Alpha 2 delta ligands act as positive modulators of adult hippocampal neurogenesis and prevent depressive-like behavior induced by chronic restraint stress (original) (raw)

2012

https://doi.org/10.1124/MOL.112.077636

checkGet notified about relevant papers

checkSave papers to use in your research

checkJoin the discussion with peers

checkTrack your impact

Abstract

Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal

Neuropsychopharmacology, 2011

The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment.

Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci 20: 9104-9110

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal-or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.

Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000

Hippocampal Neurogenesis and Antidepressive Therapy: Shocking Relations

Neural Plasticity, 2014

Speculations on the involvement of hippocampal neurogenesis, a form of neuronal plasticity, in the aetiology of depression and the mode of action of antidepressive therapies, started to arise more than a decade ago. But still, conclusive evidence that adult neurogenesis contributes to antidepressive effects of pharmacological and physical therapies has not been generated yet. This review revisits recent findings on the close relation between the mode(s) of action of electroconvulsive therapy (ECT), a powerful intervention used as second-line treatment of major depression disorders, and the neurogenic response to ECT. Following application of electroconvulsive shocks, intricate interactions between neurogenesis, angiogenesis, and microglia activation, the hypothalamic-pituitaryadrenal axis and the secretion of neurotrophic factors have been documented. Furthermore, considering the fact that neurogenesis strongly diminishes along aging, we investigated the response to electroconvulsive shocks in young as well as in aged cohorts of mice.

Role of Hippocampal Neurogenesis in the Pathophysiology and Treatment of Depression

Neurobiology of Mood Disorders, 2014

Depression and anxiety are psychiatric illnesses that are major burdens on society chronic corticosterone treatment. We discuss the pros and cons of these different approaches. Furthermore, we provide a detailed review of adult hippocampal neurogenesis, including the distinct phases that a cell passes through when transitioning from precursor to neuron. Finally, we discuss at length the experiments that have related adult hippocampal neurogenesis to treatments of depression and anxiety, and why neurogenesis might be necessary for these treatments. We end by revisiting the neurogenesis hypothesis of depression and by providing suggestions for future research directions.

P.2.d.027 Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates

European Neuropsychopharmacology, 2011

Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs.

Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal

Biological Psychiatry, 2008

Background: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.

Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

Science, 2003

Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressantinduced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts ( þ 16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons ( þ 26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5 0 -bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, ( þ 14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27 Kip1 and p57 Kip2 . In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.

The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling

2008

The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest reestablishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (60)

Aimone JB, Deng W, and Gage FH (2011) Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70: 589-596.
Alvarez-Buylla A, Garcia-Verduno JM, and Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2: 287-293.
Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, Kadurin I, Sri Ranjan Y, Fernandez-Alacid L, Millar NS, Dickenson AH, Lujan R, and Dolphin AC (2009) The increased trafficking of calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci 29: 4076-4088.
Baxter A, Brough S, Cooper A, Floettmann E, Foster S, Harding C, Kettle J, McInally T, Martin C, Nobbs M, Needham M, Newham P, Paine S, St-Gallay S, Salter S, Unitt J, and Xue Y (2004) Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors. Bioorg Med Chem Lett 14: 2817-2822.
Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP, and Walker LC (2006) Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain Res 1075: 68-80.
Bockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey CW, Busch JA, Randinitis EJ, Corrigan BW, Haig GM, Boyd RA, and Wesche DL (2010) Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol 50: 941-950.
Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, and Arango V (2009) Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34: 2376-2389.
Bourin M, Chenu F, Ripoll N, and David DJ (2005) A proposal of decision tree to screen putative antidepressants using forced swim and tail suspension tests. Behav Brain Res 164: 266-269.
Brazel CY, Limke TL, Osborne JK, Miura T, Cai J, Pevny L, and Rai MS (2005) Sox2 expression defines a heterogeneous population of neurosphere-forming cells in the adult murine brain. Aging Cell 4: 197-207.
Brown JP, Dissanayake VU, Briggs AR, Milic MR, and Gee NS (1998) Isolation of the [3H]gabapentin-binding protein/alpha 2 delta Ca2 + channel subunit from porcine brain: development of a radioligand binding assay for alpha 2 delta subunits using [3H]leucine. Anal Biochem 255: 236-243.
Couillard-Despres S, Iglseder B, and Aigner L (2011). Neurogenesis, a cellular plasticity and cognition: the impact of stem cells in the adult and aging brain. Gerontology 57: 559-564.
Cryan JF and Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discover 4: 775-790.
Cunningham MO, Woodhall GL, Thompson SE, Dooley DJ, and Jones RS (2004) Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. Eur J Neurosci 20: 1566-1576.
David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, and Hen R (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62: 479-493.
DeCarolis NA and Eisch AJ (2010) Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58: 884-893.
Deng W, Aimone JB, and Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11: 339-350.
Denis-Donini S, Caprini A, Frassoni C, and Grilli M (2005). Members of the NF-kappaB family expressed in zones of active neurogenesis in the postnatal and adult mouse brain. Brain Res Dev Brain Res 154: 81-89.
Denis-Donini S, Dellarole A, Crociara P, Francese MT, Bortolotto V, Quadrato G, Canonico PL, Orsetti M, Ghi P, Memo M, Bonini SA, Ferrari-Toninelli G, and Grilli M (2008) Impaired adult neurogenesis associated with short-term memory defects in NF-kappaB p50-deficient mice. J Neurosci 28: 3911-3919.
Duman RS, Malberg J, and Nakagawa S (2001) Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 299: 401-407.
Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, and Barres BA (2009) Gabapentin receptor alpha2delta- 1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139: 380-392.
Field MJ, Cox PJ, Stott E, Melrose H, Offord J, Su TZ, Bramwell S, Corradini L, England S, Winks J, Kinloch RA, Hendrich J, Dolphin AC, Webb T, and Williams D (2006) Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci U S A 103: 17537-17542.
Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, and Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 271: 5768-5776.
Graham V, Khudyakov J, Ellis P, Pevny L (2003) SOX2 functions to maintain neural progenitor identity. Neuron 28;39(5):749-65.
Grilli M and Memo M (1997) Transcriptional pharmacology of neurodegenerative disorders: novel venue towards neuroprotection against excitotoxicity? Mol Psychiatry 2: 192-194.
Grilli M and Meneghini V (2012) NF-κB proteins in adult neurogenesis: relevance for learning and memory in physiology and pathology. In: Transcription Factors CREB and NF-κB: Involvement in Synaptic Plasticity and Memory Formation (Albensi BC, ed) pp 199-250. Bentham ebook.
Hanson ND, Owens MJ, and Nemeroff CB (2011) Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology 36: 2589-2602.
Huang CW, Huang CC, and Wu SN (2006) The opening effect of pregabalin on ATP-sensitive potassium channels differentiated hippocampal neuron-derived H19-7 cells. Epilepsia 47: 720-726.
Kempermann G, Krebs J, and Fabel K (2008) The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatry 21: 290-295.
Kriegstein A and Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Ann Rev Neurosci 32: 149-184.
