Abstract
Rationale
Ketamine has rapid antidepressant effects that represent a significant advance in treating depression, but its poor safety and tolerability limit its clinical utility. Accreting evidence suggests that serotonergic neurotransmission participates in the rapid antidepressant effects of ketamine and hallucinogens. Thus, understanding how serotonin contributes to these effects may allow identification of novel rapid antidepressant mechanisms with improved tolerability.
Objective
The goal of this paper is to understand how serotonergic mechanisms participate in rapid antidepressant mechanisms.
Methods
We review the relevance of serotonergic neurotransmission for rapid antidepressant effects and evaluate the role of 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors in synaptic plasticity, BDNF signaling, and GSK-3β activity. Subsequently, we develop hypotheses on the relationship of these receptor systems to rapid antidepressant effects.
Results
We found that 5-HT1A and 5-HT1B receptors may participate in ketamine’s rapid antidepressant mechanisms, while agonists at 5-HT2A and 5-HT4 receptors may independently behave as rapid antidepressants. 5-HT1A, 5-HT2A, and 5-HT4 receptors increase synaptic plasticity in the cortex or hippocampus but do not consistently increase BDNF signaling. We found that 5-HT1A and 5-HT1B receptors may participate in rapid antidepressant mechanisms as a consequence of increased BDNF signaling, rather than a cause. 5-HT2A and 5-HT4 receptor agonists may increase BDNF signaling, but these relationships are tenuous and need more study. Finally, we found that ketamine and several serotonergic receptor systems may mechanistically converge on reduced GSK-3β activity.
Conclusions
We find it plausible that serotonergic neurotransmission participates in rapid antidepressant mechanisms by increasing synaptic plasticity, perhaps through GSK-3β inhibition.
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References
Abdallah CG, Averill LA, Gueorguieva R et al (2020) Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacol 45:990–997. https://doi.org/10.1038/s41386-020-0644-9
Afshar S, Shahidi S, Rohani AH et al (2018) The effect of NAD-299 and TCB-2 on learning and memory, hippocampal BDNF levels and amyloid plaques in Streptozotocin-induced memory deficits in male rats. Psychopharmacology 235:2809–2822. https://doi.org/10.1007/s00213-018-4973-x
Ago Y, Tanabe W, Higuchi M et al (2019) (R)-Ketamine induces a greater increase in prefrontal 5-HT release than (S)-ketamine and ketamine metabolites via an AMPA Receptor-independent mechanism. Int J Neuropsychopharmacol 22:665–674. https://doi.org/10.1093/ijnp/pyz041
Aguiar RP, Soares LM, Meyer E et al (2020) Activation of 5-HT1A postsynaptic receptors by NLX-101 results in functional recovery and an increase in neuroplasticity in mice with brain ischemia. Prog Neuropsychopharmacol Biol Psychiatry 99:109832. https://doi.org/10.1016/j.pnpbp.2019.109832
Aicardi G, Argilli E, Cappello S et al (2004) Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. Proc Natl Acad Sci USA 101:15788–15792. https://doi.org/10.1073/pnas.0406960101
Autry AE, Adachi M, Nosyreva E et al (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95. https://doi.org/10.1038/nature10130
Banke TG, Bowie D, Lee H et al (2000) Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci 20:89–102
Barthet G, Framery B, Gaven F et al (2007) 5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling. Mol Biol Cell 18:1979–1991. https://doi.org/10.1091/mbc.e06-12-1080
Beaulieu J-M, Zhang X, Rodriguiz RM et al (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A 105:1333–1338. https://doi.org/10.1073/pnas.0711496105
Berman RM, Cappiello A, Anand A et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354. https://doi.org/10.1016/s0006-3223(99)00230-9
