Abstract
It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56–72.
Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.[comment]. Proc Natl Acad Sci USA. 2000;97:8104–9.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment: meta-analysis of imaging studies. Arch Gen Psychiatry. 2012;66:13–20.
Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A. Pathway-specific dopamine abnormalities in schizophrenia. Biol Psychiatry. 2017;81:31–42.
Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M, et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry. 2010;67:231–9.
Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology. 2009;56:3–8.
Wang GJ, Volkow ND, Thanos PK, Fowler JS. Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. J Addict Dis. 2004;23:39–53.
Friston KJ. Hallucinations and perceptual inference. Behav brain Sci. 2005;28:764–6.
Powers AR, Mathys C, Corlett PR. Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors. Science. 2017;357:596–600.
Cassidy CM, Balsam PD, Weinstein JJ, Rosengard RJ, Slifstein M, Daw ND, et al. A perceptual inference mechanism for hallucinations linked to striatal dopamine. Curr Biol. 2018;28:503–14 e504.
Schmack K, Bosc M, Ott T, Sturgill JF, Kepecs A. Striatal dopamine mediates hallucination-like perception in mice. Science. 2021;372:eabf4740.
Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989;12:366–75.
Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011;34:441–66.
Parent A, Sato F, Wu Y, Gauthier J, Levesque M, Parent M. Organization of the basal ganglia: the importance of axonal collateralization. Trends Neurosci. 2000;23:S20–27.
Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, et al. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron. 2014;81:153–64.
Saunders A, Oldenburg IA, Berezovskii VK, Johnson CA, Kingery ND, Elliott HL, et al. A direct GABAergic output from the basal ganglia to frontal cortex. Nature. 2015;521:85–9.
Mallet N, Micklem BR, Henny P, Brown MT, Williams C, Bolam JP, et al. Dichotomous organization of the external globus pallidus. Neuron. 2012;74:1075–86.
Hernandez VM, Hegeman DJ, Cui Q, Kelver DA, Fiske MP, Glajch KE, et al. Parvalbumin+ neurons and Npas1+ neurons are distinct neuron classes in the mouse external globus pallidus. J Neurosci. 2015;35:11830–47.
Abecassis ZA, Berceau BL, Win PH, Garcia D, Xenias HS, Cui Q, et al. Npas1(+)-Nkx2.1(+) neurons are an integral part of the cortico-pallido-cortical loop. J Neurosci. 2020;40:743–68.
Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C. Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience. 1991;41:89–125.
Zahm DS. The ventral striatopallidal parts of the basal ganglia in the rat–II. Compartmentation of ventral pallidal efferents. Neuroscience. 1989;30:33–50.
Kupchik YM, Brown RM, Heinsbroek JA, Lobo MK, Schwartz DJ, Kalivas PW. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci. 2015;18:1230–2.
Lu XY, Ghasemzadeh MB, Kalivas PW. Expression of D1 receptor, D2 receptor, substance P and enkephalin messenger RNAs in the neurons projecting from the nucleus accumbens. Neuroscience. 1998;82:767–80.
Baimel C, McGarry LM, Carter AG. The projection targets of medium spiny neurons govern cocaine-evoked synaptic plasticity in the nucleus accumbens. Cell Rep. 2019;28:2256–63 e2253.
Wang H, Pickel VM. Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus. J Comp Neurol. 2002;442:392–404.
Bamford NS, Zhang H, Schmitz Y, Wu NP, Cepeda C, Levine MS, et al. Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron. 2004;42:653–63.
Clark AM, Leroy F, Martyniuk KM, Feng W, McManus E, Bailey MR, et al. Dopamine D2 Receptors in the Paraventricular Thalamus Attenuate Cocaine Locomotor Sensitization. eNeuro. 2017;4:ENEURO.0227-17.2017..
Bocarsly ME, da Silva ESD, Kolb V, Luderman KD, Shashikiran S, Rubinstein M, et al. A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors. Cell Rep. 2019;29:1147–63 e1145.
