Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion

Molecular Psychiatry volume 25, pages 2070–2085 (2020)Cite this article

Subjects

Abstract

Although long-studied in the central nervous system, there is increasing evidence that dopamine (DA) has important roles in the periphery including in metabolic regulation. Insulin-secreting pancreatic β-cells express the machinery for DA synthesis and catabolism, as well as all five DA receptors. In these cells, DA functions as a negative regulator of glucose-stimulated insulin secretion (GSIS), which is mediated by DA D2-like receptors including D2 (D2R) and D3 (D3R) receptors. However, the fundamental mechanisms of DA synthesis, storage, release, and signaling in pancreatic β-cells and their functional relevance in vivo remain poorly understood. Here, we assessed the roles of the DA precursor l-DOPA in β-cell DA synthesis and release in conjunction with the signaling mechanisms underlying DA’s inhibition of GSIS. Our results show that the uptake of l-DOPA is essential for establishing intracellular DA stores in β-cells. Glucose stimulation significantly enhances l-DOPA uptake, leading to increased DA release and GSIS reduction in an autocrine/paracrine manner. Furthermore, D2R and D3R act in combination to mediate dopaminergic inhibition of GSIS. Transgenic knockout mice in which β-cell D2R or D3R expression is eliminated exhibit diminished DA secretion during glucose stimulation, suggesting a new mechanism where D2-like receptors modify DA release to modulate GSIS. Lastly, β-cell-selective D2R knockout mice exhibit marked postprandial hyperinsulinemia in vivo. These results reveal that peripheral D2R and D3R receptors play important roles in metabolism through their inhibitory effects on GSIS. This opens the possibility that blockade of peripheral D2-like receptors by drugs including antipsychotic medications may significantly contribute to the metabolic disturbances observed clinically.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Fleischhacker WW, Siu CO, Boden R, Pappadopulos E, Karayal ON, Kahn RS et al. Metabolic risk factors in first-episode schizophrenia: baseline prevalence and course analysed from the European First-Episode Schizophrenia Trial. Int J Neuropsychopharmacol. 2013;16:987–95.

  2. Fabrazzo M, Monteleone P, Prisco V, Perris F, Catapano F, Tortorella A, et al. Olanzapine is faster than haloperidol in inducing metabolic abnormalities in schizophrenic and bipolar patients. Neuropsychobiology. 2015;72:29–36.

    Article  CAS  PubMed  Google Scholar 

  3. Freyberg Z, Aslanoglou D, Shah R, Ballon JS. Intrinsic and antipsychotic drug-induced metabolic dysfunction in schizophrenia. Front Neurosci. 2017;11:432.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rajkumar AP, Horsdal HT, Wimberley T, Cohen D, Mors O, Borglum AD, et al. Endogenous and antipsychotic-related risks for diabetes mellitus in young people with schizophrenia: a Danish population-based cohort study. Am J Psychiatry. 2017;174:686–94.

    Article  PubMed  Google Scholar 

  5. Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, Lizardi-Ortiz JE, et al. Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci. 2010;31:381–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ballon JS, Pajvani U, Freyberg Z, Leibel RL, Lieberman JA. Molecular pathophysiology of metabolic effects of antipsychotic medications. Trends Endocrinol Metab. 2014;25:593–600.

  7. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157:514–20.

    Article  CAS  PubMed  Google Scholar 

  8. Kern A, Albarran-Zeckler R, Walsh HE, Smith RG. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron. 2012;73:317–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res. 1998;779:58–74.

    Article  CAS  PubMed  Google Scholar 

  10. Rubi B, Ljubicic S, Pournourmohammadi S, Carobbio S, Armanet M, Bartley C, et al. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem. 2005;280:36824–32.

