Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions
Restricted accessResearch articleFirst published online July, 2024
Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions
Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson’s disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion – substantia nigra pars compacta (SNc), reinforcement/motivation – ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) – VTA; arousal – ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.
AlbericoSLCassellMDNarayananNS (2015) The vulnerable ventral tegmental area in Parkinson’s disease. Basal Ganglia5: 51–55.
2.
AlbrechtSBuergerE (2009) Potential neuroprotection mechanisms in PD: focus on dopamine agonist pramipexole. Curr Med Res Opin25: 2977–2987.
3.
AnastasiadesPGBoadaCCarterAG (2019) Cell-type-specific D1 dopamine receptor modulation of projection neurons and interneurons in the prefrontal cortex. Cereb Cortex29: 3224–3242.
4.
AndrabiSSAliMTabassumH, et al. (2019) Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke. Dis Model Mech12: dmm033860.
5.
AoYYangBZhangC, et al. (2021) Application of quinpirole in the paraventricular thalamus facilitates emergence from isoflurane anesthesia in mice. Brain Behav11: e01903.
6.
ArnulfI (2005) Excessive daytime sleepiness in parkinsonism. Sleep Med Rev9: 185–200.
7.
ArnulfILeu-SemenescuS (2009) Sleepiness in Parkinson’s disease. Parlinsonism Relat Disord15: 101–104.
8.
Aston-JonesGCohenJD (2005) An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance. Ann Rev Neurosci28: 403–450.
9.
BarlowRLGorgesMWearnA, et al. (2018) Ventral striatal D2/3 receptor availability is associated with impulsive choice behavior as well as limbic corticostriatal connectivity. Int J Neuropsychopharmacol21: 705–715.
10.
BeasBSWrightBJSkirzewskiM, et al. (2018) The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nat Neurosci21: 963–973.
11.
BeaulieuJ-MGainetdinovRR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev63: 182–217.
BenarrochEESchmeichelAMDuggerBN, et al. (2009) Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia. Neurology73: 106–112.
14.
BennettJPJrPierceyMF (1999) Pramipexole—a new dopamine agonist for the treatment of Parkinson’s disease. J Neurol Sci163: 25–31.
15.
Benoit-MarandMBorrelliEGononF (2001) Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo. J Neurosci21: 9134–9141.
16.
BéreauMVan Waes ServantM, et al. (2023) Apathy in Parkinson’s disease: clinical patterns and neurobiological basis. Cells12: 1599.
17.
BiglanKMHollowayRG (2002) A review of pramipexole and its clinical utility in Parkinson’s disease. Expert Opin Pharmacother3: 197–210.
18.
BjorklundADunnettSB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci30: 194–202.
BolamJPHanleyJJBoothPAC, et al. (2000) Synaptic organisation of the basal ganglia. J Anat196: 527–542.
21.
BrindaniFVitettaFGemignaniF (2009) Restless legs syndrome: differential diagnosis and management with pramipexole. Clin Interv Aging4: 305–313.
22.
BrodalP (2004) The Central Nervous System: Structure and Function, 3rd edn.Oxford: Oxford University Press.
23.
BuXChenYLvP, et al. (2022a) Glutamatergic neurones in paraventricular nucleus of the thalamus regulate the recovery from isoflurane anesthesia. BMC Anesthesiol22: 256.
24.
BuX-LLiuC-XFuB, et al. (2022b) Research progress of the paraventricular thalamus in the regulation of sleep-wake and emotional behaviors. Ibrain8: 219–226.
25.
BubserMFadelJRJacksonLL, et al. (2005) Dopaminergic regulation of orexin neurons. Eur J Neurosci21: 2993–3001.
26.
CarnicellaSDruiGBouletS, et al. (2014) Implication of dopamine D3 receptor activation in the reversion of Parkinson’s disease-related motivational deficits. Transl Psychiatry4: e401.
27.
CazorlaLde CarvalhoFDChohanMO, et al. (2014) Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron81: 153–164.
28.
ChahineLMAmaraAWVidenovicA (2016) A systematic review of the literature on disorders of sleep and wakefulness in Parkinson’s disease from 2005 to 2015. Sleep Med Rev35: 33–50.
29.
ConnollyBSLangAE (2014) Pharmacological treatment of Parkinson’s disease. JAMA311: 1670–1683.