Koo JW, Russo SJ, Ferguson D, Nestler EJ, and Duman RS (2010) Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A 107: 2669-2674.
Kurshan PT, Oztan A, and Schwarz TL (2009) Presynaptic alpha2delta-3 is required for synaptic morphogenesis indipendent of its Ca 2+ -channel functions. Nat Neurosci 12: 1415-1423.
Lazarov O and Marr RA (2010) Neurogenesis and Alzheimer's disease: at the crossroad. Exp Neurol 223: 267-281.
Lin YZ, Yao SY, Veach RA, Torgerson TR, and Hawiger J (1995) Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem 270: 14255- 14258.
Lotarski SM, Donevan S, El-Kattan A, Osgood S, Poe J, Taylor CP, and Offord J (2011) Anxiolytic-like activity of Pregabalin in the Vogel Conflict Test in α2δ-1 (R217A) and α2δ-2 (R279A) Mouse Mutants. J Pharmacol Exp Ther 338: 615-621.
Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, Oomen CA, and Czéh B (2010) Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol 20: 1-17.
Luo C, Xu H, and Li XM (2005) Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restrain stress. Brain Res 1063: 32-39.
Malberg JE (2004) Implications of adult hippocampal neurogenesis in antidepressant action. J Psychiatry Neurosci 29: 196-205.
Malberg JE and Blendy, JA (2005) Antidepressant action: the nucleus and beyond. Trends Pharmacol Sci 26: 631-638.
Maneuf YP, Hughes J, and McKnight AT (2001) Gabapentin inhibits the substance P-facilitated K(+)-evoked release of [(3)H] glutamate from rat caudial trigeminal nucleus slices. Pain 93: 191-196.
Meneghini V, Francese MT, Carraro L, and Grilli M (2010) A novel role for the Receptor for Advanced Glycation End-products in neural progenitor cells derived from adult SubVentricular Zone. Mol Cell Neurosci 45: 139-150.
Messam CA, Hou J, Berman JW, Major EO (2002) Analysis of the temporal expression of nestin in human fetal brain derived neuronal and glial progenitor cells. Dev Brain Res 134: 87-92.
Ming GL and Song H (2011) Adult neurogenesis in the Mammalian brain: significant answers and significant questions. Neuron 70: 687-702.
Mortell KH, Anderson DJ, Lynch JJ 3 rd , Nelson SL, Sarris K, McDonald H, Sabet R, Baker S, Honore P, Lee CH, Jarvis MF, and Gopalkrishnan M (2006) Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels. Bioorg Chem Med Lett 16: 1138-1141.
Pae CU (2009) Pregabalin augmentation to antidepressants in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 33: 577-578.
Pae CU, Marks DM, Han C, Masand PS, and Patkar AA (2009) Pregabalin augmentation of antidepressants in patients with accident-related posttraumatic stress disorder: an open label pilot study. Int Clin Psychopharmacol 24: 29-33.
Park S, Ahn ES, Han DW, Lee JH, Min KT, Kim H, and Hong YW (2008) Pregabalin and gabapentin inhibit substance P-induced NF-kappaB activation in neuroblastoma and glioma cells. J Cell Biochem 105: 414-423.
Perera TD, Dwork AJ, Keegan KA, Thirumangalakudi L, Lipira CM, Joyce N, Lange C, Higley JD, Rosoklija G, hen R, Sackeim HA, and Coplan JD (2011) Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One 6: e17600.
Pittenger C and Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanism. Neuropsychopharmacology 33: 88-109.
Porsolt RD (2000) Animal models of depression: utility for transgenic research. Rev Neurosci 11: 53-58.
Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, and Schwartz M (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9: 1081-1088.
Sahay A, Wilson DA, and Hen R (2011) Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70: 582-588.
Samuel BA and Hen R (2011) Neurogenesis and affective disorders. Eur J Neurosci 33: 1152- 1159.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, and Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805-809.
Shin HM, Kim MH, Kim BH, Jung SH, Kim YS, Park HJ, Hong JT, Min KR, and Kim Y (2004) Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-kappaB without affecting IkappaB degradation. FEBS Lett 571: 50-54.
Sills GJ (2006) The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 6: 108-113.
Stein DJ, Baldwin DS, Baldinetti F, and Mandel F (2008) Efficacy of pregabalin in depressive symptoms associated with generalized anxiety disorder: a pooled analysis of 6 studies. Eur Neuropsychopharmacol 18: 422-430.
Taylor CP, Angelotti T, and Fauman E (2007) Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73: 137-150.
Terada M, Kuzumaki N, Hareyama N, Imai S, Niikura K, Narita M, Yamazaki M, Suzuki T, and Narita M (2008) Suppression of enriched environment-induced neurogenesis in rodent model of neuropathic pain. Neurosci Lett 440: 314-318.
Warner-Schmidt JL and Duman RS (2006) Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16: 239-249.
Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, Yoneyama M, Ogita K, Yoneda Y, Nabeshima T, Nagai T, and Yamada K (2010) Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. J Neurochem 114: 1840-1851.