    Article  CAS  PubMed  Google Scholar 

  11. Simpson N, Maffei A, Freeby M, Burroughs S, Freyberg Z, Javitch J, et al. Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro. Mol Endocrinol. 2012;26:1757–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ustione A, Piston DW. Dopamine synthesis and D3 receptor activation in pancreatic beta-cells regulates insulin secretion and intracellular [Ca(2 + )] oscillations. Mol Endocrinol. 2012;26:1928–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Garcia-Tornadu I, Ornstein AM, Chamson-Reig A, Wheeler MB, Hill DJ, Arany E, et al. Disruption of the dopamine d2 receptor impairs insulin secretion and causes glucose intolerance. Endocrinology. 2010;151:1441–50.

    Article  CAS  PubMed  Google Scholar 

  14. Rosati G, Maioli M, Aiello I, Farris A, Agnetti V. Effects of long-term L-dopa therapy on carbohydrate metabolism in patients with Parkinson’s disease. Eur Neurol. 1976;14:229–39.

    Article  CAS  PubMed  Google Scholar 

  15. Ericson LE, Hakanson R, Lundquist I. Accumulation of dopamine in mouse pancreatic B-cells following injection of L-DOPA. Localization to secretory granules and inhibition of insulin secretion. Diabetologia. 1977;13:117–24.

    Article  CAS  PubMed  Google Scholar 

  16. Zern RT, Bird JL, Feldman JM. Effect of increased pancreatic islet norepinephrine, dopamine and serotonin concentration on insulin secretion in the golden hamster. Diabetologia. 1980;18:341–6.

    Article  CAS  PubMed  Google Scholar 

  17. Ustione A, Piston DW, Harris PE. Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet. Mol Endocrinol. 2013;27:1198–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Moritz AE, Free RB, Sibley DR. Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds. Cell Signal. 2018;41:75–81.

    Article  CAS  PubMed  Google Scholar 

  19. Diaz-Torga G, Feierstein C, Libertun C, Gelman D, Kelly MA, Low MJ, et al. Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. Endocrinology. 2002;143:1270–9.

    Article  CAS  PubMed  Google Scholar 

  20. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, et al. Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron. 1997;19:103–13.

    Article  CAS  PubMed  Google Scholar 

  21. Wang GJ, Volkow ND, Fowler JS. The role of dopamine in motivation for food in humans: implications for obesity. Expert Opin Ther Targets. 2002;6:601–9.

    Article  CAS  PubMed  Google Scholar 

  22. Garcia-Tornadu I, Perez-Millan MI, Recouvreux V, Ramirez MC, Luque G, Risso GS, et al. New insights into the endocrine and metabolic roles of dopamine D2 receptors gained from the Drd2 mouse. Neuroendocrinology. 2010;92:207–14.

    Article  CAS  PubMed  Google Scholar 

  23. Iturriza FC, Thibault J. Immunohistochemical investigation of tyrosine-hydroxylase in the islets of Langerhans of adult mice, rats and guinea pigs. Neuroendocrinology. 1993;57:476–80.

    Article  CAS  PubMed  Google Scholar 

  24. Persson-Sjogren S, Forsgren S, Taljedal IB. Tyrosine hydroxylase in mouse pancreatic islet cells, in situ and after syngeneic transplantation to kidney. Histol Histopathol. 2002;17:113–21.

    CAS  PubMed  Google Scholar 

  25. Takayanagi M, Watanabe T. Immunocytochemical colocalizations of insulin, aromatic L-amino acid decarboxylase, dopamine beta-hydroxylase, S-100 protein and chromogranin A in B-cells of the chicken endocrine pancreas. Tissue Cell. 1996;28:17–24.

    Article  CAS  PubMed  Google Scholar 

  26. Ganic E, Johansson JK, Bennet H, Fex M, Artner I. Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes. Biochem Biophys Res Commun. 2015;468:629–35.

    Article  CAS  PubMed  Google Scholar 

  27. Maffei A, Marie Segal A, Alvarez-Perez JC, Garcia-Ocana A, Harris P. Anti-incretin, anti-proliferative action of dopamine on beta-cells. Mol Endocrinol. 2015;29:542–57.

  28. Merglen A, Theander S, Rubi B, Chaffard G, Wollheim CB, Maechler P. Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. Endocrinology. 2004;145:667–78.

