (2010). "Caffeine and adenosine".J Alzheimers Dis. 20 Suppl 1: S3–15.doi:10.3233/JAD-2010-1379.hdl:10451/6361.PMID 20164566.
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  88. ^Froestl W, Muhs A, Pfeifer A (2012)."Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors"(PDF).Journal of Alzheimer's Disease.32 (4):793–887.doi:10.3233/JAD-2012-121186.PMID 22886028.S2CID 10511507. Archived fromthe original(PDF) on 15 November 2020.
  89. ^Nunes EJ, Randall PA, Santerre JL, Given AB, Sager TN, Correa M, Salamone JD (September 2010)."Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism".Neuroscience.170 (1):268–280.doi:10.1016/j.neuroscience.2010.05.068.PMC 3268040.PMID 20600675.
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  102. ^abRoberts C, Sahakian BJ, Robbins TW (December 2020). "Psychological mechanisms and functions of 5-HT and SSRIs in potential therapeutic change: Lessons from the serotonergic modulation of action selection, learning, affect, and social cognition".Neurosci Biobehav Rev.119:138–167.doi:10.1016/j.neubiorev.2020.09.001.PMID 32931805.[...] 5-HT2C receptors are linked to some of the adverse motivational effects corresponding with dimensions of approach/avoidance behaviours in both aversive and appetitive paradigms. 5-HT2CR antagonism reduces the inhibitory effects of citalopram and SERT-KO mice on reward-seeking after conditioned reinforcers (Brown & Fletcher, 2016), paralleling other experiments showing that 5-HT2CR antagonism exacerbates impulsivity (Winstanley et al, 2004b; Robinson et al, 2008b). 5-HT2CR antagonists increase motivation alongside extracellular DA in the dorsomedial striatum (Bailey et al, 2018), and others have suggested that 5-HT2CR antagonists may be a valuable adjunctive treatment to SSRIs to attenuate motivational side effects such as apathy, decreased libido, and general emotional blunting (Demireva et al, 2018). 5-HT2C receptors, including its negative interactions with DA, appear to increase the latency of active responses to rewards and constrain motivation, consistent with its inhibitory effects on locomotion also seen in uncertain and potentially aversive contexts. [...] 5-HT2C antagonists could prove to be a useful adjunctive treatment to attenuate unwanted anxiogenic and motivational deficits associated with SSRIs.
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  109. ^abNorman 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.
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  113. ^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.
  114. ^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.
  115. ^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.
  116. ^abZhang 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.
  117. ^abMünster 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.
  118. ^ab"TAK 041".AdisInsight. 26 September 2023. Retrieved26 September 2024.
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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. Retrieved26 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. ^abLee 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.
  123. ^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.PMC 10942546.PMID 39289477.
  124. ^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.398 (2):1081–1097.doi:10.1007/s00210-024-03397-w.PMID 39225829.
  125. ^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.PMC 11892342.PMID 38959503.
  126. ^Noback M, Kenton JA, Klein AK, Hughes ZA, Kruegel AC, Schmid Y, Halberstadt AL, Young JW (February 2025). "Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice".Neuropharmacology.268: 110334.doi:10.1016/j.neuropharm.2025.110334.PMID 39900138.