α2δ Ligands Act as Positive Modulators of Adult Hippocampal Neurogenesis and Prevent Depressive-like Behavior Induced by Chronic Restraint Stress

Molecular pharmacology, 2012

Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggest that the process is involved in cognitive and emotional functions and deregulated in various neuropsychiatric disorders, including major depression. Interestingly, several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the alpha2delta α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid; GBP] and pregabalin [S-[+]-3-isobutylGABA or (S)-3-(aminomethyl)-5-methylhexanoic acid; PGB] can produce a concentration-dependent increase in the number of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells (NPC), and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, since a significantly increased number of adult generated neurons was observed in the hippocampal region of mice chronically treated with...

Adult hippocampal neurogenesis: Is it the alpha and omega of antidepressant action

Hoda Eliwa, 2017

It is now well established that all clinically available antidepressants share a common aptitude: they increase the production of adult-generated neurons in the dentate gyrus of the hippocampus. This was first observed in animal models and subsequently in human populations, highlighting the clinical relevance of this finding. Later, it was suggested that hippocampal neurogenesis was not an epiphenomenal correlate of antidepressant action but was causally involved. Indeed, when neurogenesis is suppressed, antidepressant compounds can no longer achieve remission. This action of adult-born neurons seems necessary to achieve remission, but less evidence exists to show that it is sufficient alone. In the following decades, a new generation of putative antidepressants that act through different non-monoaminergic mechanisms were proposed in preclinical research as potential therapies. Interestingly, these treatments all increased neurogenesis in animal models of pathological states: this was observed with drugs acting through peptidergic or glutamatergic mechanisms and with neurostimulation strategies not targeting the hippocampus. However, the involvement of neurogenesis was not always causal. To advance further in this field, an understanding of how adult-generated neurons induce therapeutic effects and how this is related to the pathophysiology of depression are required.

Implications of adult hippocampal neurogenesis in antidepressant action

Journal of psychiatry & neuroscience : JPN, 2004

In the dentate gyrus of the hippocampus, cell birth and maturation into neurons, or neurogenesis, occur throughout the lifetime of animals and humans. Multiple factors have been shown to regulate adult neurogenesis, and a number of findings in this field have had a large impact on basic and clinical research in depression. It has been reported that both physical and psychosocial stress paradigms, as well as some animal models of depression, produce a decrease in hippocampal cell proliferation and neurogenesis. Conversely, long-term, but not short-term, treatment with different classes of antidepressant drug increases cell proliferation and neurogenesis. Patients with depressive disorders or post-traumatic stress disorder have reduced hippocampal volume. Given this interaction of stress, depression and neurogenesis, a current hypothesis is that reduced adult hippocampal cell proliferation or neurogenesis may be involved in the pathophysiology of depression and that reversal or preven...

Regulation of Adult Neurogenesis by Antidepressant Treatment

Neuropsychopharmacology, 2001

Demonstration of neurogenesis in adult brain represents a major advance in our understanding of the cellular mechanisms underlying neuronal remodeling and complex behavior. Recent studies from our laboratory and others demonstrate that chronic administration of an antidepressant, including either a 5-HT or norepinephrine selective reuptake inhibitor, up-regulates neurogenesis in adult rodent hippocampus. Up-regulation of neurogenesis could block or reverse the effects of stress on hippocampal neurons, which include down-regulation of neurogenesis, as well as atrophy. The possibility that the cAMP signal transduction cascade contributes to the regulation of neurogenesis by antidepressants is supported by previous studies and by recent work. Although additional studies must be conducted to determine the significance of adult neurogenesis in humans, these findings will stimulate new avenues of research to identify the cellular and molecular basis of stress-related mood disorders as well as the development of novel therapeutic strategies.