    Article  CAS  PubMed  Google Scholar 

  29. Romanova IV, Derkach KV, Mikhrina AL, Sukhov IB, Mikhailova EV, Shpakov AO. The leptin, dopamine and serotonin receptors inhypothalamic POMC-neurons of normal and obese rodents. Neurochem Res. 2018;43:821–837.

  30. Newman AH, Grundt P, Cyriac G, Deschamps JR, Taylor M, Kumar R, et al. N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists. J Med Chem. 2009;52:2559–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xiao J, Free RB, Barnaeva E, Conroy JL, Doyle T, Miller B, et al. Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists. J Med Chem. 2014;57:3450–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Herrera PL. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development. 2000;127:2317–22.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jung MY, Skryabin BV, Arai M, Abbondanzo S, Fu D, Brosius J, et al. Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors. Neuroscience. 1999;91:911–24.

    Article  CAS  PubMed  Google Scholar 

  35. Carter JD, Dula SB, Corbin KL, Wu R, Nunemaker CS. A practical guide to rodent islet isolation and assessment. Biol Proceed Online. 2009;11:3–31.

    Article  CAS  Google Scholar 

  36. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  37. Feigin A, Fukuda M, Dhawan V, Przedborski S, Jackson-Lewis V, Mentis MJ, et al. Metabolic correlates of levodopa response in Parkinson’s disease. Neurology. 2001;57:2083–8.

    Article  CAS  PubMed  Google Scholar 

  38. Aslanoglou D, George EW, Freyberg Z. Homogeneous time-resolved forster resonance energy transfer-based assay for detection of insulin secretion. J Vis Exp. 2018;135:e57531.

  39. Farino ZJ, Morgenstern TJ, Vallaghe J, Gregor N, Donthamsetti P, Harris PE, et al. Development of a rapid insulin assay by homogenous time-resolved fluorescence. PLoS ONE. 2016;11:e0148684.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Li X, Wu X, Camacho R, Schwartz GJ, LeRoith D. Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms. PLoS ONE. 2011;6:e17058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zaafar DK, Zaitone SA, Moustafa YM. Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation. PLoS ONE. 2014;9:e100562.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  CAS  PubMed  Google Scholar 

  43. Olofsson CS, Gopel SO, Barg S, Galvanovskis J, Ma X, Salehi A, et al. Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells. Pflug Arch. 2002;444:43–51.

    Article  CAS  Google Scholar 

  44. Barg S, Lindqvist A, Obermuller S. Granule docking and cargo release in pancreatic beta-cells. Biochem Soc Trans. 2008;36:294–9.

    Article  CAS  PubMed  Google Scholar 

  45. Feldman JM, Chapman B. Characterization of pancreatic islet monoamine oxidase. Metabolism. 1975;24:581–8.

    Article  CAS  PubMed  Google Scholar 

  46. Uchino H, Kanai Y, Kim DK, Wempe MF, Chairoungdua A, Morimoto E, et al. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol. 2002;61:729–37.

    Article  CAS  PubMed  Google Scholar 

  47. Khunweeraphong N, Nagamori S, Wiriyasermkul P, Nishinaka Y, Wongthai P, Ohgaki R, et al. Establishment of stable cell lines with high expression of heterodimers of human 4F2hc and human amino acid transporter LAT1 or LAT2 and delineation of their differential interaction with alpha-alkyl moieties. J Pharmacol Sci. 2012;119:368–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Camargo SM, Vuille-dit-Bille RN, Mariotta L, Ramadan T, Huggel K, Singer D, et al. The molecular mechanism of intestinal levodopa absorption and its possible implications for the treatment of Parkinson’s disease. J Pharmacol Exp Ther. 2014;351:114–23.

    Article  PubMed  CAS  Google Scholar 

  49. Sulzer D, Cragg SJ, Rice ME. Striatal dopamine neurotransmission: regulation of release and uptake. Basal ganglia. 2016;6:123–48.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Pivonello R, Ferone D, Lombardi G, Colao A, Lamberts SW, Hofland LJ. Novel insights in dopamine receptor physiology. Eur J Endocrinol. 2007;156:S13–21.