  127. ^Noback M, Kenton J, Klein A, Hughes Z, Kruegel A, Young J (December 2022)."ACNP 61st Annual Meeting: Poster Abstracts P541 - P809: P572. 2,5-Dimethoxy-4-Propylamphetamine (DOPR) Increased Effortful Motivation in Mice".Neuropsychopharmacology.47 (Suppl 1): 371–520 (390–390).doi:10.1038/s41386-022-01486-z.PMC 9714408.PMID 36456695.DOPR caused a dose-dependent increase in HTR (F(5,30)=60.0, p < 0.0001), with doses of 3.2 and 10 mg/kg passing a Bonferroni post hoc correction relative to vehicle (p < 0.002), and peak effect at 3.2 mg/kg. [...] The binding affinity at 5-HT2A of the two compounds was similar, with DOPR having a Ki of 17.56 nM and DOI having a Ki of 14.51 nM. [...] DOPR and DOI also show agonist activity at 5-HT2A (EC50 of 0.12 and 0.19 nM, respectively) and 5-HT2C (EC50 of 0.27 and 0.82 nM, respectively) receptors, with >25-fold lower potency at 5-HT2B receptors and no significant activity at 5-HT1A (both > 1,000 nM EC50). [...] The positive effect of DOPR on effortful motivation points to possible therapeutic applications in psychiatric illness states characterized by reduced effortful motivation as measured by the PRBT. The similarity of effects of DOPR to well-studied drugs such as DOI and amphetamine provides a useful reference point to interpret its pharmacological effects. Importantly, the doses needed to increase breakpoint in the PRBT were as low as 0.0106 mg/kg. While 0.1 mg/kg increased HTR, this effect was not significant, and maximal effect at 3.2 mg/kg, supporting the premise that low doses of DOPR may be therapeutic in anhedonia states without causing unwanted hallucinogenic side effects.
  128. ^Baggott MJ (1 October 2023)."Learning about STP: A Forgotten Psychedelic from the Summer of Love"(PDF).History of Pharmacy and Pharmaceuticals.65 (1):93–116.doi:10.3368/hopp.65.1.93.ISSN 2694-3034. Retrieved26 January 2025.
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  131. ^Snyder SH, Faillace LA, Weingartner H (July 1969). "A new psychotropic agent. Psychological and physiological effects of 2,5-dimethoxy-4-ethyl amphetamine (DOET) in man".Arch Gen Psychiatry.21 (1):95–101.doi:10.1001/archpsyc.1969.01740190097014.PMID 4389442.
  132. ^Snyder SH, Weingartner H, Faillace LA (January 1971). "DOET (2,5-dimethoxy-4-ethylamphetamine), a new psychotropic drug. Effects of varying doses in man".Arch Gen Psychiatry.24 (1):50–55.doi:10.1001/archpsyc.1971.01750070052006.PMID 4923215.
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  134. ^Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, Lankri D, Duggan P, Nazarova AL, Cao AB, Calkins MM, Khirsariya P, Hwu C, Katritch V, Chandra SS, McCorvy JD, Sames D (January 2023)."Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs".ACS Chemical Neuroscience.14 (1):119–135.doi:10.1021/acschemneuro.2c00597.PMC 10147382.PMID 36521179.We propose the following rationale for the rapid effects of Ariadne in the mouse [Parkinson's disease (PD)] model, as an initial guiding hypothesis for future studies. The in vitro profile suggests that Ariadne's effect on dopamine neurotransmission is indirect, namely not via direct modulation of DAT or dopamine receptors. It has been demonstrated that 5-HT2A agonists increase dopamine release in nucleus accumbens and other regions of the mesolimbic system.43 It is therefore likely that 5-HT2A agonists also stimulate DA release in more dorsal areas of the striatum that are compromised by the PD pathology.
  135. ^Alexander T. Shulgin;Ann Shulgin (1991)."#8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE; 1-(2,5- DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE; 2,5- DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE".PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. pp. 475–480.ISBN 978-0-9630096-0-9.OCLC 25627628.His company did many animal tests, one of which showed that it was not hallucinogenic (a cat whose tail erected dramatically with DOM did nothing with ARIADNE) and another that showed re-motivation (some old maze-running monkeys who had decided not to run any more mazes changed their minds with ARIADNE).
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  148. ^abTaylor 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.
  149. ^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]. [...]
  150. ^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.
  151. ^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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Major chemical drug groups – based upon theAnatomical Therapeutic Chemical Classification System
gastrointestinal tract
/metabolism (A)
blood and blood
forming organs (B)
cardiovascular
system (C)
skin (D)
genitourinary
system (G)
endocrine
system (H)
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infestations (J,P,QI)
malignant disease
(L01–L02)
immune disease
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andjoints (M)
brain and
nervous system (N)
respiratory
system (R)
sensory organs (S)
otherATC (V)
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