Abstract
Dopamine and serotonin signalling are associated with major depressive disorder, which is a prevalent life-threatening illness worldwide. Numerous FDA-approved dopamine/serotonin signalling-modifying drugs are available but are associated with concurrent side effects and limited efficacy. Thus, identifying and targeting their signalling pathway is crucial for improving depression treatment. Here, we determined that serotonin receptor 2A (5-HT2AR) abundantly forms a protein complex with dopamine receptor 1 (D1R) in high abundance via its carboxy-terminus in the brains of mice subjected to various chronic stress paradigms. Furthermore, the D1R/5-HT2AR interaction elicited CREB/ERK/AKT modulation during synaptic regulation. An interfering peptide (TAT-5-HT2AR-SV) agitated the D1R/5-HT2AR interaction and attenuated depressive symptoms accompanied by CREB/ERK molecule costimulation. Interestingly, HDAC antagonism but not TrkB antagonism reversed the antidepressant effect of competitive peptides. These findings revealed a novel D1R/5-HT2AR heteroreceptor complex mechanism in the pathophysiology of depression, and their uncoupling ameliorates depressive-like behaviours through HDAC-, and not BDNF-, dependent mechanisms.
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References
Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902.
Willner P, Scheel-Krüger J, Belzung C. The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev. 2013;37(10 Pt 1):2331–71.
Duman RS. Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections. Depress Anxiety. 2014;31(4):291–6.
Block SG, Nemeroff CB. Emerging antidepressants to treat major depressive disorder. Asian J Psychiatr. 2014;12:7–16.
Niederkofler V, Asher TE, Dymecki SM. Functional interplay between dopaminergic and serotonergic neuronal systems during development and adulthood. ACS Chem Neurosci. 2015;6(7):1055–70.
Di Matteo V, Di Giovanni G, Pierucci M, Esposito E. Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog Brain Res. 2008;172:7–44.
Hyman SE. Neurotransmitters. Curr Biol. 2005;15(5):R154–8.
Belujon P, Grace AA. Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol. 2017;20(12):1036–46.
Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG. Dopamine: functions, signaling, and association with neurological diseases. Cell Mol Neurobiol. 2019;39(1):31–59.
Felger JC. The role of dopamine in inflammation-associated depression: mechanisms and therapeutic implications. Curr Top Behav Neurosci. 2017;31:199–219.
Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69(Suppl E1):4–7.
Dixon ML, Thiruchselvam R, Todd R, Christoff K. Emotion and the prefrontal cortex: An integrative review. Psychol Bull. 2017;143(10):1033–81.
Kram ML, Kramer GL, Ronan PJ, Steciuk M, Petty F. Dopamine receptors and learned helplessness in the rat: an autoradiographic study. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(4):639–45.
Du H, Deng W, Aimone JB, Ge M, Parylak S, Walch K, et al. Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding. Proc Natl Acad Sci U S A. 2016;113(37):E5501–10.
D’Aquila PS, Collu M, Pani L, Gessa GL, Serra G. Antidepressant-like effect of selective dopamine D1 receptor agonists in the behavioural despair animal model of depression. Eur J Pharmacol. 1994;262(1–2):107–11.
Tyler CR, Solomon BR, Ulibarri AL, Allan AM. Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism. Neurotoxicology. 2014;44:98–109.
Demontis F, Serra F, Serra G. Antidepressant-induced dopamine receptor dysregulation: a valid animal model of manic-depressive illness. Curr Neuropharmacol. 2017;15(3):417–23.
Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry. 2004;6(4):159–66.
Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. J Psychopharmacol. 2017;31(9):1091–120.
Murnane KS. Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder. Behav Pharmacol. 2019;30(2 and 3 Spec Issue):151–62.
Bankson MG, Cunningham KA. 3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions. J Pharmacol Exp Ther. 2001;297(3):846–52.
Pitts EG, Minerva AR, Chandler EB, Kohn JN, Logun MT, Sulima A, et al. 3,4-Methylenedioxymethamphetamine increases affiliative behaviors in squirrel monkeys in a serotonin 2A receptor-dependent manner. Neuropsychopharmacology. 2017;42(10):1962–71.
Egerton A, Ahmad R, Hirani E, Grasby PM. Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat. Psychopharmacology. 2008;200(4):487–96.
Schmidt CJ, Fadayel GM. The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat. Eur J Pharmacol. 1995;273(3):273–9.
Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;28(2):402–12.
Celada P, Puig M, Amargós-Bosch M, Adell A, Artigas F. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci. 2004;29(4):252–65.
Borroto-Escuela DO, Tarakanov AO, Fuxe K. FGFR1-5-HT1A heteroreceptor complexes: implications for understanding and treating major depression. Trends Neurosci. 2016;39(1):5–15.
Borroto-Escuela DO, Narváez M, Ambrogini P, Ferraro L, Brito I, Romero-Fernandez W, et al. Receptor–receptor interactions in multiple 5-HT1A heteroreceptor complexes in raphe-hippocampal 5-HT transmission and their relevance for depression and its treatment. Molecules (Basel, Switzerland). 2018;23(6).
Pei L, Li S, Wang M, Diwan M, Anisman H, Fletcher PJ, et al. Uncoupling the dopamine D1–D2 receptor complex exerts antidepressant-like effects. Nat Med. 2010;16(12):1393–5.
Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19(6):773–7.
Li W, Ali T, Zheng C, Liu Z, He K, Shah FA, et al. Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression. J Neuroinflammation. 2021;18(1):38.
Li W, Ali T, He K, Liu Z, Shah FA, Ren Q, et al. Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression. Brain Behav Immun. 2020.
Ali T, Rahman SU, Hao Q, Li W, Liu Z, Ali Shah F, et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J Pineal Res. 2020;69(2):e12667.
Ali T, Hao Q, Ullah N, Rahman SU, Shah FA, He K, et al. Melatonin act as an antidepressant via attenuation of neuroinflammation by targeting Sirt1/Nrf2/HO-1 signaling. Front Mol Neurosci. 2020;13:96.
Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64(3):327–37.
Dudman JT, Eaton ME, Rajadhyaksha A, Macías W, Taher M, Barczak A, et al. Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1. J Neurochem. 2003;87(4):922–34.
Kojima N, Shirao T. Synaptic dysfunction and disruption of postsynaptic drebrin-actin complex: a study of neurological disorders accompanied by cognitive deficits. Neurosci Res. 2007;58(1):1–5.
Bilbao A, Rieker C, Cannella N, Parlato R, Golda S, Piechota M, et al. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects. Front Behav Neurosci. 2014;8:212.
Zhang B, Guo F, Ma Y, Song Y, Lin R, Shen F-Y, et al. Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD. Sci Rep. 2017;7(1):3809.
Kowiański P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J. BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol. 2018;38(3):579–93.
Covington HE 3rd, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, et al. Antidepressant actions of histone deacetylase inhibitors. J Neurosci. 2009;29(37):11451–60.
Alzarea SI, Alhassan HH, Alzarea AI, Al-Oanzi ZH, Afzal M. Antidepressant-like Effects of renin inhibitor aliskiren in an inflammatory mouse model of Depression. Brain Sci. 2022;12(5).
Ding Y, Bu F, Chen T, Shi G, Yuan X, Feng Z, et al. A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress–induced depressive-like behavior in mice by regulating gut microbiota and metabolites. Appl Microbiol Biotechnol. 2021;105(21):8411–26.
Graeff FG, Guimarães FS, De Andrade TG, Deakin JF. Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav. 1996;54(1):129–41.
Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol. 2015;6:225.
Göőz M, Göőz P, Luttrell LM, Raymond JR. 5-HT2A receptor induces ERK phosphorylation and proliferation through ADAM-17 tumor necrosis factor-alpha-converting enzyme (TACE) activation and heparin-bound epidermal growth factor-like growth factor (HB-EGF) shedding in mesangial cells. J Biol Chem. 2006;281(30):21004–12.
Matsuda S, Ikeda Y, Murakami M, Nakagawa Y, Tsuji A, Kitagishi Y. Roles of PI3K/AKT/GSK3 pathway involved in psychiatric illnesses. Diseases. 2019;7(1).
Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13(10):1161–9.
Bergeron Y, Bureau G, Laurier-Laurin M, Asselin E, Massicotte G, Cyr M. Genetic deletion of Akt3 induces an endophenotype reminiscent of psychiatric manifestations in mice. Front Mol Neurosci. 2017;10:102.
Dwivedi Y, Rizavi HS, Conley RR, Pandey GN. ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf. Mol Psychiatry. 2006;11(1):86–98.
Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN. Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem. 2001;77(3):916–28.
Wang JQ, Mao L. The ERK pathway: molecular mechanisms and treatment of depression. Mol Neurobiol. 2019;56(9):6197–205.
Yan L, Xu X, He Z, Wang S, Zhao L, Qiu J, et al. Antidepressant-like effects and cognitive enhancement of coadministration of chaihu shugan san and fluoxetine: dependent on the BDNF-ERK-CREB signaling pathway in the hippocampus and frontal cortex. Biomed Res Int. 2020;2020:2794263.
Guan L, Jia N, Zhao X, Zhang X, Tang G, Yang L, et al. The involvement of ERK/CREB/Bcl-2 in depression-like behavior in prenatally stressed offspring rats. Brain Res Bull. 2013;99:1–8.
Blendy JA. The role of CREB in depression and antidepressant treatment. Biol Psychiatry. 2006;59(12):1144–50.
Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223–50.
Sartor GC, Malvezzi AM, Kumar A, Andrade NS, Wiedner HJ, Vilca SJ, et al. Enhancement of BDNF expression and memory by HDAC inhibition requires BET bromodomain reader proteins. J Neurosci. 2019;39(4):612–26.
Bagheri A, Habibzadeh P, Razavipour SF, Volmar CH, Chee NT, Brothers SP, et al. HDAC inhibitors induce BDNF expression and promote neurite outgrowth in human neural progenitor cells-derived neurons. Int J Mol Sci. 2019;20(5).
Colucci-D'Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci. 2020;21(20).
Arioz BI, Tastan B, Tarakcioglu E, Tufekci KU, Olcum M, Ersoy N, et al. Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway. Front Immunol. 2019;10:1511.
McGrory CL, Ryan KM, Kolshus E, Finnegan M, McLoughlin DM. Peripheral blood SIRT1 mRNA levels in depression and treatment with electroconvulsive therapy. Eur Neuropsychopharmacol. 2018;28(9):1015–23.
Qian W, Yu C, Wang S, Niu A, Shi G, Cheng Y, et al. Depressive-like behaviors induced by chronic social defeat stress are associated with HDAC7 reduction in the nucleus accumbens. Front Psychiatry. 2021;11(1662).
Zheng Y, Fan W, Zhang X, Dong E. Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus. Epigenetics. 2016;11(2):150–62.
Dong E, Pandey SC. Prenatal stress induced chromatin remodeling and risk of psychopathology in adulthood. Int Rev Neurobiol. 2021;156:185–215.
Schroeder FA, Lin CL, Crusio WE, Akbarian S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry. 2007;62(1):55–64.
Sada N, Fujita Y, Mizuta N, Ueno M, Furukawa T, Yamashita T. Inhibition of HDAC increases BDNF expression and promotes neuronal rewiring and functional recovery after brain injury. Cell Death Dis. 2020;11(8):655.
Dwivedi Y. Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat. 2009;5:433–49.
Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife. 2016;5.
De Deurwaerdère P, Chagraoui A, Di Giovanni G. Serotonin/dopamine interaction: Electrophysiological and neurochemical evidence. Prog Brain Res. 2021;261:161–264.
Esposito E. Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets. 2006;7(2):177–85.
Schweimer JV, Coullon GS, Betts JF, Burnet PW, Engle SJ, Brandon NJ, et al. Increased burst-firing of ventral tegmental area dopaminergic neurons in D-amino acid oxidase knockout mice in vivo. Eur J Neurosci. 2014;40(7):2999–3009.
Puig MV, Gulledge AT. Serotonin and prefrontal cortex function: neurons, networks, and circuits. Mol Neurobiol. 2011;44(3):449–64.
Berumen LC, Rodríguez A, Miledi R, García-Alcocer G. Serotonin receptors in hippocampus. Sci World J. 2012;2012:823493.
McNamara CG, Dupret D. Two sources of dopamine for the hippocampus. Trends Neurosci. 2017;40(7):383–4.
Banasr M, Hery M, Printemps R, Daszuta A. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology. 2004;29(3):450–60.
Shuto T, Kuroiwa M, Sotogaku N, Kawahara Y, Oh YS, Jang JH, et al. Obligatory roles of dopamine D1 receptors in the dentate gyrus in antidepressant actions of a selective serotonin reuptake inhibitor, fluoxetine. Mol Psychiatry. 2020;25(6):1229–44.
Pehek EA, Hernan AE. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release. Neuroscience. 2015;290:159–64.
Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113(2):296–320.
Acknowledgements
Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China
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This work was supported by Grants Science and Technology Innovation Committee of Shenzhen No: JCYJ20170810163329510; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2019SHIBS0004; Sanming Project of Medicine in Shenzhen (No. SZSM201911003) Shenzhen Key Medical Discipline Construction Fund (No.SZXK06162). National Natural Science Foundation of China (82072112). Guangdong Basic and Applied Basic Research Foundation (2022A1515110205;2023A1515011957).
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Conceptualization: WL, TA, SL; Methodology: WL, SM, and QG, Investigation and Analysis: WL, TA, and NL: Writing: TA, SL; Supervision: SL and ZY. All authors reviewed and approved the manuscript.
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Li, W., Ali, T., Mou, S. et al. D1R-5-HT2AR Uncoupling Reduces Depressive Behaviours via HDAC Signalling. Neurotherapeutics 20, 1875–1892 (2023). https://doi.org/10.1007/s13311-023-01436-7
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DOI: https://doi.org/10.1007/s13311-023-01436-7