    Article  CAS  PubMed  Google Scholar 

  51. Kongpracha P, Nagamori S, Wiriyasermkul P, Tanaka Y, Kaneda K, Okuda S, et al. Structure-activity relationship of a novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). J Pharmacol Sci. 2017;133:96–102.

    Article  CAS  PubMed  Google Scholar 

  52. Koller WC, Rueda MG. Mechanism of action of dopaminergic agents in Parkinson’s disease. Neurology. 1998;50:S11–14.

    Article  CAS  PubMed  Google Scholar 

  53. Kostrzewa RM. Dopamine receptor supersensitivity. Neurosci Biobehav Rev. 1995;19:1–17.

    Article  CAS  PubMed  Google Scholar 

  54. Lopez Vicchi F, Luque GM, Brie B, Nogueira JP, Garcia Tornadu I, Becu-Villalobos D. Dopaminergic drugs in type 2 diabetes and glucose homeostasis. Pharmacol Res. 2016;109:74–80.

    Article  CAS  PubMed  Google Scholar 

  55. Guo N, Guo W, Kralikova M, Jiang M, Schieren I, Narendran R, et al. Impact of D2 receptor internalization on binding affinity of neuroimaging radiotracers. Neuropsychopharmacology. 2010;35:806–17.

    Article  CAS  PubMed  Google Scholar 

  56. Gangarossa G, Espallergues J, Mailly P, De Bundel D, de Kerchove d’Exaerde A, Herve D, et al. Spatial distribution of D1R- and D2R-expressing medium-sized spiny neurons differs along the rostro-caudal axis of the mouse dorsal striatum. Front Neural Circuits. 2013;7:124.

    PubMed  PubMed Central  Google Scholar 

  57. Armando I, Konkalmatt P, Felder RA, Jose PA. The renal dopaminergic system: novel diagnostic and therapeutic approaches in hypertension and kidney disease. Transl Resd. 2015;165:505–11.

    Article  CAS  Google Scholar 

  58. Tayebati SK, Lokhandwala MF, Amenta F. Dopamine and vascular dynamics control: present status and future perspectives. Curr Neurovasc Res. 2011;8:246–57.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang MZ, Harris RC. Antihypertensive mechanisms of intra-renal dopamine. Curr Opin Nephrol Hypertens. 2015;24:117–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Choi MR, Kouyoumdzian NM, Rukavina Mikusic NL, Kravetz MC, Roson MI, Rodriguez Fermepin M, et al. Renal dopaminergic system: Pathophysiological implications and clinical perspectives. World J Nephrol. 2015;4:196–212.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wang X, Villar VA, Armando I, Eisner GM, Felder RA, Jose PA. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice. Pediatr Nephrol. 2008;23:2131–46.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zeng C, Armando I, Luo Y, Eisner GM, Felder RA, Jose PA. Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice. Am J Physiol Heart Circ Physiol. 2008;294:H551–569.

    Article  CAS  PubMed  Google Scholar 

  63. Morla L, Edwards A, Crambert G. New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors. World J Biol Chem. 2016;7:44–63.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Mitok KA, Freiberger EC, Schueler KL, Rabaglia ME, Stapleton DS, Kwiecien NW et al. Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion. J Biol Chem. 2008;293:5860–5877.

  65. Borelli MI, Rubio M, Garcia ME, Flores LE, Gagliardino JJ. Tyrosine hydroxylase activity in the endocrine pancreas: changes induced by short-term dietary manipulation. BMC Endocr Disord. 2003;3:2.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Vazquez P, Robles AM, de Pablo F, Hernandez-Sanchez C. Non-neural tyrosine hydroxylase, via modulation of endocrine pancreatic precursors, is required for normal development of beta cells in the mouse pancreas. Diabetologia. 2014;57:2339–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004;56:331–49.