Increasing Hippocampal Neurogenesis: A Novel Mechanism for Antidepressant Drugs

Current Pharmaceutical Design, 2005

The birth of new neurons, or neurogenesis, in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans. A major finding in the field of depression is that treatment with antidepressant drugs increases hippocampal neurogenesis. This review presents a current summary of this field of study and presents the hypothesis that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs. It has been demonstrated that multiple classes of antidepressant drugs increase hippocampal cell proliferation and neurogenesis in a chronic and not acute time course, which corresponds to the therapeutic time course necessary for effects. Conversely, animal models of depression or stress paradigms decrease cell proliferation. Clinically, there is evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders. Taken together, this data indicates that reduced hippocampal cell number may be involved in the pathophysiology of depression and reversal of this may be one way the antidepressant drugs exert their effects. We hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors. In addition, the ability of novel compounds to be tested for the neurogenic potential may become an additional way to evaluate a compound for putative antidepressant effects.

Neurogenesis and the Effect of Antidepressants

Drug Target Insights, 2006

The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs) reside in the adult central nervous system (CNS) suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fl uoxetine, increase neurogenesis in the dentate gyrus (DG) and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

PLOS One, 2011

Sustained remission from depressive-like behavior depends on hippocampal neurogenesis

Translational Psychiatry, 2013

Impairment of hippocampal neurogenesis has been associated with the expression of depressive-like symptoms and some studies have suggested neurogenesis as a critical factor in the normalization of behavior by antidepressant (AD) drugs. This study provides robust evidence that ongoing neurogenesis is essential for the maintenance of behavioral homeostasis and that its pharmacological arrest precipitates symptoms commonly found in depressed patients. Further, the incorporation of newly born neurons and astrocytes into the preexisting hippocampal neurocircuitry is shown to be necessary for the spontaneous recovery from the adverse effects of stress and for long-term benefits of AD treatments.

Increased Hippocampal Neurogenesis and p21 Expression in Depression: Dependent on Antidepressants, Sex, Age, and Antipsychotic Exposure.

The mammalian hippocampus continues to generate new neurons throughout life. The function of adult-generated neurons remains controversial, but adult neurogenesis in the hippocampus is related to depression. Studies show that neurogenesis in the hippocampus is regulated by antidepressants in both humans and rodents, but no studies have examined the effects of age, sex, or antipsychotic exposure on the relationship between depression, antidepressant exposure, and hippocampal neurogenesis in humans. Hippocampal sections were obtained from the Stanley Medical Research Institute and were immunohistochemically labeled for the immature neuron marker doublecortin and the cell cycle arrest marker p21. We compared the number of cells in the granule cell layer and subgranular zone that expressed these proteins in brains from control subjects (n ¼ 12), patients with major depressive disorder (MDD) without psychotic symptoms (n ¼ 12), and patients with MDD and psychotic symptoms (n ¼ 12). We show here that the density of doublecortin/NeuN expression was increased in MDD patients compared with controls and MDD patients with psychosis, with the effect greater in women. Further, we show that older depressed patients without psychosis had higher levels of p21/NeuN expression and that depressed individuals prescribed antidepressants had higher levels of p21/NeuN expression, but only in older women. We show for the first time that changes in neurogenesis due to prescribed antidepressants or depression are dependent on age, sex, and the presence of antipsychotics or psychotic symptoms.