Aghajanian GK, Bunney BS. Dopamine“autoreceptors”: pharmacological characterization by microiontophoretic single cell recording studies. Naunyn Schmiedebergs Arch Pharm. 1977;297:1–7.
Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014;282:13–22.
De Camilli P, Macconi D, Spada A. Dopamine inhibits adenylate cyclase in human prolactin-secreting pituitary adenomas. Nature. 1979;278:252–4.
Greengard P, Allen PB, Nairn AC. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron. 1999;23:435–47.
Lacey MG, Mercuri NB, North RA. Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta. J Physiol. 1987;392:397–416.
Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H, et al. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade. J Neurosci. 2000;20:8987–95.
Yan Z, Song WJ, Surmeier J. D2 dopamine receptors reduce N-type Ca2+ currents in rat neostriatal cholinergic interneurons through a membrane-delimited, protein-kinase-C-insensitive pathway. J Neurophysiol. 1997;77:1003–15.
Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA. Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature. 1996;380:258–62.
Ikeda SR. Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits. Nature. 1996;380:255–8.
Martel P, Leo D, Fulton S, Berard M, Trudeau LE. Role of Kv1 potassium channels in regulating dopamine release and presynaptic D2 receptor function. PLoS One. 2011;6:e20402.
Cooper AJ, Stanford IM. Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABA(A) IPSCs in vitro. Neuropharmacology. 2001;41:62–71.
Floran B, Floran L, Sierra A, Aceves J. D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus. Neurosci Lett. 1997;237:1–4.
Tecuapetla F, Koos T, Tepper JM, Kabbani N, Yeckel MF. Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals. J Neurosci. 2009;29:8977–90.
Dobbs LK, Kaplan AR, Lemos JC, Matsui A, Rubinstein M, Alvarez VA. Dopamine regulation of lateral inhibition between striatal neurons gates the stimulant actions of cocaine. Neuron. 2016;90:1100–13.
Gallo EF, Meszaros J, Sherman JD, Chohan MO, Teboul E, Choi CS, et al. Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum. Nat Commun. 2018;9:1086.
Chuhma N, Mingote S, Moore H, Rayport S. Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling. Neuron. 2014;81:901–12.
Kharkwal G, Brami-Cherrier K, Lizardi-Ortiz JE, Nelson AB, Ramos M, Del Barrio D, et al. Parkinsonism driven by antipsychotics originates from dopaminergic control of striatal cholinergic interneurons. Neuron. 2016;91:67–78.
Augustin SM, Chancey JH, Lovinger DM. Dual dopaminergic regulation of corticostriatal plasticity by cholinergic interneurons and indirect pathway medium spiny neurons. Cell Rep. 2018;24:2883–93.
Lefkowitz RJ, Inglese J, Koch WJ, Pitcher J, Attramadal H, Caron MG. G-protein-coupled receptors: regulatory role of receptor kinases and arrestin proteins. Cold Spring Harb Symp Quant Biol. 1992;57:127–33.
Shenoy SK, Lefkowitz RJ. beta-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharm Sci. 2011;32:521–33.
Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005;122:261–73.
Beaulieu JM, Tirotta E, Sotnikova TD, Masri B, Salahpour A, Gainetdinov RR, et al. Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci. 2007;27:881–5.
Wei J, Liu W, Yan Z. Regulation of AMPA receptor trafficking and function by glycogen synthase kinase 3. J Biol Chem. 2010;285:26369–76.
Girgis RR, Slifstein M, Brucato G, Kegeles LS, Colibazzi T, Lieberman JA, et al. Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [(11)C]-(+)-PHNO PET with methylphenidate challenge study. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-00934-w.
Salamone JD, Correa M, Farrar A, Mingote SM. Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacol (Berl). 2007;191:461–82.
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66:13–20.
Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.[see comment]. Neuron. 2006;49:603–15.
Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med. 1998;42:211–21.
Drew MR, Simpson EH, Kellendonk C, Herzberg WG, Lipatova O, Fairhurst S, et al. Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing. J Neurosci. 2007;27:7731–9.
Bach ME, Simpson EH, Kahn L, Marshall JJ, Kandel ER, Kellendonk C. Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning. Proc Natl Acad Sci USA. 2008;105:16027–32.