Beurel E, Grieco SF, Amadei C et al (2016) Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord 18:473–480. https://doi.org/10.1111/bdi.12436
Beurel E, Song L, Jope RS (2011) Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16:1068–1070. https://doi.org/10.1038/mp.2011.47
Blier P, Ward NM (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiat 53:193–203
Bohn LM, Schmid CL (2010) Serotonin receptor signaling and regulation via β-arrestins. Crit Rev Biochem Mol Biol 45:555–566. https://doi.org/10.3109/10409238.2010.516741
Boschert U, Amara DA, Segu L, Hen R (1994) The mouse 5-hydroxytryptamine1B receptor is localized predominantly on axon terminals. Neuroscience 58:167–182
Browne GJ, Proud CG (2004) A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 24:2986–2997. https://doi.org/10.1128/mcb.24.7.2986-2997.2004
Bruinvels AT, Landwehrmeyer B, Gustafson EL et al (1994) Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology 33:367–386. https://doi.org/10.1016/0028-3908(94)90067-1
Bruinvels AT, Palacios JM, Hoyer D (1993) Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain. Naunyn-Schmiedeberg’s Arch Pharmacol 347:569–582
Burke TF, Advani T, Adachi M et al (2013) Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice. Int J Neuropsychopharmacol 16:631–645. https://doi.org/10.1017/S1461145712000466
Cai C-Y, Wu H-Y, Luo C-X et al (2019) Extracellular regulated protein kinaseis critical for the role of 5-HT1a receptor in modulating nNOS expression and anxiety-related behaviors. Behav Brain Res 357–358:88–97. https://doi.org/10.1016/j.bbr.2017.12.017
Cai X, Flores-Hernandez J, Feng J, Yan Z (2002) Activity-dependent bidirectional regulation of GABA(A) receptor channels by the 5-HT(4) receptor-mediated signalling in rat prefrontal cortical pyramidal neurons. J Physiol 540:743–759. https://doi.org/10.1113/jphysiol.2001.013391
Caldeira MV, Melo CV, Pereira DB et al (2007) Brain-derived neurotrophic factor regulates the Expression and synaptic delivery ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. J Biol Chem 282:12619–12628. https://doi.org/10.1074/jbc.M700607200
Camargo A, Pazini FL, Rosa JM et al (2019) Augmentation effect of ketamine by guanosine in the novelty-suppressed feeding test is dependent on mTOR signaling pathway. J Psychiatr Res 115:103–112. https://doi.org/10.1016/j.jpsychires.2019.05.017
Carhart-Harris RL, Bolstridge M, Day CMJ et al (2018) Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology 235:399–408. https://doi.org/10.1007/s00213-017-4771-x
Celada P, Puig MV, Artigas F (2013) Serotonin modulation of cortical neurons and networks. Front Integr Neurosci 7:25. https://doi.org/10.3389/fnint.2013.00025
Celada P, Puig MV, Casanovas JM et al (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 21:9917–9929
Chen S, Owens GC, Crossin KL, Edelman DB (2007) Serotonin stimulates mitochondrial transport in hippocampal neurons. Mol Cell Neurosci 36:472–483. https://doi.org/10.1016/j.mcn.2007.08.004
Clements JA, Nimmo WS, Grant IS (1982) Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci 71:539–542. https://doi.org/10.1002/jps.2600710516
du Jardin KG, Liebenberg N, Cajina M et al (2017) S-Ketamine mediates its acute and sustained antidepressant-like activity through a 5-HT1B receptor dependent mechanism in a genetic rat model of depression. Front Pharmacol 8:978. https://doi.org/10.3389/fphar.2017.00978
du Jardin KG, Liebenberg N, Müller HK et al (2016) Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression. Psychopharmacology 233:2813–2825. https://doi.org/10.1007/s00213-016-4327-5
Dunlap LE, Azinfar A, Ly C et al (2020) Identification of psychoplastogenic N, N-dimethylaminoisotryptamine (isoDMT) analogues through structure–activity relationship studies. J Med Chem 63:1142–1155. https://doi.org/10.1021/acs.jmedchem.9b01404
Fukumoto K, Iijima M, Chaki S (2016) The antidepressant effects of an mGlu2/3 receptor antagonist and ketamine require AMPA receptor stimulation in the mPFC and subsequent activation of the 5-HT neurons in the DRN. Neuropsychopharmacology 41:1046–1056. https://doi.org/10.1038/npp.2015.233
Fukumoto K, Iijima M, Chaki S (2014) Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S–2-amino-2-(1S,2S–2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test. Psychopharmacology 231:2291–2298. https://doi.org/10.1007/s00213-013-3378-0
Gigliucci V, O’Dowd G, Casey S et al (2013) Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology 228:157–166. https://doi.org/10.1007/s00213-013-3024-x
Graef JD, Newberry K, Newton A et al (2015) Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus. Brain Res 1609:31–39. https://doi.org/10.1016/j.brainres.2015.03.019
Griffiths RR, Johnson MW, Carducci MA et al (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol 30:1181–1197. https://doi.org/10.1177/0269881116675513
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426. https://doi.org/10.1016/s0301-0082(01)00011-9
Hartmann M, Heumann R, Lessmann V (2001) Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 20:5887–5897. https://doi.org/10.1093/emboj/20.21.5887
Hensler JG, Advani T, Monteggia LM (2007) Regulation of serotonin-1A receptor function in inducible brain-derived neurotrophic factor knockout mice after administration of corticosterone. Biol Psychiatry 62:521–529. https://doi.org/10.1016/j.biopsych.2006.10.015
Hibicke M, Landry AN, Kramer HM et al (2020) Psychedelics, but not ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression. ACS Chem Neurosci 11:864–871. https://doi.org/10.1021/acschemneuro.9b00493
Hikosaka O (2010) The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 11:503–513. https://doi.org/10.1038/nrn2866
Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500. https://doi.org/10.1523/JNEUROSCI.2213-07.2007
Huang Y-Y, Kandel ER (2007) 5-Hydroxytryptamine induces a protein kinase A/mitogen-activated protein kinase-mediated and macromolecular synthesis-dependent late phase of long-term potentiation in the amygdala. J Neurosci 27:3111–3119. https://doi.org/10.1523/JNEUROSCI.3908-06.2007
Jones KA, Srivastava DP, Allen JA et al (2009) Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci U S A 106:19575–19580. https://doi.org/10.1073/pnas.0905884106
Jope RS, Johnson GVW (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95–102. https://doi.org/10.1016/j.tibs.2003.12.004
Karyo R, Eskira Y, Pinhasov A et al (2010) Identification of eukaryotic elongation factor-2 as a novel cellular target of lithium and glycogen synthase kinase-3. Mol Cell Neurosci 45:449–455. https://doi.org/10.1016/j.mcn.2010.08.004
Katz EG, Hough D, Doherty T et al (2020) Benefit-risk assessment of esketamine nasal spray versus placebo in treatment-resistant depression. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.2024
Kinoshita H, Nishitani N, Nagai Y et al (2018) Ketamine-induced prefrontal serotonin release is mediated by cholinergic neurons in the pedunculopontine tegmental nucleus. Int J Neuropsychopharmacol 21:305–310. https://doi.org/10.1093/ijnp/pyy007
Klein AB, Santini MA, Aznar S et al (2010) Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice. Neuroscience 169:1007–1016. https://doi.org/10.1016/j.neuroscience.2010.05.054
Koike H, Chaki S (2014) Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav Brain Res 271:111–115. https://doi.org/10.1016/j.bbr.2014.05.065
Kozono N, Ohtani A, Shiga T (2017) Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro. Brain Res 1655:114–121. https://doi.org/10.1016/j.brainres.2016.11.021
Lecourtier L, DeFrancesco A, Moghaddam B (2008) Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release. Eur J Neurosci 27:1755–1762. https://doi.org/10.1111/j.1460-9568.2008.06130.x
