Skip to main content
    • Aa
    • Aa

The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats

  • Lisa Conboy (a1), Cihan Tanrikut (a1), Phillip R. Zoladz (a2) (a3) (a4), Adam M. Campbell (a5), Collin R. Park (a2) (a3) (a4), Cecilia Gabriel (a6), Elisabeth Mocaer (a6), Carmen Sandi (a1) and David M. Diamond (a2) (a7) (a3) (a4)...

Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT2C receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.

Corresponding author
Address for correspondence: Dr L. Conboy, Laboratory of Behavioural Genetics, Brain Mind Institute, Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland. Tel.: +41 21 693 16 75Fax: +41 21 693 96 37E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

I Akirav , M Kozenicky , D Tal , C Sandi , C Venero , G Richter-Levin (2004). A facilitative role for corticosterone in the acquisition of a spatial task under moderate stress. Learning & Memory 11, 188195.

J Alfonso , LR Frick , DM Silberman , ML Palumbo , AM Genaro , AC Frasch (2006). Regulation of hippocampal gene expression is conserved in two species subjected to different stressors and antidepressant treatments. Biological Psychiatry 59, 244251.

SM Armstrong , OM McNulty , B Guardiola-Lemaitre , JR Redman (1993). Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS). Pharmacology, Biochemistry, and Behavior 46, 4549.

M Banasr , A Soumier , M Hery , E Mocaer , A Daszuta (2006). Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biological Psychiatry 59, 10871096.

DM Bannerman , MA Good , SP Butcher , M Ramsay , RG Morris (1995). Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378, 182186.

DM Bannerman , JN Rawlins , SB McHugh , RM Deacon , BK Yee , T Bast , WN Zhang , HH Pothuizen , J Feldon (2004). Regional dissociations within the hippocampus – memory and anxiety. Neuroscience and Biobehavioral Reviews 28, 273283.

N Barden , E Shink , M Labbe , R Vacher , J Rochford , E Mocaer (2005). Antidepressant action of agomelatine (S 20098) in a transgenic mouse model. Progress in Neuro-Psychopharmacology & Biological Psychiatry 29, 908916.

G Baydas , VS Nedzvetsky , PA Nerush , SV Kirichenko , HM Demchenko , RJ Reiter (2002). A novel role for melatonin: regulation of the expression of cell adhesion molecules in the rat hippocampus and cortex. Neuroscience Letters 326, 109112.

G Baydas , M Ozer , A Yasar , M Tuzcu , ST Koz (2005). Melatonin improves learning and memory performances impaired by hyperhomocysteinemia in rats. Brain Research 1046, 187194.

L Bonfanti (2006). PSA-NCAM in mammalian structural plasticity and neurogenesis. Progress in Neurobiology 80, 129164.

V Bertaina-Anglade , CD la Rochelle , PA Boyer , E Mocaer (2006). Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model. Behavioural Pharmacology 17, 703713.

JD Bremner , M Narayan , ER Anderson , LH Staib , HL Miller , DS Charney (2000). Hippocampal volume reduction in major depression. American Journal of Psychiatry 157, 115118.

JD Bremner , E Vermetten (2001). Stress and development: behavioral and biological consequences. Development and Psychopathology 13, 473489.

AM Campbell , CR Park , PR Zoladz , C Munoz , M Fleshner , DM Diamond (2008). Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress. European Neuropsychopharmacology 18, 8798.

A Chagraoui , P Protais , T Filloux , E Mocaer (2003). Agomelatine (S 20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats. Psychopharmacology 170, 1722.

DJ de Quervain , B Roozendaal , RM Nitsch , JL McGaugh , C Hock (2000). Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nature Neuroscience 3, 313314.

DM Diamond , CR Park , KL Heman , GM Rose (1999). Exposing rats to a predator impairs spatial working memory in the radial arm water maze. Hippocampus 9, 542552.

DM Diamond , A Campbell , CR Park , RM Vouimba (2004). Preclinical research on stress, memory, and the brain in the development of pharmacotherapy for depression. European Neuropsychopharmacology 14 (Suppl. 5), S491495.

DM Diamond , AM Campbell , CR Park , JC Woodson , CD Conrad , AD Bachstetter , RF Mervis (2006). Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 16, 571576.

HS Donohue , PL Gabbott , HA Davies , JJ Rodriguez , MI Cordero , C Sandi , NI Medvedev , VI Popov , FM Colyer , CJ Peddie , MG Stewart (2006). Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience 140, 597606.

J Ferbinteanu , C Ray , RJ McDonald (2003). Both dorsal and ventral hippocampus contribute to spatial learning in Long-Evans rats. Neuroscience Letters 345, 131135.