Duvarci S, Simpson EH, Schneider G, Kandel ER, Roeper J, Sigurdsson T. Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression. Nat Commun. 2018;9:2822.
Ward RD, Simpson EH, Richards VL, Deo G, Taylor K, Glendinning JI, et al. Dissociation of hedonic reaction to reward and incentive motivation in an animal model of the negative symptoms of schizophrenia. Neuropsychopharmacology. 2012;37:1699–707.
Bailey MR, Chun E, Schipani E, Balsam PD, Simpson EH. Dissociating the effects of dopamine D2 receptors on effort-based versus value-based decision making using a novel behavioral approach. Behav Neurosci. 2020;134:101–18.
Filla I, Bailey MR, Schipani E, Winiger V, Mezias C, Balsam PD, et al. Striatal dopamine D2 receptors regulate effort but not value-based decision making and alter the dopaminergic encoding of cost. Neuropsychopharmacology. 2018;43:2180–9.
Hodos W. Progressive ratio as a measure of reward strength. Science. 1961;134:943–4.
Bailey MR, Jensen G, Taylor K, Mezias C, Williamson C, Silver R, et al. Dissecting goal-directed action and arousal components of motivated behavior. Behav Neurosci. 2015;129:269–80.
Simpson EH, Waltz JA, Kellendonk C, Balsam PD. Schizophrenia in translation: dissecting motivation in schizophrenia and rodents. Schizophr Bull. 2012;38:1111–7.
Gard DE, Kring AM, Gard MG, Horan WP, Green MF. Anhedonia in schizophrenia: distinctions between anticipatory and consummatory pleasure. Schizophr Res. 2007;93:253–60.
Gold JM, Strauss GP, Waltz JA, Robinson BM, Brown JK, Frank MJ. Negative symptoms of schizophrenia are associated with abnormal effort-cost computations. Biol Psychiatry. 2013;74:130–6.
Treadway MT, Peterman JS, Zald DH, Park S. Impaired effort allocation in patients with schizophrenia. Schizophr Res. 2015;161:382–5.
Barch DM, Treadway MT, Schoen N. Effort, anhedonia, and function in schizophrenia: reduced effort allocation predicts amotivation and functional impairment. J Abnorm Psychol. 2014;123:387–97.
Cazorla M, Shegda M, Ramesh B, Harrison NL, Kellendonk C. Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels. J Neurosci. 2012;32:2398–409.
Simpson EH, Kellendonk C, Ward RD, Richards V, Lipatova O, Fairhurst S, et al. Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of schizophrenia. Biol Psychiatry. 2011;69:928–35.
Krabbe S, Duda J, Schiemann J, Poetschke C, Schneider G, Kandel ER, et al. Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. Proc Natl Acad Sci USA. 2015;112:E1498–1506.
Aberman JE, Ward SJ, Salamone JD. Effects of dopamine antagonists and accumbens dopamine depletions on time-constrained progressive-ratio performance. Pharm Biochem Behav. 1998;61:341–8.
Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD, Taylor KM, et al. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol Psychiatry. 2013;18:1025–33.
Gallo EF, Salling MC, Feng B, Moron JA, Harrison NL, Javitch JA, et al. Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption. Neuropsychopharmacology. 2015;40:1609–18.
Mayorga AJ, Popke EJ, Fogle CM, Paule MG. Similar effects of amphetamine and methylphenidate on the performance of complex operant tasks in rats. Behav Brain Res. 2000;109:59–68.
Phillips PE, Walton ME, Jhou TC. Calculating utility: preclinical evidence for cost-benefit analysis by mesolimbic dopamine. Psychopharmacol (Berl). 2007;191:483–95.
Augustin SM, Loewinger GC, O’Neal TJ, Kravitz AV, Lovinger DM. Dopamine D2 receptor signaling on iMSNs is required for initiation and vigor of learned actions. Neuropsychopharmacology. 2020;45:2087–97.
Carvalho Poyraz F, Holzner E, Bailey MR, Meszaros J, Kenney L, Kheirbek MA, et al. Decreasing striatopallidal pathway function enhances motivation by energizing the initiation of goal-directed action. J Neurosci. 2016;36:5988–6001.
Natsubori A, Tsutsui-Kimura I, Nishida H, Bouchekioua Y, Sekiya H, Uchigashima M, et al. ventrolateral striatal medium spiny neurons positively regulate food-incentive, goal-directed behavior independently of D1 and D2 selectivity. J Neurosci. 2017;37:2723–33.
Soares-Cunha C, Coimbra B, Sousa N, Rodrigues AJ. Reappraising striatal D1- and D2-neurons in reward and aversion. Neurosci Biobehav Rev. 2016;68:370–86.
Olivetti PR, Balsam PD, Simpson EH, Kellendonk C. Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders. Basic Clin Pharm Toxicol. 2020;126:47–55.
Farrar AM, Font L, Pereira M, Mingote S, Bunce JG, Chrobak JJ, et al. Forebrain circuitry involved in effort-related choice: Injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior. Neuroscience. 2008;152:321–30.
Vachez YM, Tooley JR, Abiraman K, Matikainen-Ankney B, Casey E, Earnest T, et al. Ventral arkypallidal neurons inhibit accumbal firing to promote reward consumption. Nat Neurosci. 2021;24:379–90.
Ferrario CR, Labouebe G, Liu S, Nieh EH, Routh VH, Xu S, et al. Homeostasis meets motivation in the battle to control food intake. J Neurosci. 2016;36:11469–81.
Michaelides M, Miller ML, DiNieri JA, Gomez JL, Schwartz E, Egervari G, et al. Dopamine D2 receptor signaling in the nucleus accumbens comprises a metabolic-cognitive brain interface regulating metabolic components of glucose reinforcement. Neuropsychopharmacology. 2017;42:2365–76.
Friend DM, Devarakonda K, O’Neal TJ, Skirzewski M, Papazoglou I, Kaplan AR, et al. Basal ganglia dysfunction contributes to physical inactivity in obesity. Cell Metab. 2017;25:312–21.
Welch AC, Zhang J, Lyu J, McMurray MS, Javitch JA, Kellendonk C, et al. Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0633-8.
Labouesse MA, Sartori AM, Weinmann O, Simpson EH, Kellendonk C, Weber-Stadlbauer U. Striatal dopamine 2 receptor upregulation during development predisposes to diet-induced obesity by reducing energy output in mice. Proc Natl Acad Sci USA. 2018;115:10493–8.
Berthoud HR, Munzberg H. The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics. Physiol Behav. 2011;104:29–39.
Straub C, Tritsch NX, Hagan NA, Gu C, Sabatini BL. Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents. J Neurosci. 2014;34:8557–69.
Wieland S, Du D, Oswald MJ, Parlato R, Kohr G, Kelsch W. Phasic dopaminergic activity exerts fast control of cholinergic interneuron firing via sequential NMDA, D2, and D1 receptor activation. J Neurosci. 2014;34:11549–59.
Gallo EF, Greenwald J, Teboul E, Martyniuk K, Li Y, Javitch JA, et al. Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning. BioRxiv. 2020. https://doi.org/10.1101/2020.09.07.284612.
Sulzer D, Cragg SJ, Rice ME. Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. 2016;6:123–48.
Bello EP, Mateo Y, Gelman DM, Noain D, Shin JH, Low MJ, et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci. 2011;14:1033–8.
Holroyd KB, Adrover MF, Fuino RL, Bock R, Kaplan AR, Gremel CM, et al. Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues. Neuropsychopharmacology. 2015;40:1495–509.
de Jong JW, Roelofs TJ, Mol FM, Hillen AE, Meijboom KE, Luijendijk MC, et al. Reducing ventral tegmental dopamine D2 receptor expression selectively boosts incentive motivation. Neuropsychopharmacology. 2015;40:2085–95.
Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, et al. Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci USA. 2011;108:18488–93.
Urs NM, Gee SM, Pack TF, McCorvy JD, Evron T, Snyder JC, et al. Distinct cortical and striatal actions of a beta-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci USA. 2016;113:E8178–E8186.
Donthamsetti P, Gallo EF, Buck DC, Stahl EL, Zhu Y, Lane JR, et al. Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Mol Psychiatry. 2020;25:2086–100.
Rose SJ, Pack TF, Peterson SM, Payne K, Borrelli E, Caron MG. Engineered D2R variants reveal the balanced and biased contributions of g-protein and beta-arrestin to dopamine-dependent functions. Neuropsychopharmacology. 2018;43:1164–73.
Dobbs LK, Kaplan AR, Bock R, Phamluong K, Shin JH, Bocarsly ME, et al. D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors. Neuropsychopharmacology. 2019;44:805–16.
Kozorovitskiy Y, Saunders A, Johnson CA, Lowell BB, Sabatini BL. Recurrent network activity drives striatal synaptogenesis. Nature. 2012;485:646–50.
Lieberman OJ, McGuirt AF, Mosharov EV, Pigulevskiy I, Hobson BD, Choi S, et al. Dopamine triggers the maturation of striatal spiny projection neuron excitability during a critical period. Neuron. 2018;99:540–54 e544.
Wong DF, Wagner HN Jr., Tune LE, Dannals RF, Pearlson GD, Links JM, et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics.[erratum appears in Science 1987 Feb 6;235(4789):623]. Science. 1986;234:1558–63.
Brugger SP, Angelescu I, Abi-Dargham A, Mizrahi R, Shahrezaei V, Howes OD. Heterogeneity of striatal dopamine function in schizophrenia: meta-analysis of variance. Biol Psychiatry. 2020;87:215–24.
Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M. Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry. 2009;65:1091–3.
Kegeles LS, Slifstein M, Xu X, Urban N, Thompson JL, Moadel T, et al. Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography. Biol Psychiatry. 2010;68:634–41.
Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu JM, Gainetdinov RR, et al. Antagonism of dopamine D2 receptor/{beta}-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci USA. 2008;105:13656–61.
Avlar B, Kahn JB, Jensen G, Kandel ER, Simpson EH, Balsam PD. Improving temporal cognition by enhancing motivation. Behav Neurosci. 2015;129:576–88.
Ward RD, Kellendonk C, Simpson EH, Lipatova O, Drew MR, Fairhurst S, et al. Impaired timing precision produced by striatal D2 receptor overexpression is mediated by cognitive and motivational deficits. Behav Neurosci. 2009;123:720–30.
Hamill S, Trevitt JT, Nowend KL, Carlson BB, Salamone JD. Nucleus accumbens dopamine depletions and time-constrained progressive ratio performance: effects of different ratio requirements. Pharm Biochem Behav. 1999;64:21–7.
Bari AA, Pierce RC. D1-like and D2 dopamine receptor antagonists administered into the shell subregion of the rat nucleus accumbens decrease cocaine, but not food, reinforcement. Neuroscience. 2005;135:959–68.
Sokolowski JD, Salamone JD. The role of accumbens dopamine in lever pressing and response allocation: effects of 6-OHDA injected into core and dorsomedial shell. Pharm Biochem Behav. 1998;59:557–66.
Acknowledgements
This manuscript has been based on research funded by NIH MH107648 for E.F.G., NIH MH068073 for P.B, NIH MH054137 and Hope for Depression Research Foundation for J.A.J. and NIH MH093672 for C.K. Figures were created with BioRender.com.
Author information
Authors and Affiliations
Contributions
EHS, EFG and CK wrote the initial version and edited the manuscript. PB and JAJ added to and edited the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Simpson, E.H., Gallo, E.F., Balsam, P.D. et al. How changes in dopamine D2 receptor levels alter striatal circuit function and motivation. Mol Psychiatry 27, 436–444 (2022). https://doi.org/10.1038/s41380-021-01253-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-021-01253-4
This article is cited by
-
Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification
Molecular Psychiatry (2023)
-
Translational profiling of mouse dopaminoceptive neurons reveals region-specific gene expression, exon usage, and striatal prostaglandin E2 modulatory effects
Molecular Psychiatry (2022)