Lepack AE, Fuchikami M, Dwyer JM, et al (2014) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18:. https://doi.org/10.1093/ijnp/pyu033
Lessmann V (1998) Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol 31:667–674. https://doi.org/10.1016/s0306-3623(98)00190-6
Levine ES, Crozier RA, Black IB, Plummer MR (1998) Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-d-aspartic acid receptor activity. PNAS 95:10235–10239. https://doi.org/10.1073/pnas.95.17.10235
Li N, Lee B, Liu R-J et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964. https://doi.org/10.1126/science.1190287
Li X, Polter A (2011) Glycogen synthase kinase-3 is an intermediate modulator of serotonin neurotransmission. Front Mol Neurosci 4:. https://doi.org/10.3389/fnmol.2011.00031
Li X, Zhu W, Roh M-S et al (2004) In vivo regulation of glycogen synthase kinase-3 β (GSK3 β ) by serotonergic activity in mouse brain. Neuropsychopharmacology 29:1426–1431. https://doi.org/10.1038/sj.npp.1300439
Licht CL, Knudsen GM, Sharp T (2010) Effects of the 5-HT(4) receptor agonist RS67333 and paroxetine on hippocampal extracellular 5-HT levels. Neurosci Lett 476:58–61. https://doi.org/10.1016/j.neulet.2010.04.002
Lindefors N, Barati S, O’Connor WT (1997) Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex. Brain Res 759:205–212. https://doi.org/10.1016/s0006-8993(97)00255-2
Liu R-J, Fuchikami M, Dwyer JM et al (2013) GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 38:2268–2277. https://doi.org/10.1038/npp.2013.128
Lucas G, Compan V, Charnay Y et al (2005) Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists. Biol Psychiatry 57:918–925. https://doi.org/10.1016/j.biopsych.2004.12.023
Lucas G, Debonnel G (2002) 5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphé nucleus 5-HT neuronal activity. Eur J Neurosci 16:817–822. https://doi.org/10.1046/j.1460-9568.2002.02150.x
Lucas G, Du J, Romeas T et al (2010) Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat. PLoS ONE 5:e9253. https://doi.org/10.1371/journal.pone.0009253
Lucas G, Rymar VV, Du J et al (2007) Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712–725. https://doi.org/10.1016/j.neuron.2007.07.041
Ly C, Greb AC, Cameron LP et al (2018) Psychedelics promote structural and functional neural plasticity. cell reports 23:3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022
Ly C, Greb AC, Vargas MV et al (2021) Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth. ACS Pharmacol Transl Sci 4:452–460. https://doi.org/10.1021/acsptsci.0c00065
Maeng S, Zarate CA, Du J et al (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiat 63:349–352. https://doi.org/10.1016/j.biopsych.2007.05.028
McIntyre RS, Carvalho IP, Lui LMW et al (2020) The effect of intravenous, intranasal, and oral ketamine in mood disorders: a meta-analysis. J Affect Disord 276:576–584. https://doi.org/10.1016/j.jad.2020.06.050
Mendez-David I, David DJ, Darcet F et al (2014) Rapid anxiolytic effects of a 5-HT4 receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology 39:1366–1378. https://doi.org/10.1038/npp.2013.332
Messaoudi E, Bardsen K, Srebro B, Bramham CR (1998) Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus. J Neurophysiol 79:496–499
Metzger M, Bueno D, Lima LB (2017) The lateral habenula and the serotonergic system. Pharmacol Biochem Behav 162:22–28. https://doi.org/10.1016/j.pbb.2017.05.007
Middei S, Houeland G, Cavallucci V et al (2013) CREB is necessary for synaptic maintenance and learning-induced changes of the AMPA receptor GluA1 subunit. Hippocampus 23:488–499. https://doi.org/10.1002/hipo.22108
Miyake A, Kitamura Y, Miyazaki I et al (2014) Effects of (+)-8-OH-DPAT on the duration of immobility during the forced swim test and hippocampal cell proliferation in ACTH-treated rats. Pharmacol Biochem Behav 122:240–245. https://doi.org/10.1016/j.pbb.2014.04.003
Mogha A, Guariglia SR, Debata PR et al (2012) Serotonin 1A receptor-mediated signaling through ERK and PKCα is essential for normal synaptogenesis in neonatal mouse hippocampus. Transl Psychiatry 2:e66. https://doi.org/10.1038/tp.2011.58
Morrison RL, Fedgchin M, Singh J et al (2018) Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology 235:1107–1119. https://doi.org/10.1007/s00213-018-4828-5
Nelson JC, Papakostas GI (2009) Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 166:980–991. https://doi.org/10.1176/appi.ajp.2009.09030312
Nishi M, Whitaker-Azmitia PM, Azmitia EC (1996) Enhanced synaptophysin immunoreactivity in rat hippocampal culture by 5-HT 1A agonist, S100b, and corticosteroid receptor agonists. Synapse 23:1–9. https://doi.org/10.1002/(SICI)1098-2396(199605)23:1%3c1::AID-SYN1%3e3.0.CO;2-E
Nosyreva E, Szabla K, Autry AE et al (2013) Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci 33:6990–7002. https://doi.org/10.1523/JNEUROSCI.4998-12.2013
Ortega F, Pérez-Sen R, Morente V et al (2010) P2X7, NMDA and BDNF receptors converge on GSK3 phosphorylation and cooperate to promote survival in cerebellar granule neurons. Cell Mol Life Sci 67:1723–1733. https://doi.org/10.1007/s00018-010-0278-x
Palhano-Fontes F, Barreto D, Onias H et al (2019) Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med 49:655–663. https://doi.org/10.1017/S0033291718001356
Pałucha-Poniewiera A, Podkowa K, Pilc A (2019) Role of AMPA receptor stimulation and TrkB signaling in the antidepressant-like effect of ketamine co-administered with a group II mGlu receptor antagonist, LY341495, in the forced swim test in rats. Behav Pharmacol 30:471–477. https://doi.org/10.1097/FBP.0000000000000471
Pascual-Brazo J, Castro E, Díaz A et al (2012) Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT4 receptor agonist RS67333. Int J Neuropsychopharmacol 15:631–643. https://doi.org/10.1017/S1461145711000782
Pehrson AL, Jeyarajah T, Sanchez C (2016) Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission. CNS Spectr 21:162–183. https://doi.org/10.1017/S1092852915000486
Pham TH, Mendez-David I, Defaix C et al (2017) Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice. Neuropharmacology 112:198–209. https://doi.org/10.1016/j.neuropharm.2016.05.010
Polter AM, Li X (2010) 5-HT1A receptor-regulated signal transduction pathways in brain. Cell Signal 22:1406–1412. https://doi.org/10.1016/j.cellsig.2010.03.019
Polter AM, Yang S, Jope RS, Li X (2012) Functional significance of glycogen synthase kinase-3 regulation by serotonin. Cell Signal 24:265–271. https://doi.org/10.1016/j.cellsig.2011.09.009
Qiao H, An S-C, Xu C, Ma X-M (2017) Role of proBDNF and BDNF in dendritic spine plasticity and depressive-like behaviors induced by an animal model of depression. Brain Res 1663:29–37. https://doi.org/10.1016/j.brainres.2017.02.020
Restivo L, Roman F, Dumuis A et al (2008) The promnesic effect of G-protein-coupled 5-HT4 receptors activation is mediated by a potentiation of learning-induced spine growth in the mouse hippocampus. Neuropsychopharmacology 33:2427–2434. https://doi.org/10.1038/sj.npp.1301644
Roberts D, Wolfarth A, Sanchez C, Pehrson AL (2018) Frontal cortex dysfunction as a target for remediation in opiate use disorder: role in cognitive dysfunction and disordered reward systems. Prog Brain Res 239:179–227. https://doi.org/10.1016/bs.pbr.2018.07.001
Rojas PS, Neira D, Muñoz M et al (2014) Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons. J Neurosci Res 92:1000–1009. https://doi.org/10.1002/jnr.23390
Roppongi RT, Kojima N, Hanamura K et al (2013) Selective reduction of drebrin and actin in dendritic spines of hippocampal neurons by activation of 5-HT(2A) receptors. Neurosci Lett 547:76–81. https://doi.org/10.1016/j.neulet.2013.04.061
Rumajogee P, Madeira A, Vergé D et al (2002) Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B-dependent mechanisms. J Neurochem 83:1525–1528. https://doi.org/10.1046/j.1471-4159.2002.01264.x
Saland SK, Kabbaj M (2018) Sex differences in the pharmacokinetics of low-dose ketamine in plasma and brain of male and female rats. J Pharmacol Exp Ther 367:393–404. https://doi.org/10.1124/jpet.118.251652
Sanches RF, de Lima OF, dos Santos RG et al (2016) Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J Clin Psychopharmacol 36:77–81. https://doi.org/10.1097/JCP.0000000000000436
Sari Y, Miquel MC, Brisorgueil MJ et al (1999) Cellular and subcellular localization of 5-hydroxytryptamine1B receptors in the rat central nervous system: immunocytochemical, autoradiographic and lesion studies. Neuroscience 88:899–915
Sasi M, Vignoli B, Canossa M, Blum R (2017) Neurobiology of local and intercellular BDNF signaling. Pflugers Arch - Eur J Physiol 469:593–610. https://doi.org/10.1007/s00424-017-1964-4
Schill Y, Bijata M, Kopach O et al (2020) Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin. Commun Biol 3:76. https://doi.org/10.1038/s42003-020-0791-x
Schmid CL, Raehal KM, Bohn LM (2008) Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc Natl Acad Sci U S A 105:1079–1084. https://doi.org/10.1073/pnas.0708862105
Schmid CL, Streicher JM, Meltzer HY, Bohn LM (2014) Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a βArrestin2-independent activation of Akt. Neuropsychopharmacology 39:1902–1913. https://doi.org/10.1038/npp.2014.38
Sowa J, Kusek M, Bobula B et al (2019) Ketamine administration reverses corticosterone-induced alterations in excitatory and inhibitory transmission in the rat dorsal raphe nucleus. Neural Plast 2019:3219490. https://doi.org/10.1155/2019/3219490
Spies M, James GM, Berroterán-Infante N et al (2018) Assessment of ketamine binding of the serotonin transporter in humans with positron emission tomography. Int J Neuropsychopharmacol 21:145–153. https://doi.org/10.1093/ijnp/pyx085
Svenningsson P, Chergui K, Rachleff I et al (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77–80. https://doi.org/10.1126/science.1117571
Svenningsson P, Tzavara ET, Carruthers R et al (2003) Diverse psychotomimetics act through a common signaling pathway. Science 302:1412–1415. https://doi.org/10.1126/science.1089681
Takahashi K, Kitamura Y, Ushio S, Sendo T (2020) Immobility-reducing effects of ketamine during the forced swim test on 5-HT1A receptor activity in the medial prefrontal cortex in an intractable depression model. Acta Med Okayama 74:301–306. https://doi.org/10.18926/AMO/60368
Tamburella A, Micale V, Navarria A, Drago F (2009) Antidepressant properties of the 5-HT4 receptor partial agonist, SL65.0155: behavioral and neurochemical studies in rats. Prog Neuropsychopharmacol Biol Psychiatry 33:1205–1210. https://doi.org/10.1016/j.pnpbp.2009.07.001
Tizabi Y, Bhatti BH, Manaye KF et al (2012) Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience 213:72–80. https://doi.org/10.1016/j.neuroscience.2012.03.052
Tornese P, Sala N, Bonini D et al (2019) Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine. Neurobiol Stress 10:100160. https://doi.org/10.1016/j.ynstr.2019.100160
Torres GE, Chaput Y, Andrade R (1995) Cyclic AMP and protein kinase A mediate 5-hydroxytryptamine type 4 receptor regulation of calcium-activated potassium current in adult hippocampal neurons. Mol Pharmacol 47:191–197
Trivedi MH, Rush AJ, Wisniewski SR et al (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40. https://doi.org/10.1176/appi.ajp.163.1.28
Vaidya VA, Castro ME, Pei Q et al (2001) Influence of thyroid hormone on 5-HT1A and 5-HT2A receptor-mediated regulation of hippocampal BDNF mRNA expression. Neuropharmacology 40:48–56. https://doi.org/10.1016/S0028-3908(00)00094-0
Vaidya VA, Marek GJ, Aghajanian GK, Duman RS (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17:2785–2795. https://doi.org/10.1523/JNEUROSCI.17-08-02785.1997
Warner-Schmidt JL, Chen EY, Zhang X et al (2010) A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiat 68:528–535. https://doi.org/10.1016/j.biopsych.2010.04.029
Widman AJ, Stewart AE, Erb EM et al (2018) Intravascular ketamine increases theta-burst but not high frequency tetanus induced LTP at CA3-CA1 synapses within three hours and devoid of an increase in spine density. Front Synaptic Neurosci 10:8. https://doi.org/10.3389/fnsyn.2018.00008
Wu YC, Hill RA, Klug M, van den Buuse M (2012) Sex-specific and region-specific changes in BDNF–TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice. Brain Res 1452:10–17. https://doi.org/10.1016/j.brainres.2012.03.011
Yadav PN, Kroeze WK, Farrell MS, Roth BL (2011) Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo. J Pharmacol Exp Ther 339:99–105. https://doi.org/10.1124/jpet.111.183780
Yamamoto S, Ohba H, Nishiyama S et al (2013) Subanesthetic doses of ketamine transiently decrease serotonin transporter activity: a PET study in conscious monkeys. Neuropsychopharmacology 38:2666–2674. https://doi.org/10.1038/npp.2013.176
Yamanaka H, Yokoyama C, Mizuma H et al (2014) A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques. Transl Psychiatry 4:e342. https://doi.org/10.1038/tp.2013.112
Yang Y, Cui Y, Sang K et al (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature London 554:317 322-322A 322O. https://doi.org/10.1038/nature25509
Yang Y, Ju W, Zhang H, Sun L (2018b) Effect of ketamine on lTP and NMDAR EPSC in hippocampus of the chronic social defeat stress mice model of depression. Front Behav Neurosci 12:. https://doi.org/10.3389/fnbeh.2018.00229
Zanos P, Gould TD (2018) Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23:801–811. https://doi.org/10.1038/mp.2017.255
Zanos P, Moaddel R, Morris PJ et al (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481–486. https://doi.org/10.1038/nature17998
Zarate CA, Singh JB, Carlson PJ et al (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864. https://doi.org/10.1001/archpsyc.63.8.856
Zhang J, Cai C-Y, Wu H-Y et al (2016) CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors. Sci Rep 6:29551. https://doi.org/10.1038/srep29551
Zhang K, Xu T, Yuan Z et al (2016) Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine. Sci Signal 9:ra123. https://doi.org/10.1126/scisignal.aai7884
Zhou J, Cao X, Mar AC et al (2014) Activation of postsynaptic 5-HT1A receptors improve stress adaptation. Psychopharmacology 231:2067–2075. https://doi.org/10.1007/s00213-013-3350-z
Zhou M-H, Sun F-F, Xu C et al (2019) Modulation of Kalirin-7 expression by hippocampal CA1 5-HT1B receptors in spatial memory consolidation. Behav Brain Res 356:148–155. https://doi.org/10.1016/j.bbr.2018.06.021
Zhou W, Dong L, Wang N et al (2014) Akt mediates GSK-3β phosphorylation in the rat prefrontal cortex during the process of ketamine exerting rapid antidepressant actions. NeuroImmunoModulation 21:183–188. https://doi.org/10.1159/000356517
Zhou W, Wang N, Yang C et al (2014) Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 29:419–423. https://doi.org/10.1016/j.eurpsy.2013.10.005
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The authors would like to thank Connie Sanchez, D.Sc. for her thoughtful suggestions on this manuscript.
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Pehrson, A.L., Roberts, D., Khawaja, A. et al. The role of serotonin neurotransmission in rapid antidepressant actions. Psychopharmacology 239, 1823–1838 (2022). https://doi.org/10.1007/s00213-022-06098-5
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DOI: https://doi.org/10.1007/s00213-022-06098-5