AG Foley , BP Hartz , HC Gallagher , LC Ronn , V Berezin , E Bock , CM Regan (2000). A synthetic peptide ligand of neural cell adhesion molecule (NCAM) IgI domain prevents NCAM internalization and disrupts passive avoidance learning. Journal of Neurochemistry 74, 26072613.

AG Foley , WD Hirst , HC Gallagher , C Barry , JJ Hagan , N Upton , FS Walsh , AJ Hunter , CM Regan (2008). The selective 5-HT(6) receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats. Neuropharmacology 54, 11661174.

MS Hammond , C Sims , K Parameshwaran , V Suppiramaniam , M Schachner , A Dityatev (2006). Neural cell adhesion molecule-associated polysialic acid inhibits NR2B-containing N-methyl-d-aspartate receptors and prevents glutamate-induced cell death. Journal of Biological Chemistry 281, 3485934869.

D Healy , JM Waterhouse (1995). The circadian system and the therapeutics of the affective disorders. Pharmacology & Therapeutics 65, 241263.

C Heim , CB Nemeroff (1999). The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biological Psychiatry 46, 15091522.

S Hitoshi , N Maruta , M Higashi , A Kumar , N Kato , K Ikenaka (2007). Antidepressant drugs reverse the loss of adult neural stem cells following chronic stress. Journal of Neuroscience Research 85, 35743585.

KB Hoffman , BA Murray , G Lynch , S Munirathinam , BA Bahr (2001). Delayed and isoform-specific effect of NMDA exposure on neural cell adhesion molecules in hippocampus. Neuroscience Research 39, 167173.

SH Kennedy , R Emsley (2006). Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. European Neuropsychopharmacology 16, 93100.

C Kirschbaum , OT Wolf , M May , W Wippich , DH Hellhammer (1996). Stress- and treatment-induced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sciences 58, 14751483.

MA Lopez-Fernandez , MF Montaron , E Varea , G Rougon , C Venero , DN Abrous , C Sandi (2007). Upregulation of polysialylated neural cell adhesion molecule in the dorsal hippocampus after contextual fear conditioning is involved in long-term memory formation. Journal of Neuroscience 27, 45524561.

MA Lynch , KL Voss (1991). Presynaptic changes in long-term potentiation: elevated synaptosomal calcium concentration and basal phosphoinositide turnover in dentate gyrus. Journal of Neurochemistry 56, 113118.

GM MacQueen , S Campbell , BS McEwen , K Macdonald , S Amano , RT Joffe , C Nahmias , LT Young (2003). Course of illness, hippocampal function, and hippocampal volume in major depression. Proceedings of the National Academy of Sciences USA 100, 13871392.

L Martinet , B Guardiola-Lemaitre , E Mocaer (1996). Entrainment of circadian rhythms by S-20098, a melatonin agonist, is dose and plasma concentration dependent. Pharmacology, Biochemistry, and Behavior 54, 713718.

CA McClung (2007). Circadian genes, rhythms and the biology of mood disorders. Pharmacology & Therapeutics 114, 222232.

BS McEwen , JP Olie (2005). Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine. Molecular Psychiatry 10, 525537.

JJ Merino , MI Cordero , C Sandi (2000). Regulation of hippocampal cell adhesion molecules NCAM and L1 by contextual fear conditioning is dependent upon time and stressor intensity. European Journal of Neuroscience 12, 32833290.

MJ Millan , A Gobert , F Lejeune , A Dekeyne , A Newman-Tancredi , V Pasteau , JM Rivet , D Cussac (2003). The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. Journal of Pharmacology and Experimental Therapeutics 306, 954964.

MJ Millan , M Brocco , A Gobert , A Dekeyne (2005). Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology 177, 448458.

SA Montgomery (2006). Major depressive disorders: clinical efficacy and tolerability of agomelatine, a new melatonergic agonist. European Neuropsychopharmacology 16, S633S638.

RG Morris , E Anderson , GS Lynch , M Baudry (1986). Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774776.

MB Moser , EI Moser , E Forrest , P Andersen , RG Morris (1995). Spatial learning with a minislab in the dorsal hippocampus. Proceedings of the National Academy of Sciences USA 92, 96979701.

KJ Murphy , AW O'Connell , CM Regan (1996). Repetitive and transient increases in hippocampal neural cell adhesion molecule polysialylation state following multitrial spatial training. Journal of Neurochemistry 67, 12681274.

M Papp , P Gruca , PA Boyer , E Mocaer (2003). Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 28, 694703.

CR Park , AM Campbell , JC Woodson , TP Smith , M Fleshner , DM Diamond (2006). Permissive influence of stress in the expression of a U-shaped relationship between serum corticosterone levels and spatial memory errors in rats. Dose-Response 4, 5574.

