Skip to main content
SpringerLink
Log in

Linoleic Acid Derivative DCP-LA Ameliorates Stress-Induced Depression-Related Behavior by Promoting Cell Surface 5-HT1A Receptor Translocation, Stimulating Serotonin Release, and Inactivating GSK-3β

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Impairment of serotonergic neurotransmission is the major factor responsible for depression and glycogen synthase kinase 3β (GSK-3β) participates in serotonergic transmission-mediated signaling networks relevant to mental illnesses. In the forced-swim test to assess depression-like behavior, the immobility time for mice with restraint stress was significantly longer than that for nonstressed control mice. Postsynaptic cell surface localization of 5-HT1A receptor, but not 5-HT2A receptor, in the hypothalamus for mice with restraint stress was significantly reduced as compared with that for control mice, which highly correlated to prolonged immobility time, i.e., depression-like behavior. The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) restored restraint stress-induced reduction of cell surface 5-HT1A receptor and improved depression-like behavior in mice with restraint stress. Moreover, DCP-LA stimulated serotonin release from hypothalamic slices and cancelled restraint stress-induced reduction of GSK-3β phosphorylation at Ser9. Taken together, the results of the present study indicate that DCP-LA could ameliorate depression-like behavior by promoting translocation of 5-HT1A receptor to the plasma membrane on postsynaptic cells, stimulating serotonin release, and inactivating GSK-3β.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289(23):3095–3105

    Article  PubMed  Google Scholar 

  2. Zarate C, Duman RS, Liu G, Sartori S, Quiroz J, Murck H (2003) New paradigms for treatment-resistant depression. Ann N Y Acad Sci 1292:21–31

    Article  Google Scholar 

  3. Jans LA, Riedel WJ, Markus CR, Blokland A (2007) Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol Psychiatry 12(6):522–543

    Article  CAS  PubMed  Google Scholar 

  4. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71(4):533–554

    Article  CAS  PubMed  Google Scholar 

  5. Lesch KP, Gutknecht L (2004) Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. Int J Neuropsychopharmacol 7(4):381–385

    Article  CAS  PubMed  Google Scholar 

  6. Sharp T, Boothman L, Raley J, Queree P (2007) Important messages in the ‘post’: recent discoveries in 5-HT neurone feedback control. Trends Pharmacol Sci 28(12):629–636

    Article  CAS  PubMed  Google Scholar 

  7. Savitz J, Lucki I, Drevets w (2009) 5-HT1A receptor function in major depressive disorder. Prog Neurobiol 88(1):17–31

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Albert PR, Le François B, Millar AM (2011) Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness. Mol Brain 4:21

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Latapy C, Rioux V, Guitton MJ, Beaulieu JM (2012) Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour. Philos Trans R Soc Lond B Biol Sci 367(1601):2460–2474

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Li X, Jope RS (2010) Is glycogen synthase kinase-3 a central modulator in mood regulation? Neuropsychopharmacology 35(11):2143–2154

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Polter AM, Yang S, Jope RS, Li X (2012) Functional significance of glycogen synthase kinase-3 regulation by serotonin. Cell Signal 24(1):265–271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347

    Article  CAS  PubMed  Google Scholar 

  13. Tanaka A, Nishizaki T (2003) The newly synthesized linoleic acid derivative FR236924 induces a long-lasting facilitation of hippocampal neurotransmission by targeting nicotinic acetylcholine receptors. Bioorg Med Chem Lett 13(6):1037–1040

    Article  CAS  PubMed  Google Scholar 

  14. Kanno T, Yamamoto H, Yaguchi T, Hi R, Mukasa T, Fujikawa H, Nagata T, Yamamoto S, Tanaka A, Nishizaki T (2006) The linoleic acid derivative DCP-LA selectively activates PKC-ε, possibly binding to the phosphatidylserine binding site. J Lipid Res 47(6):1146–1156

    Article  CAS  PubMed  Google Scholar 

  15. Shimizu T, Kanno T, Tanaka A, Nishizaki T (2011) α, β-DCP-LA selectively activates PKC-ε and stimulates neurotransmitter release with the highest potency among 4 diastereomers. Cell Physiol Biochem 27(2):149–158

    CAS  PubMed  Google Scholar 

  16. Kanno T, Tanaka A, Nishizaki T (2012) Linoleic acid derivative DCP-LA stimulates vesicular transport of α7 ACh receptors towards surface membrane. Cell Physiol Biochem 30(1):75–82

    Article  CAS  PubMed  Google Scholar 

  17. Kanno T, Tsuchiya A, Tanaka A, Nishizaki T (2013) The linoleic acid derivative DCP-LA increases membrane surface localization of the α7 ACh receptor in a protein 4.1N-dependent manner. Biochem J 450(2):303–309

    Article  CAS  PubMed  Google Scholar 

  18. Kanno T, Yaguchi T, Yamamoto S, Yamamoto H, Fujikawa H, Nagata T, Tanaka A, Nishizaki T (2005) 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid stimulates GABA release from interneurons projecting to CA1 pyramidal neurons in the rat hippocampus via pre-synaptic α7 acetylcholine receptors. J Neurochem 95(3):695–702

    Article  CAS  PubMed  Google Scholar 

  19. Yamamoto S, Kanno T, Nagata T, Yaguchi T, Tanaka A, Nishizaki T (2005) The linoleic acid derivative FR236924 facilitates hippocampal synaptic transmission by enhancing activity of presynaptic α7 acetylcholine receptors on the glutamatergic terminals. Neuroscience 130(1):207–213

    Article  CAS  PubMed  Google Scholar 

  20. Kanno T, Tsuchiya A, Shimizu T, Tanaka A, Nishizaki T (2012) Indomethacin serves as a potential inhibitor of protein phosphatases. Cell Physiol Biochem 30(4):1014–1022

    Article  CAS  PubMed  Google Scholar 

  21. Kanno T, Yaguchi T, Nagata T, Tanaka A, Nishizaki T (2009) DCP-LA stimulates AMPA receptor exocytosis through CaMKII activation due to PP-1 inhibition. J Cell Physiol 221(1):183–188

    Article  CAS  PubMed  Google Scholar 

  22. Cowen DS, Johnson-Farley NN, Travkina T (2005) 5-HT receptors couple to activation of Akt, but not extracellular-regulated kinase (ERK), in cultured hippocampal neurons. J Neurochem 93(4):910–917

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Disclosure Statement

The authors state that there are no actual or potential conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan

    Takeshi Kanno & Tomoyuki Nishizaki

  2. Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, Japan

    Akito Tanaka

Authors
  1. Takeshi Kanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akito Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoyuki Nishizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomoyuki Nishizaki.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanno, T., Tanaka, A. & Nishizaki, T. Linoleic Acid Derivative DCP-LA Ameliorates Stress-Induced Depression-Related Behavior by Promoting Cell Surface 5-HT1A Receptor Translocation, Stimulating Serotonin Release, and Inactivating GSK-3β. Mol Neurobiol 51, 523–532 (2015). https://doi.org/10.1007/s12035-014-8718-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8718-5

Keywords

Search

Navigation