    Article  CAS  PubMed  Google Scholar 

  68. Cheng Q, Beltran VD, Chan SM, Brown JR, Bevington A, Herbert TP. System-L amino acid transporters play a key role in pancreatic beta-cell signalling and function. J Mol Endocrinol. 2016;56:175–87.

    Article  CAS  PubMed  Google Scholar 

  69. Carranza A, Musolino PL, Villar M, Nowicki S. Signaling cascade of insulin-induced stimulation of L-dopa uptake in renal proximal tubule cells. Am J Physiol Cell Physiol. 2008;295:C1602–1609.

    Article  CAS  PubMed  Google Scholar 

  70. Eldrup E, Moller SE, Andreasen J, Christensen NJ. Effects of ordinary meals on plasma concentrations of 3,4-dihydroxyphenylalanine, dopamine sulphate and 3,4-dihydroxyphenylacetic acid. Clin Sci. 1997;92:423–30.

    Article  CAS  Google Scholar 

  71. Eldrup E, Richter EA. DOPA, dopamine, and DOPAC concentrations in the rat gastrointestinal tract decrease during fasting. Am J Physiol Endocrinol Metab. 2000;279:E815–22.

    Article  CAS  PubMed  Google Scholar 

  72. Goldstein DS, Eisenhofer G, Kopin IJ. Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther. 2003;305:800–11.

    Article  CAS  PubMed  Google Scholar 

  73. Goldstein DS, Swoboda KJ, Miles JM, Coppack SW, Aneman A, Holmes C, et al. Sources and physiological significance of plasma dopamine sulfate. J Clin Endocrinol Metab. 1999;84:2523–31.

    Article  CAS  PubMed  Google Scholar 

  74. Eldrup E, Richter EA, Christensen NJDOPA. norepinephrine, and dopamine in rat tissues: no effect of sympathectomy on muscle DOPA. Am J Physiol. 1989;256:E284–287.

    CAS  PubMed  Google Scholar 

  75. Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. Br J Pharmacol. 2015;172:1–23.

    Article  CAS  PubMed  Google Scholar 

  76. Leggio GM, Bucolo C, Platania CB, Salomone S, Drago F. Current drug treatments targeting dopamine D3 receptor. Pharmacol Ther. 2016;165:164–77.

    Article  CAS  PubMed  Google Scholar 

  77. Newman AH, Beuming T, Banala AK, Donthamsetti P, Pongetti K, LaBounty A, et al. Molecular determinants of selectivity and efficacy at the dopamine D3 receptor. J Med Chem. 2012;55:6689–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014;282:13–22.

    Article  CAS  PubMed  Google Scholar 

  79. Mims RB, Scott CL, Modebe OM, Bethune JE. Prevention of L-dopa-induced growth hormone stimulation by hyperglycemia. J Clin Endocrinol Metab. 1973;37:660–3.

    Article  CAS  PubMed  Google Scholar 

  80. Sandyk R. The relationship between diabetes mellitus and Parkinson’s disease. Int J Neurosci. 1993;69:125–30.

    Article  CAS  PubMed  Google Scholar 

  81. Furman BL, Wilson GA. The effects of levodopa on plasma glucose in two strains of rat. Eur J Pharmacol. 1979;55:241–6.

    Article  CAS  PubMed  Google Scholar 

  82. Hahn M, Chintoh A, Giacca A, Xu L, Lam L, Mann S, et al. Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: an animal model. Schizophr Res. 2011;131:90–95.

    Article  PubMed  Google Scholar 

  83. Lako IM, van den Heuvel ER, Knegtering H, Bruggeman R, Taxis K. Estimating dopamine D(2) receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33:675–81.

    Article  CAS  PubMed  Google Scholar 

  84. Kopf D, Gilles M, Paslakis G, Medlin F, Lederbogen F, Lehnert H, et al. Insulin secretion and sensitivity after single-dose amisulpride, olanzapine or placebo in young male subjects: double blind, cross-over glucose clamp study. Pharmacopsychiatry. 2012;45:223–8.

    Article  CAS  PubMed  Google Scholar 

  85. Teff KL, Rickels MR, Grudziak J, Fuller C, Nguyen HL, Rickels K. Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes. 2013;62:3232–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kowalchuk C, Castellani L, Chintoh A, Remington G, Giacca A, Hahn M. Antipsychotics and glucose metabolism: how brain and body collide. Am J Physiol Endocrinol Metab. 2019;316:E1–15.

  87. Hahn MK, Wolever TM, Arenovich T, Teo C, Giacca A, Powell V, et al. Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol. 2013;33:740–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully thank and acknowledge Drs. Domenico Accili, Rudolph Leibel, Amy Newman, Marcelo Rubinstein, Lori Sussel, Ruth Singer, Jacob Ballon, Michael McCarthy, Mark Sonders, Nicolas Pierre, Marília Gueiros, Thue Schwartz, Birgitte Holst, Andreas Madsen, Jeffrey Brodsky, and Ms. Emily George for helpful discussions, reagents, and assistance throughout this work. This research was supported by a Department of Defense PRMRP Investigator Initiated Award PR141292 (Z.F.), NIDA K08 DA031241 award (Z.F.), Louis V. Gerstner, Jr., Scholars Program (Z.F.), Leon Levy Foundation (Z.F.), the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation (Z.F.), NIDA F32 DA044696 (P.C.D.), NINDS R01 NS075222 (E.V.M.), NIMH R01 MH093672 (C.K.), NINDS Intramural Program (D.R.S., R.B.F.), NIDDK R01 DK116583 (P.E.H.), NARSAD Distinguished Investigator Award (J.A.J.), NIMH R01 MH54137 (J.A.J.), and NIMH T32 MH018870 (J.A.J.).

Author information

Author notes

  1. Zachary J. Farino

    Present address: Kallyope Inc., New York, NY, USA

  2. Pattama Wiriyasermkul

    Present address: Department of Collaborative Research, Nara Medical University, Kashihara, Nara, Japan

  3. Prashant Donthamsetti

    Present address: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Zachary J. Farino, Robin J. Freyberg, Despoina Aslanoglou, Denise Sorisio & Zachary Freyberg

  2. Department of Psychiatry, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Travis J. Morgenstern, Matthias Quick, Pattama Wiriyasermkul, Benjamin P. Inbar, Prashant Donthamsetti, Eugene V. Mosharov, Christoph Kellendonk, Claudia Schmauss, Holly Moore & Jonathan A. Javitch

  3. Division of Endocrinology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Antonella Maffei & Paul E. Harris

  4. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA

    Matthias Quick, Eugene V. Mosharov, Christoph Kellendonk, Claudia Schmauss & Jonathan A. Javitch

  5. Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA

    Alain J. De Solis & Lori M. Zeltser

  6. Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    R. Benjamin Free & David R. Sibley

  7. Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Eugene V. Mosharov

  8. Department of Pharmacology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Christoph Kellendonk & Jonathan A. Javitch

  9. Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA

    Gary J. Schwartz

  10. Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Lori M. Zeltser

  11. Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA

    Holly Moore

  12. Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Zachary Freyberg

Authors
  1. Zachary J. Farino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Travis J. Morgenstern
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonella Maffei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias Quick
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alain J. De Solis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pattama Wiriyasermkul
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robin J. Freyberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Despoina Aslanoglou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Denise Sorisio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Benjamin P. Inbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R. Benjamin Free
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Prashant Donthamsetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Eugene V. Mosharov
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christoph Kellendonk
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gary J. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David R. Sibley
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Claudia Schmauss
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Lori M. Zeltser
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Holly Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Paul E. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Jonathan A. Javitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Zachary Freyberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zachary Freyberg.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farino, Z.J., Morgenstern, T.J., Maffei, A. et al. New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. Mol Psychiatry 25, 2070–2085 (2020). https://doi.org/10.1038/s41380-018-0344-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-018-0344-6

This article is cited by

Search

Advanced search

Quick links