Antidepressant-Induced Neurogenesis in the Hippocampus of Adult Nonhuman Primates

Journal of Neuroscience, 2007

New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the

Cited by

Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine

Neuropsychopharmacology, 2013

Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-kB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-kB pathway, and in particular by p65 acetylation, and subsequent NF-kB-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants.

NF-B Mediated Regulation of Adult Hippocampal Neurogenesis: Relevance to Mood Disorders and Antidepressant Activity

BioMed Research International, 2014

Adult hippocampal neurogenesis is a peculiar form process of neuroplasticity that in recent years has gained great attention for its potential implication in cognition and in emotional behavior in physiological conditions. Moreover, a vast array of experimental studies suggested that adult hippocampal neurogenesis may be altered in various neuropsychiatric disorders, including major depression, where its disregulation may contribute to cognitive impairment and/or emotional aspects associated with those diseases. An intriguing area of interest is the potential influence of drugs on adult neurogenesis. In particular, several psychoactive drugs, including antidepressants, were shown to positively modulate adult hippocampal neurogenesis. Among molecules which could regulate adult hippocampal neurogenesis the NF-κB family of transcription factors has been receiving particular attention from our and other laboratories. Herein we review recent data supporting the involvement of NF-B signaling pathways in the regulation of adult neurogenesis and in the effects of drugs that are endowed with proneurogenic and antidepressant activity. The potential implications of these findings on our current understanding of the process of adult neurogenesis in physiological and pathological conditions and on the search for novel antidepressants are also discussed.

l-Acetylcarnitine: A Mechanistically Distinctive and Potentially Rapid-Acting Antidepressant Drug

International journal of molecular sciences, 2017

Current therapy of mood disorders has several limitations. Although a high number of drugs are clinically available, as of today, nearly two-thirds of individuals do not achieve full symptomatic remission after treatment with conventional antidepressants. Moreover, several weeks of drug treatment are usually required to obtain clinical effects, a limitation that has considerable clinical implications, ranging from high suicide risk to reduced compliance. The characteristic lag time in classical antidepressant effectiveness has given great impulse to the search for novel therapeutics with more rapid effects. l-acetylcarnitine (LAC), a small molecule of growing interest for its pharmacological properties, is currently marketed for treatment of neuropathic pain. Recent preclinical and clinical data suggested that LAC may exert antidepressant effects with a more rapid onset than conventional drugs. Herein, we review data supporting LAC antidepressant activity and its distinctive mechani...

Operant self-administration of pregabalin in a mouse model of neuropathic pain

European Journal of Pain, 2017

This study shows that mice with a nerve injury self-administer pregabalin at doses effective reducing nociceptive hypersensitivity and depressive-like behavior associated with the neuropathic pain model. Interestingly, mice without neuropathy also develop operant self-administration behavior, suggesting potential abuse liability of this first-line drug for neuropathic pain treatment.

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Toxicology Mechanisms and Methods, 2017

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment. Methods: In this study the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10 mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals' locomotor activity was also studied. Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (P < 0.05). During the acquisition phase of the Morris water maze pregabalin-treated memory-impaired mice performed the test with longer escape latencies than the vehicle-treated mice (significant at P < 0.05 on day 5, and at P < 0.001 on day 6). There were no differences in this parameter between the scopolamine-treated control group and pregabalintreated memory-impaired mice, which indicated that pregabalin had no influence on spatial learning in this task. During the probe trial a significant difference (P < 0.05) was observed in terms of the mean number of target crossings between vehicle-treated mice and pregabalin-treated memoryimpaired mice but there was no difference between the scopolamine-treated control group and mice treated with pregabalin+scopolamine. Pregabalin did not influence locomotor activity increased by scopolamine. Discussion: In passive avoidance task pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).

Alpha 2 delta ligands act as positive modulators of adult hippocampal neurogenesis and prevent depressive-like behavior induced by chronic restraint stress (original) (raw)

Sign up for access to the world's latest research

Abstract

Related papers

References (60)

Related papers

Related topics

Cited by