CR Park , PR Zoladz , CD Conrad , M Fleshner , DM Diamond (2008). Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats. Learning & Memory 15, 271280.

K Pham , J Nacher , PR Hof , BS McEwen (2003). Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. European Journal of Neuroscience 17, 879886.

JR Redman , B Guardiola-Lemaitre , M Brown , P Delagrange , SM Armstrong (1995). Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms. Psychopharmacology 118, 385390.

C Rocher , M Spedding , C Munoz , TM Jay (2004). Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cerebral Cortex 14, 224229.

M Sairanen , OF O'Leary , JE Knuuttila , E Castren (2007). Chronic antidepressant treatment selectively increases expression of plasticity-related proteins in the hippocampus and medial prefrontal cortex of the rat. Neuroscience 144, 368374.

C Sandi , JJ Merino , MI Cordero , K Touyarot , C Venero (2001). Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, its polysialylation, and L1. Neuroscience 102, 329339.

C Sandi , HA Davies , MI Cordero , JJ Rodriguez , VI Popov , MG Stewart (2003). Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training. European Journal of Neuroscience 17, 24472456.

C Sandi (2004). Stress, cognitive impairment and cell adhesion molecules. Nature Reviews Neuroscience 5, 917930.

C Sandi , JC Woodson , VF Haynes , CR Park , K Touyarot , MA Lopez-Fernandez , C Venero , DM Diamond (2005). Acute stress-induced impairment of spatial memory is associated with decreased expression of neural cell adhesion molecule in the hippocampus and prefrontal cortex. Biological Psychiatry 57, 856864.

YI Sheline , MH Gado , HC Kraemer (2003). Untreated depression and hippocampal volume loss. American Journal of Psychiatry 160, 15161518.

MG Stewart , HA Davies , C Sandi , IV Kraev , VV Rogachevsky , CJ Peddie , JJ Rodriguez , MI Cordero , HS Donohue , PL Gabbott , VI Popov (2005). Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities. Neuroscience 131, 4354.

CA Stockmeier , GJ Mahajan , LC Konick , JC Overholser , GJ Jurjus , HY Meltzer , HB Uylings , L Friedman , G Rajkowska (2004). Cellular changes in the postmortem hippocampus in major depression. Biological Psychiatry 56, 640650.

K Touyarot , C Sandi (2002). Chronic restraint stress induces an isoform-specific regulation on the neural cell adhesion molecule in the hippocampus. Neural Plasticity 9, 147159.

MT Tsuang (2000). Genes, environment, and mental health wellness. American Journal of Psychiatry 157, 489491.

O Van Reeth , E Olivares , Y Zhang , PC Zee , E Mocaer , R Defrance , FW Turek (1997). Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters. Brain Research 762, 185194.

E Varea , JM Blasco-Ibanez , MA Gomez-Climent , E Castillo-Gomez , C Crespo , FJ Martinez-Guijarro , J Nacher (2007a). Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex. Neuropsychopharmacology 32, 803812.

E Varea , E Castillo-Gomez , MA Gomez-Climent , JM Blasco-Ibanez , C Crespo , FJ Martinez-Guijarro , J Nacher (2007b). Chronic antidepressant treatment induces contrasting patterns of synaptophysin and PSA-NCAM expression in different regions of the adult rat telencephalon. European Neuropsychopharmacology 17, 546557.

C Venero , AI Herrero , K Touyarot , K Cambon , MA Lopez-Fernandez , V Berezin , E Bock , C Sandi (2006). Hippocampal up-regulation of NCAM expression and polysialylation plays a key role on spatial memory. European Journal of Neuroscience 23, 15851595.

RM Vouimba , C Munoz , DM Diamond (2006). Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala. Stress 9, 2940.

JC Woodson , D Macintosh , M Fleshner , DM Diamond (2003). Emotion-induced amnesia in rats: working memory-specific impairment, corticosterone-memory correlation, and fear versus arousal effects on memory. Learning & Memory 10, 326336.

SW Ying , B Rusak , P Delagrange , E Mocaer , P Renard , B Guardiola-Lemaitre (1996). Melatonin analogues as agonists and antagonists in the circadian system and other brain areas. European Journal of Pharmacology 296, 3342.

S Yous , J Andrieux , HE Howell , PJ Morgan , P Renard , B Pfeiffer , D Lesieur , B Guardiola-Lemaitre (1992). Novel naphthalenic ligands with high affinity for the melatonin receptor. Journal of Medicinal Chemistry 35, 14841486.

PR Zoladz , AM Campbell , CR Park , D Schaefer , W Danysz , DM Diamond (2006). Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane. Pharmacology, Biochemistry, and Behavior 85, 298306.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *