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The role of the dorsal hippocampus on the Ginkgo biloba facilitation effect of fear extinction as assessed with fear-potentiated startle

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Abstract

Rationale

Ginkgo biloba extract, EGb761, is widely used as herbal supplements throughout Western society. It has been used in the treatment of various common geriatric complaints including short-term memory loss. Our previous study has shown that acute systemic administration of EGb761 enhanced extinction of fear-potentiated startle (FPS) in rats. Little is known about the behavioral effects of hippocampally administered EGb761 on the extinction of FPS.

Objective

The current study was performed to evaluate the involvement of the dorsal hippocampus (DH) in the EGb761 facilitation effect on the extinction of FPS.

Methods and result

Male adult SD rats were used. EGb761 (28 ng/side, bilaterally) was infused into DH bilaterally 10 min prior to extinction training. Animals were then tested for FPS 24 h later. Results showed that intra-hippocampal infusion of EGb761 prior to extinction training facilitated extinction, which was not due to impairments of expression of conditioned fear. Intra-hippocampal injection of ERK1/2 inhibitor PD98059 partially attenuates the above EGb761 effect. Therefore, acute EGb761 administration modulated extinction of conditioned fear, which might be mediated by more than one signal cascade.

Conclusions

These results suggest that DH may participate in the facilitation effect of EGb761 on the extinction of conditioned fear. In addition to ERK1/2, another signal cascade may also be involved in the EGb761 facilitation effect on extinction.

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References

  • Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt D (1998) The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1:602–609

    Article  PubMed  CAS  Google Scholar 

  • Bading H, Greenberg ME (1991) Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253:912–914

    Article  PubMed  CAS  Google Scholar 

  • Blum S, Moore AN, Adams F, Dash PK (1999) A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 19:3535–3544

    PubMed  CAS  Google Scholar 

  • Cammarota M, Bevilaqua RM, Rossato JI, Ramirezz M, Medina JH (2005) Relationship between short- and long-term memory and short- and long-term extinction. Neurobiol Learn Mem 84:25–32

    Article  PubMed  Google Scholar 

  • Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB (1998) A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20:895–904

    Article  PubMed  CAS  Google Scholar 

  • Chetkovich DM, Gray R, Jonhston D, Sweatt JD (1991) N-methyl-D-aspartate receptor activation increases cAMP levels and voltage-gated Ca2+ channel activity in area CA1 of hippocampus. Proc Natl Acad Sci USA 88:6467–6471

    Article  PubMed  CAS  Google Scholar 

  • Clostre F (2000) Ginkgo biloba extract (EGb761). State of knowledge in the dawn of the year 2000. Ann Pharm Fr 57:1S8–1S88

    Google Scholar 

  • Curtis-Prior P, Vere D, Fray P (1999) Therapeutic value of Ginkgo biloba in reducing symptoms of decline in mental function. J Pharm Pharmacol 51:535–541

    Article  PubMed  CAS  Google Scholar 

  • Davis M (1986) Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm. Behav Neurosci 100:814–824

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Myers KM (2002) The role of glutamate and gamma-aminobutyric acid in fear extinction: clinical implications for exposure therapy. Biol Psychiatry 52:998–1007

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Falls WA, Gewirtz J (2000a) Neural systems involved in fear inhibition: extinction and conditioned inhibition. In: Myslobodsky M, Weiner I (eds) Contemporary issues in modeling psychopathology. Kluwer, Boston, pp 113–142

    Google Scholar 

  • Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S (2000b) The MAPK/ERK cascade targets both Elk-1 and cAMP response element binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 20:4563–4572

    CAS  Google Scholar 

  • DeFeudis FV (1991) Ginkgo biloba extract (EGb 761): pharmacological activities and clinical applications. Elsevier, Amsterdam

    Google Scholar 

  • DeFeudis FV, Drieu K (2000) Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 1:25–58

    Article  PubMed  CAS  Google Scholar 

  • Diamond BJ, Shifflett C, Feiwel N (2000) Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 81:668–678

    PubMed  CAS  Google Scholar 

  • Dillon GM, Qu XL, Marcus JN, Dodart JC (2008) Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice. Neurobiol Learn Mem 90:426–433

    Article  PubMed  Google Scholar 

  • Drieu K (1986) Preparation et definition de l'extrait de Ginkgo biloba. Presse Méd 15:1455–1457

    PubMed  CAS  Google Scholar 

  • English JD, Sweatt JD (1996) Activation of p42 mitogen-activated protein kinase in hippocampal long-term potentiation. J Biol Chem 271:24329–24332

    Article  PubMed  CAS  Google Scholar 

  • Gong OH, Wu Q, Huang XN, Sun AS, Shi JS (2005) Protective effects of Ginkgo biloba leaf extract on aluminum-induced brain dysfunction in rats. Life Sci 77:140–148

    Article  PubMed  CAS  Google Scholar 

  • Grewal SS, York RD, Stork PJ (1998) Extracellular-signal-regulated kinase signalling in neurons. Curr Opin Neurobiol 9:544–553

    Article  Google Scholar 

  • Hasenöhrl RU, Nichau CH, Frisch CH, De Souza Silva MA, Huston JP, Mattern CM, Häcker R (1996) Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze. Pharmacol Biochem Behav 53:271–275

    Article  PubMed  Google Scholar 

  • Hasenöhrl RU, Topic B, Frisch C, Häcker R, Mattern CM, Huston JP (1998) Dissociation between anxiolytic and hypomnestic effects for combined extracts of Zingiber officinale and Ginkgo biloba to healthy young volunteers. Pharmacol Biochem Behav 59:527–535

    Article  PubMed  Google Scholar 

  • Herry C, Garcia R (2002) Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J Neurosci 22:577–583

    PubMed  CAS  Google Scholar 

  • Hikind N, Maroun M (2008) Microinfusion of the D1 receptor antagonist, SCH23390 into the IL but not the BLA impairs consolidation of extinction of auditory fear conditioning. Neurobiol Learn Mem 90:217–222

    Article  PubMed  CAS  Google Scholar 

  • Hsu E, Packard MG (2008) Medial prefrontal cortex infusions of bupivavaine or AP-5 block extinction of amphetamine conditioned place preference. Neurobiol Learn Mem 89:504–512

    Article  PubMed  CAS  Google Scholar 

  • Hugues S, Deschaux O, Garcia R (2004) Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear. Learn Mem 11:540–543

    Article  PubMed  Google Scholar 

  • Kornhauser JM, Greenberg ME (1997) A kinase to remember: dual roles for MAP kinase in long-term memory. Neuron 18:839–842

    Article  PubMed  CAS  Google Scholar 

  • Krieglstein J, Beck T, Seibert A (1986) Influence of an extract of Ginkgo biloba on cerebral blood flow and metabolism. Life Sci 39:2327–2334

    Article  PubMed  CAS  Google Scholar 

  • Krieglstein J, Ausmeier F, Ei-Abhar H, Lippert K, Welsch JM, Rupalla K (1995) Neuroprotective effects of Ginkgo biloba constituents. Eur J Pharm Sci 3:9–48

    Article  Google Scholar 

  • Landes P (1997) Market report: whole food magazine's 2nd annual herb market survey for U.S. health food stores. Herbal Gram 40:52

    Google Scholar 

  • Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF (1997) A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 278:1327–1332

    Article  PubMed  Google Scholar 

  • Le Bars PL, Koeser M, Itil KZ (2000) A 26-week analysis of a double-blind, placebo-controlled trial of the Ginkgo Biloba extract EGb761 in dementia. Dement Geriatr Cogn Disord 11:230–237

    Article  PubMed  Google Scholar 

  • Lebrón K, Milad MR, Quirk GJ (2004) Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. Learn Mem 11(5):544–548

    Article  PubMed  Google Scholar 

  • Ledgerwood L, Richardson R, Cranney J (2003) Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci 117:341–349

    Article  PubMed  CAS  Google Scholar 

  • Ledgerwood L, Richardson R, Cranney J (2004) D-cycloserine and the facilitation of extinction of conditioned fear. Consequences for reinstatement. Behav Neurosci 118:505–513

    Article  PubMed  Google Scholar 

  • Lin CCK, Cheng WL, Hsu SH, Chang CMJ (2003a) The effects of Ginkgo biloba extracts on the memory and motor functions of rats with chronic cerebral insufficiency. Neuropsychobiology 47:47–51

    Article  Google Scholar 

  • Lin CH, Yeh SH, Lu HY, Gean PW (2003b) The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. J Neurosci 23:8310–8317

    CAS  Google Scholar 

  • Lu KT, Walker DL, Davis M (2001) Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear potentiated startle. J Neurosci 21(RC162):1–5

    Google Scholar 

  • Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74

    Article  PubMed  CAS  Google Scholar 

  • Millan SJ, Gacia de la Asuncion J, Pallardo JG, O'Conner E, Martin J, Droy-Lefaiz MT, Vina J (1998) A Ginkgo biloba extract (EGb761) prevents mitochondrial aging by protecting against oxidative stress. Free Radical Biol Med 24:298–304

    Article  Google Scholar 

  • O'Hara M, Kiefer D, Farrell K, Kemper K (1998) A review of 12 commonly used medicinal herbs. Arch Fam Med 7:523–536

    Article  PubMed  Google Scholar 

  • Porsolt RD, Martin P, Lenegre A, Fromage S, Drieu K (1990) Effects of an extract of Ginkgo biloba (EGb761) on ‘learned helplessness’ and other models of stress in rodents. Pharmacol Biochem Behav 36:963–971

    Article  PubMed  CAS  Google Scholar 

  • Quirk GJ, Garcia R, Gonzalez-Lim F (2006) Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 60:337–343

    Article  PubMed  Google Scholar 

  • Ressler KJ, Rothbaum BO, Tannebaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobics to facilitate extinction of fear. Arch Gen Psychiatry 61:1136–1144

    Article  PubMed  Google Scholar 

  • Roberson ED, English JD, Adams JP, Selcher JC, Kondratick C, Sweatt JD (1999) The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 19:4337–4348

    PubMed  CAS  Google Scholar 

  • Roozendaal B (2003) Systems mediating acute glucocorticoid effects on memory consolidation and retrieval. Prog Neuropsychopharmacol Biol Psychiatry 27:1213–1223

    Article  PubMed  CAS  Google Scholar 

  • Roozendaal B, Griffith QK, Buranday J, de Quervain DJF, McGaugh JL (2002) The hippocampus mediates glucocorticoid-induced impairment of spatial memory retrieval: dependence on the basolateral amygdala. Proc Natl Acad Sci 100:1328–1333

    Article  Google Scholar 

  • Santini E, Ge H, Ren K, Peña de Ortiz S, Quirk GJ (2004) Consolidation of fear extinction requires protein synthesis in the medial prefrontal cortex. J Neurosci 24:5704–5710

    Article  PubMed  CAS  Google Scholar 

  • Schafe GE, Nadel NV, Sullivan GM, Harris A, LeDoux JE (1999) Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem 6:97–110

    PubMed  CAS  Google Scholar 

  • Stackman RW, Eckenstein F, Frei B, Kulhanek D, Nowlin J, Quinn JF (2003) Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment. Exp Neurol 184:510–520

    Article  PubMed  Google Scholar 

  • Tang F, Nag S, Shiu SYW, Pang SF (2002) The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with β-amyloid 1–40. Life Sci 71:2625–2631

    Article  PubMed  CAS  Google Scholar 

  • Taylor JE (1992) In vitro interactions of EGb 761 with biogenic amine uptake sites and NMDA receptors. In: Christen Y, Costintin J, Lacour M (eds) Effects of Ginkgo biloba extract (EGb 761) on the central nervous system. Elsevier, Paris

    Google Scholar 

  • Van Dongen MC, Van Rossum E, Kessels AG, Sielhorst HJ, Knipschild PG (2000) The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 48:1183–1194

    PubMed  Google Scholar 

  • Vianna MR, Igaz LM, Coitinho AD, Medina JH, Izquierdo I (2003) Memory extinction requires gene expression in rat hippocampus. Neurobiol Learn Mem 79:199–203

    Article  PubMed  CAS  Google Scholar 

  • Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear potentiated startle in rats. J Neurosci 22(6):2343–2351

    PubMed  CAS  Google Scholar 

  • Walz R, Roesler R, Quevedo J, Rockenbach IC, Amaral OB, Vianna MR, Lenz G, Medina JH, Izquierdo I (1999a) Dose-dependent impairment of inhibitory avoidance retention in rats by immediate post-training infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures. Behav Brain Res 105:219–223

    Article  PubMed  CAS  Google Scholar 

  • Walz R, Roesler R, Barros DM, de Souza MM, Rodrigues C, Sant'Anna MK, Quevedo J, Choi HK, Neto WP, DeDavid e Silva TL, Medina JH, Izquierdo I (1999b) Effects of post-training infusions of a mitogen activated protein kinase kinase inhibitor into the hippocampus or entorhinal cortex on short- and long-term retention of inhibitory avoidance. Behav Pharmacol 10:723–730

    Article  PubMed  CAS  Google Scholar 

  • Ward CP, Redd K, Williams BM, Caler JR, Luo Y, McCoy JG (2002) Ginkgo biloba extract: cognitive enhancer or antistress buffer. Pharmacol Biochem Behav 72:913–922

    Article  PubMed  CAS  Google Scholar 

  • Yang YL, Lu KT (2005) Facilitation of conditioned fear extinction by D-cycloserine is mediated by mitogen activated protein kinase and PI-3 kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala. Neuroscience 134:247–260

    Article  PubMed  CAS  Google Scholar 

  • Yang YL, Su YW, Ng MC, Chang CL, Lu KT (2005) Extract of Ginkgo biloba EGb 761 facilitates fear conditioning measured by fear potentiated startle. Neurosci Lett 383:145–150

    Article  PubMed  CAS  Google Scholar 

  • Yang YL, Chao PK, Lu KT (2006) Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear. Neuropsychopharmacology 31:912–924

    Article  PubMed  CAS  Google Scholar 

  • Yang YL, Chao PK, Ro LS, Wo YYP, Lu KT (2007a) Glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats. Neuropsychopharmacology 32:1042–1051

    Article  CAS  Google Scholar 

  • Yang YL, Su YW, Ng MC, Chao PK, Tung LC, Lu KT (2007b) Extract of Ginkgo biloba EGb761 facilitates extinction of conditioned fear measured by fear potentiated startle. Neuropsychopharmacology 32:332–342

    Article  CAS  Google Scholar 

  • Yang YL, Hsieh CW, Wo YY, Yang YC, Lu KT (2009) Intra-amygdaloid infusion of Ginkgo biloba leaf extract (EGb761) facilitates fear potentiated startle in rats. Psychopharmacology 202:187–196

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Chiayi Christian Hospital to Y.H.C. (R97-2), funding from the Hsin-Sheng College of Medical Care and Management to Y.F.S., and support from the National Science Council, Taiwan, to K.T.L.

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  1. Yu-Hsuan Chou

    Present address: Ching-Ho Hospital, Taichung, Taiwan

Authors and Affiliations

  1. Department of Nursing, Hsin Sheng College of Medical Care and Management, Tao Yuan, Taiwan

    Yu-Fang Shen

  2. Department of Psychiatry, Chia-Yi Christian Hospital, Chia-Yi, Taiwan

    Yu-Hsuan Chou

  3. Department of Biochemical Science and Technology, National Chia-Yi University, Chia-Yi, Taiwan

    Yi-Ling Yang

  4. Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

    Kwok-Tung Lu

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  1. Yu-Fang Shen
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Correspondence to Kwok-Tung Lu.

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Yu-Fang Shen and Yu-Hsuan Chou gave equal contributions to the study.

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Shen, YF., Chou, YH., Yang, YL. et al. The role of the dorsal hippocampus on the Ginkgo biloba facilitation effect of fear extinction as assessed with fear-potentiated startle. Psychopharmacology 215, 403–411 (2011). https://doi.org/10.1007/s00213-011-2244-1

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