30.
CroftJLSchroederRTBertramJEA (2017) The goal of locomotion: separating the fundamental task from the mechanisms that accomplish it. Psychon Bull Rev24: 1675–1685.
31.
DautanDKovácsABayasgalanT, et al. (2021) Modulation of motor behavior by the mesencephalic locomotor region. Cell Rep36: 109594.
32.
De MeiCRamosMItakaC, et al. (2009) Getting specialized: presynaptic and postsynaptic dopamine D2 receptors. Curr Opin Pharmacol9: 53–58.
33.
Del TrediciKBraakH (2013) Dysfunction of the locus coeruleus-norepinephrine system and related circuitry in Parkinson disease-related dementia. J Neurol Neurosurg Psychiatry84: 774–783.
34.
DeutchAYGoldsteinMRothRH (1986) Activation of the locus coeruleus induced by selective stimulation of the ventral tegmental area. Brain Res363: 307–314.
35.
DruiGCarnicellaSCarcenacC, et al. (2014) Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson’s disease. Mol Psychiatry19: 358–367.
36.
DurieuxPFBearzattoBGuiducciS, et al. (2009) D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci12: 393–395.
EgusquizaIMunarriz-Cuezva SegarraR, et al. (2021) Characterization of dopamine D2 receptor coupling in post-mortem brain of subjects with schizophrenia. Pharmacol Rep73: 1136–1146.
39.
EilamDSzechtmanH (1989) Biphasic effect of D-2 agonist quinpirole on locomotion and movements. Eur J Pharmacol161: 151–157.
40.
EngelnMFoxMELoboMK (2018) Dopamine is differentially encoded by D2 receptors in striatal subregions. Neuron98: 459–461.
41.
EnglishJGRothBL (2015) Chemogenetics—a transformational and translational platform. JAMA Neurol72: 1361–1366.
42.
EspositoMSArberS (2016) Motor control: illuminating an enigmatic midbrain locomotor center. Curr Biol26: R291–R293.
43.
EtminanMSodhiMSamilA, et al. (2017) Risk of gambling disorder and impulse control disorder with aripiprazole, pramipexole, and ropinirole: a pharmacoepidemiologic study. J Clin Psychopharmacol27: 102–104.
44.
FahnS (2008) The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord23: S497–S508.
45.
FavierMDuranTCarcenacC, et al. (2014) Pramipexole reverses Parkinson’s disease-related motivational deficits in rats. Mov Disord29: 912–920.
46.
FerraioloMHermansE (2023) The complex molecular pharmacology of the dopamine D2 receptor: implications for pramipexole, ropinirole, and rotigotine. Pharmacol Ther245: 108392.
47.
Ferrari-ToninelliGMaccarinelliGUbertiD, et al. (2010) Mitochondria-targeted antioxidant effects of S(−) and (R+) pramipexole. BMC Pharmacol10: 2.
48.
FloranBFloranLSierraA, et al. (1997) D2 receptor-mediated inhibition of GABA release by endogeneous dopamine in the rat globus pallidus. Neurosci Lett237: 1–4.
49.
FordCP (2014) The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience282: 13–22.
50.
FougèreMFlaiveAFrigonA, et al. (2019) Descending dopaminergic control of brainstem locomotor circuits. Curr Opin Physiol8: 30–35.
51.
FrancisTCYanoHDemarestTG, et al. (2019) High-frequency activation of nucleus accumbens D1-MSNs drives excitatory potentiation on D2-MSNs. Neuron103: 432–444.e3.
52.
FreemanACiliaxBBakayR, et al. (2001) Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models. Ann Neurol50: 321–329.
53.
FreezeBSKravitzAVHammackN, et al. (2013) Control of basal ganglia output by direct and indirect pathway projection neurons. J Neurosci33: 18531–18539.
54.
Garcia-RuizPJMartinez CastrilloJCAlonso-CanovasA, et al. (2013) Impulse control disorder in patients with Parkinson’s disease under dopamine agonist therapy: a multicentre study. J Neurol Neurosurg Psychiatry85: 840–844.
55.
GeiblFFHenrichMTOertelWH (2019) Mesencephalic and extramesencephalic dopaminergic systems in Parkinson’s disease. J Neural Transm126: 377–396.
56.
GerfenCRSurmeierDJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci34: 441–466.
GomesPSoares-Da-SilvaP (2002) D2-like receptor-mediated inhibition of Na+-ATPase activity is dependent on the opening of K+ channels. Am J Physiol Renal Physiol283: F114–F123.
59.
GorelovaNAYangCR (2000) Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro. J Neurophysiol84: 75–87.
60.
GovindaiahGCoxCL (2005) Excitatory actions of dopamine via D1-like receptors in the rat lateral geniculate nucleus. J Neurophysiol94: 3708–3718.
61.
GroenewegenHJ (2003) The basal ganglia and motor control. Neural Plast10: 107–120.
62.
GroenewegenHJBerendseHW (1994) The specificity of the ‘nonspecific’ midline and intrathalamic thalamic nuclei. Trends Neurosci17: 52–57.
63.
GroenewegenHJBerendseHWHaberSN (1993) Organization of the output of the ventral striatopallidal system in the rat: ventral pallidal efferents. Neuroscience57: 113–142.
64.
GuMIrvaniMMarJ, et al. (2004) Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem91: 1075–1081.
65.
GuttmanMJaskolkaJ (2001) The use of pramipexole in Parkinson’s disease: are its actions D(3) mediated?. Parkinsonism Relat Disord7: 231–234.
66.
HaberSNGroenewgenHJGroveEA, et al. (1985) Efferent connections of the ventral pallidum: evidence of a dual striato pallidofugal pathway. J Comp Neurol235: 322–335.
67.
HauserRAGaugerLAndersonWM, et al. (2000a) Pramipexole-induced somnolence and episodes of daytime sleep. Mov Disord15: 658–663.
68.
HauserRAWahbaMNAndersonWM (2000b) Modafinil treatment of pramipexole-associated somnolence. Mov Disord15: 1269–1271.
69.
HenzeDAGonzález-Burgos UrbanNN, et al. (2000) Dopamine increases excitability of pyramidal neurons in primate prefrontal cortex. J Neurophysiol84: 2799–2809.
70.
HezemansFHWolpeNO’CallaghanC, et al. (2022) Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes. PLoS Comput Biol18: e1010079.
71.
HikidaTMoritaMMacphersonT (2016) Neural mechanisms of the nucleus accumbens circuit in reward and aversive learning. Neurosci Res108: 1–5.
72.
HikidaTYawataSYamagochiT, et al. (2013) Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors. Proc Natl Acad Sci U S A110: 342–347.
HornykiewiczO (2008) Basic research on dopamine in Parkinson’s disease and the discovery of the nigrostriatal dopamine pathway: the view of an eyewitness. Neurodegener Dis5: 114–117.
76.
HouRHFreemanCLangleyRE, et al. (2005) Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers. Psychopharmacology (Berl) 181: 537–549.
77.
JainSSiegleGJGuC, et al. (2011) Pupillary unrest correlates with arousal symptoms and motor signs in Parkinson disease. Mov Disord26: 1344–1347.
78.
JonesBE (2020) Arousal and sleep circuits. Neuropsychopharmacology45: 6–20.
79.
Jones-TabahJMohammadHPaulusEG, et al. (2022) The signalling and pharmacology of the dopamine D1 receptor. Front Cell Neurosci15: 806618.
KeelerJFPretsellDORobbinsTW (2014) Functional implications of dopamine D1 vs. D2 receptors: a ‘prepare and select’ model of the striatal direct vs. indirect pathways. Neuroscience282: 156–175.
82.
KelbschCStrasserTChenY, et al. (2019) Standards in pupillography. Front Neurol 10: 129.
83.
KimK-M (2023) Unveiling the differences in signalling and regulatory mechanisms between dopamine D2 and D3 receptors and their impact on behavioural sensitization. Int J Mol Sci24: 6742.
84.
KleinMOBattagelloDSCardosoA, et al. (2019) Dopamine: functions, signalling, and association with neurological diseases. Cell Mol Neurobiol39: 31–59.
85.
KolajMZhangLHermesMLH, et al. (2014) Intrinsic properties and neuropharmacology of midline paraventricular thalamic nucleus neurons. Front Behav Neurosci8: 32.
86.
KravitzAVFreezeBSParkerPRL, et al. (2010) Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature466: 622–626.
87.
KreissDSBergstromDAGonzalezAM, et al. (1995) Dopamine receptor agonist potencies for inhibition of cell firing correlate with dopamine D3 receptor binding affinities. Eur J Pharmacol277: 209–214.
KupchikYPrasadAA (2021) Ventral pallidum cellular and pathway specificity in drug seeking. Neurosci Biobehav Rev131: 373–386.
90.
KupchikYMKalivasPW (2017) The direct and indirect pathways of the nucleus accumbens are not what you think. Neuropsychopharmacology42: 368–369.
91.
KupchikYMBrownRMHeinsbroekJA, et al. (2015) Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci28: 1230–1232.
92.
KvernmoTHärtterSBurgerE (2006) A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther28: 1065–1078.
93.
LaceyMGMercuriNBNorthRA (1987) Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta. J Physiol392: 397–416.
94.
LanciegoJLLuquinNObedsoJA (2012) Functional neuroanatomy of the basal ganglia. Cold Spring Harb Perspect Med2: a009621.
LeWDJankovicJXieW, et al. (2000) Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection. J Neural Transm (Vienna) 107: 1165–1173.
97.
LeesAJTolosaEOlanowCW (2015) Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr. Mov Disord30: 19–36.
98.
LewisBLO’DonnellP (2000) Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential ‘up’ states in pyramidal neurons via D1 dopamine receptors. Cereb Cortex10: 1168–1175.
99.
LiJYuTShiF, et al. (2018) Involvement of ventral periaqueductal gray dopaminergic neurons in propofol anesthesia. Neurochem Res43: 838–847.
100.
LidowMSGoldman-RakicPSGallagerDW, et al. (1991) Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390. Neuroscience40: 657–671.
101.
LinJ-SAnacletCSergeevaOA, et al. (2011) The waking brain: an update. Cell Mol Life Sci68: 2499–2512.
102.
LiuCZhouXZhuQ, et al. (2020) Dopamine neurons in the ventral periaqueductal gray modulate isoflurane anesthesia in rats. CNS Neurosci Ther26: 1121–1133.
103.
LiuGJWuLWangSL, et al. (2016) Efficacy of pramipexole for the treatment of primary restless leg syndrome: a systematic review and meta-analysis of randomized clinical trials. Clin Ther38: 162–179.
104.
LoewenfeldIE (1993) The Pupil: Anatomy, Physiology, and Clinical Applications. Detroit, MI: Wayne State University Press.
105.
LopezAMWeintraubDClaassenDO (2017) Impulse control disorders and related complications of Parkinson’s disease therapy. Semin Neurol37: 186–192.
106.
Loued-KhenissiLPreuschoffK (2015) Apathy and noradrenaline: silent partners to mild cognitive impairment in Parkinson’s disease?Curr Opin Neurol28: 344–350.
107.
LuJJhouTCSaperCB (2006) Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci26: 193–202.
108.
LüdtkeHWilhelmBAdlerM, et al. (1998) Mathematical procedures in data recording and processing of pupillary fatigue waves. Vision Res38: 2889–2896.
109.
LuoY-JGeJChenZ-K, et al. (2023) Ventral pallidal glutamatergic neurons regulate wakefulness and emotion through separated projections. iScience26: 107385.
110.
LuoY-JLiY-DWangL, et al. (2018) Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors. Nat Commun9: 1576.
111.
LuppiP-HFortP (2019) Neuroanatomical and neurochemical bases of vigilance states. Handb Exp Pharmacol253: 35–58.
112.
MaTP (2006) The basal nuclei. In: HainesDE (ed.) Fundamental Neuroscience for Basic and Clinical Applications. Philadelphia: Churchill Livingstone Elsevier, pp. 414–430.
113.
MaedaTKitahamaKGeffardM (1994) Dopaminergic innervation of rat locus coeruleus: a light and electron microscopic immunohistochemical study. Microsc Res Tech29: 211–218.
114.
MagnardRVachezYCarcenacC, et al. (2016) What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson’s disease?Transl Psychiatry6: 753.
115.
MajJRogózZSkuzaG, et al. (1997) The behavioural effects of pramipexole, a novel dopamine receptor agonist. Eur J Pharmacol324: 31–37.
116.
MannourylaCourCVidalSPasteauV, et al. (2007) Dopamine D1 receptor coupling to Gs/olf and Gq in rat striatum and cortex: a scintillation proximity assay (SPD)/antibody-capture characterisation of benzapine agonists. Neuropharmacology52: 1003–1014.
117.
MansourAWatsonSJ (1995) Dopamine receptor expression in the central nervous system. In: FEBloomDJKupfer (ed.) Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 207–219.
118.
MarcottPFGongSDonthamsettiP, et al. (2018) Regional heterogeneity of D2-receptor signalling in the dorsal striatum and nucleus accumbens. Neuron98: 575–587.
119.
MartelJCMcArthurSG (2020) Dopamine receptor subtypes, physiology and pharmacology: new ligands and concepts in schizophrenia. Front Pharmacol11: 1003.
120.
MeleBVanSHolroyd-LeducJ, et al. (2020) Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. BMJ Open10: e037632.
121.
MicallefJReyMEusebioA, et al. (2009) Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects. Br J Clin Pharmacol67: 333–340.
122.
MontiJMMontiD (2007) The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev11: 113–133.
123.
MierauJSchneiderFJEnsingerHA, et al. (1995) Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors. Eur J Pharmacol290: 29–36.
124.
MontiJMJantosHFernándezM (1989) Effects of the selective dopamine D-2 receptor agonist, quinpirole on sleep and wakefulness in the rat. Eur J Pharmacol169: 61–66.
125.
MoruzziGMagounHW (1949) Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol1: 455–473.
126.
NakanishiSHikidaTYawataS. (2014) Distinct dopaminergic control of the direct and indirect pathways in reward-based and avoidance learning behaviour. Neuroscience282: 49–59.
127.
NieuwenhuysR (1985) Chemoarchitecture of the Brain. Berlin: Springer-Verlag.
OishiYLazarusM (2017) The control of sleep and wakefulness by mesolimbic dopamine systems. Neurosci Res118: 66–73.
130.
OishiYSuzukiYTakahashiK, et al. (2017) Activation of ventral tegmental area dopamine neurons produces wakefulness through dopamine D2-like receptors in mice. Brain Struct Funct222: 2907–2915.
131.
OlivettiPRBalsamPDSimpsonE, et al. (2020) Emerging roles of striatal dopamine D2 receptors in motivated behaviour: implications for psychiatric disorders. Basic Clin Pharmacol Toxicol126: 47–55.
132.
OrnsteinKMilonHMc-Rae-DegueurceA, et al. (1987) Biochemical and radioautographic evidence for dopaminergic afferents of the locus coeruleus originating in the ventral tegmental area. J Neural Transm70: 183–191.
133.
PagonabarragaJKulisevskyJ (2017) Apathy in Parkinson’s disease. Int Rev Neurobiol1333: 657–678.
134.
PausSBrechtHMKösterJ, et al. (2003) Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord18: 659–667.
135.
PerreaultM-CGloverJC (2013) Glutamatergic reticulospinal neurons in the mouse: developmental origins, axon projections, and functional connectivity. Ann N Y Acad Sci1279: 80–89.
136.
PierceyMFHoffmannWESmithMW, et al. (1996) Inhibition of dopamine neuron firing by pramipexole, a dopamine D£ receptor preferring agonist: comparison to the dopamine receptor agonists. Eur J Pharmacol312: 35–44.
137.
PoddaMVRicardiED’AscenzoM, et al. (2010) Dopamine D1-like receptor activation depolarizes medium spiny neurons of the mouse nucleus accumbens by inhibiting inwardly rectifying K+ currents through a cAMP-dependent protein kinase A-independent mechanism. Neuroscience167: 678–690.
138.
Porter-StranskyKCentanniSWKarneSL, et al. (2019) Noradrenergic transmission at alpha1-asrenergic receptors in the ventral periaqueductal gray modulates arousal. Biol Psychiatry85: 237–247.
139.
RenSWangYYueF, et al. (2018) The paraventricular thalamus is a critical thalamic area for wakefulness. Science362: 429–434.
140.
RichfieldEKYoungABPenneyJB (1989) Comparative distributions of dopamine D-1 and D-2 receptors in the cerebral cortex of rats, cats, and monkeys. J Comp Neurol286: 409–426.
141.
RobinsonSESohalVS (2017) Dopamine D2 receptors modulate pyramidal neurons in mouse medial prefrontal cortex through a stimulatory G-protein pathway. J Neurosci37: 10063–10073.
142.
RootDHMelendezRIZaborskyL, et al. (2015) The ventral pallidum: subregion-specific functional anatomy and roles in motivated behaviors. Prog Neurobiol130: 29–70.
143.
RoseberryTKLeeAMLaliveAL, et al. (2016) Cell-type-specific control of brainstem locomotor circuits by basal ganglia. Cell164: 526–537.
144.
RyczkoDJacksonJCAlpertMH (2016) A descending dopamine pathway conserved from basal vertebrates to mammals. Proc Natl Acad Sci U S A113: E2440–E2449.
145.
SaalmannYB (2014) Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition. Front Syst Neurosci8: 83.
146.
SamuelsERSzabadiE (2008) Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alteration of locus coeruleus activity in humans. Curr Neuropharmacol6: 254–285.
147.
SamuelsERHouRHLangleyRW, et al. (2006a) Comparison of pramipexole and modafinil on arousal, autonomic and endocrine functions in healthy volunteers. J Psychopharmacol20: 756–770.
148.
SamuelsERHouRHLangleyRW, et al. (2006b) Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers. Psychopharmacology (Berl) 187: 498–510.
149.
SamuelsERHouRHLangleyRW, et al. (2007) Comparison of pramipexole with and without domperidone on alertness, autonomic and endocrine functions in healthy volunteers. Br J Clin Pharmacol64: 591–602.
150.
ScammellTEArrigoniELiptonJO (2017) Neural circuitry of wakefulness and sleep. Neuron93: 747–765.
151.
SeemanP (2015) Parkinson’s disease treatment may Cause impulse-control disorder via dopamine D3 receptors. Synapse69: 183–189.
152.
SeidelKMahlkeJSiswantoS, et al. (2015) The brainstem pathologies of Parkinson’s disease and dementia with Lewy bodies. Brain Pathol25: 121–135.
ShaoY-FLinJ-SHouY-P (2019) Paraventricular thalamus as a major thalamic structure for wake control. Neurosci Bull35: 946–948.
155.
SharmaSKimLHMyrKA, et al. (2018) Parallel descending dopaminergic connectivity of A13 cells to the brainstem locomotor centers. Sci Rep8: 7972.
156.
SierraMCarnicellaSStrafellaAP, et al. (2015) Apathy and impulse control disorders: Yin & Yang of dopamine dependent behaviors. J Parkinsons Dis5: 625–636.
157.
SinhaNManoharSHusainM (2013) Impulsivity and apathy in Parkinson’s disease. J Neuropsychol7: 255–283.
158.
SmithKSTindellAJAldridgeJW, et al. (2009) Ventral pallidum roles in reward and motivation. Behav Brain Res196: 155–167.
159.
Soares-CunhaACoimbraBDavid-PeeiraA, et al. (2016a) Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation. Nat Commun7: 11829.
160.
Soares-CunhaACoimbraBDominguesAV, et al. (2018) Nucleus accumbens microcircuit underlying D2-MSN-driven increase in motivation. eNeuro5: ENEURO.0386-18.2018.
161.
Soares-CunhaCHeinsbroekJA (2023) Ventral pallidal regulation of motivated behaviors and reinforcement. Front Neural Circuits17: 1086053.
162.
Soares-CunhaCCoimbraBSousaN, et al. (2016b) Reappraising striatal D1- and D2-neurons in reward and aversion. Neurosci Biobehav Rev68: 370–386.
163.
Soares-CunhaCde VasoncelosNAPCoimbraB, et al. (2020) Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion. Mol Psychiatry25: 3241–3255.
164.
Soares-CunhaCDominguesAVCorreiraR, et al. (2022) Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior. Cell Rep38: 110380.
165.
SunH-XWangD-RYeC-B, et al. (2017) Activation of the ventral tegmental area increased wakefulness in mice. Sleep Biol Rhythms15: 107–115.
166.
SurmeierDJCarrillo-ReidFBargasJ (2011) Dopaminergic modulation of striatal neurons, circuits, and assemblies. Neuroscience198: 3–18.
167.
SurmeierDJDingJDayM, et al. (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signalling in striatal medium spiny neurons. Trends Neurosci30: 228–235.
168.
SurmeierDJGravesSMShenW (2014) Dopaminergic modulation of striatal networks in health and Parkinson’s disease. Curr Opin Neurobiol29: 109–117.
169.
SvenningssonPNishiAFisoneG, et al. (2004) DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol44: 269–296.
170.
SzabadiE (2008) The integrated control of arousal and pupil function: role of the noradrenergic locus coeruleus. Neuro-ophthalmol Jpn25: 176–189.
171.
SzabadiE (2015) Neuronal networks regulating sleep and arousal: effect of drugs. In: AGuglietta (ed.) Drug Treatment of Sleep Disorders. Cham, Switzerland: Springer, pp. 25–70.
172.
SzabadiE (2018) Functional organization of the sympathetic pathways controlling the pupil: light-inhibited and light-stimulated pathways. Front Neurol9: 1069.
173.
TamaeANakatsukaTKogaK, et al. (2005) Direct inhibition of substantia gelatinosa neurones in the rat spinal cord by activation of dopamine D2-like receptors. J Physiol568: 243–253.
TaylorNEVan DortCJKennyJD, et al. (2016) Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia. Proc Natl Acad Sci U S A113: 12826–12831.
176.
ThoboisSLhomméeEKlingerH, et al. (2013) Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain136: 1568–1577.
177.
TundoAde FilippisRDe CescenzoF (2019) Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis. Acta Psychiatr Scand140: 116–125.
178.
VallarLMeldolesiJ (1989) Mechanisms of signal transduction at the dopamine D2 receptor. Trends Pharmacol Sci10: 74–77.
179.
Van der WerfYDWitterMPGroenewegenHJ (2002) The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness. Brain Res Brain Res Rev39: 107–140.
180.
VertesRPLinleySBRojasAKP (2022) Structural and functional organization of the midline and intralaminar nuclei of the thalamus. Front Behav Neurosci16: 964644.
181.
VlasovKVan DortCJSoltK (2018) Optogenetics and chemogenetics. Methods Enzymol603: 181–196.
182.
VolkowNDFowlerJSLoganJ, et al. (2009) Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA301: 1148–1154.
183.
VolkowNDWiseRABakerR (2017) The dopamine motive system: implications for drug and food addiction. Nat Rev Neurosci18: 741–752.
184.
WallNRDe La ParraMCallawayEM, et al. (2013) Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron79: 347–360.
185.
WangJMiaoXSunY, et al, (2023a) Dopaminergic system in promoting recovery from general anesthesia. Brain Sci13: 538.
186.
WangY-LWangLXuW, et al. (2023b) Paraventricular thalamus controls consciousness transitions during propofol anaesthesia in mice. Br J Anaesth130: 698–708.
187.
WhiteNM (2011) Reward: what is it? How can it be inferred from behaviour? In: GottfriedJA (ed.) Neurobiology of Sensation and Reward, chapter 3. Boca Raton, FL: CRC Press/Taylor and Francis.
188.
WilsonSMWurstMGWhatleyMF, et al. (2020) Classics in chemical neuroscience: pramipexole. ACS Chem Neurosci11: 2506–2512.
189.
WisorJ (2013) Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol4: 139.
190.
WisorJP (2019) Dopamine and wakefulness: pharmacology, genetics, and circuitry. Handb Exp Pharmacol253: 321–335.
191.
WisorJPNishinoSSoraI, et al. (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci21: 1787–1794.
192.
WolfschlagMHåkanssonA (2021) Increased risk for developing gambling disorder under the treatment with pramipexole, ropinirole and aripiprazole: a nationwide register study in Sweden. PLoS One16: e0252516.
193.
YangY-FDongHShenY, et al. (2020) Mesencephalic dopamine neurons are essential for modafinil-induced arousal. Br J Pharmacol178: 4808–4825.
194.
YelnickJ (2002) Functional anatomy of the basal ganglia. Mov Disord17: S15–S21.
195.
YeungEYHCavannaAE (2014) Sleep attacks in patients with Parkinson’s disease on dopaminergic medications: a systematic review. Mov Disord Clin Pract1: 307–316.
196.
ZahmDS (1989) The ventral striatopallidal parts of the basal ganglia in the rat—II. Compartmentation of ventral pallidal efferents. Neuroscience30: 33–50.
