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Molecular Pharmacology

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Research ArticleArticle

Augmentation of Fear Extinction by Infusion of Glycine Transporter Blockers into the Amygdala

Sheng-Chun Mao, Hui-Ching Lin and Po-Wu Gean
Molecular Pharmacology August 2009, 76 (2) 369-378; DOI: https://doi.org/10.1124/mol.108.053728
Sheng-Chun Mao
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Hui-Ching Lin
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Po-Wu Gean
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Abstract

It is known that fear extinction is blocked by the N-methyl d-aspartate (NMDA) receptor antagonist. In this study, we investigate whether extinction could be facilitated by the enhancement of NMDA response, achieved by the blocking of glycine transporters. In amygdala slices, NMDA at a concentration that normally does not have a long-term effect was found to reduce the cellular levels of postsynaptic density protein 95 and synapse-associated protein 97, in addition to the surface expression of GluR1/2, in the presence of a glycine transporter blocker, N[3-(4-fluorophenil)-3-(4′-phenilphenoxy)] propylsarcosine (NFPS). In in vivo experiments, extinction training applied 24 h after conditioning reduced startle potentiation without influencing the conditioning-induced increase in the surface expression of GluR1/2. However, NFPS augmented extinction and reversed the conditioning-induced increase in GluR1/2 when infused bilaterally into the amygdala before extinction training. The effects of NFPS were therefore blocked by the NMDA antagonist. In parallel, NFPS treatment in conjunction with extinction reversed the conditioning-induced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/NMDA ratio. In behavioral tests, Tat-GluR23Y, a synthetic peptide that has been shown to block AMPA receptor endocytosis, inhibited only the additional reduction caused by NFPS treatment, rather than returning the fear potentiation levels to those of fear-conditioned animals that did not undergo extinction. These results suggest that NFPS in combination with extinction training reverses GluR1/2 surface expression and thus augments the extinction of conditioned fear.

Footnotes

  • This study was supported by the National Health Research Institute [Grant N08I97N]; the National Science Council [Grant NSC94-2752-B-006-001-PAE]; and a Landmark Project of National Cheng-Kung University of Taiwan [Grant A0031].

  • ABBREVIATIONS: NMDA, N-methyl d-aspartate; ACSF, artificial cerebrospinal fluid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ANOVA, analysis of variance; BLA, basolateral nucleus of the amygdala; CNQX, 6-cyano-2,3-dihydroxy-7-nitroquinoxaline; CS, conditioned stimulus; d-APV, d-2-amino-5-phosphonovalerate; DCS, d-cycloserine; DMSO, dimethyl sulfoxide; fEPSP, field excitatory postsynaptic potential; GlyT1, glycine transporter type 1; LA, lateral nucleus of the amygdala; LTD, long-term depression; NFPS, N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine; PSD-95, postsynaptic density protein 95; SAP97, synapse-associated protein 97; US, unconditioned stimulus; ITI, intertrial time interval; EPSC, excitatory postsynaptic current; PKA, protein kinase A; CGP52432, 3-[[(3,4-dichlorophenyl)methyl]amino]propyl(diethoxymethyl)phosphinic acid; HA-966, 3-amino-1-hydroxypyrrolid-2-one.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Accepted May 1, 2009.
    • Received November 26, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (2)
Molecular Pharmacology
Vol. 76, Issue 2
1 Aug 2009
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Research ArticleArticle

Augmentation of Fear Extinction by Infusion of Glycine Transporter Blockers into the Amygdala

Sheng-Chun Mao, Hui-Ching Lin and Po-Wu Gean
Molecular Pharmacology August 1, 2009, 76 (2) 369-378; DOI: https://doi.org/10.1124/mol.108.053728

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Research ArticleArticle

Augmentation of Fear Extinction by Infusion of Glycine Transporter Blockers into the Amygdala

Sheng-Chun Mao, Hui-Ching Lin and Po-Wu Gean
Molecular Pharmacology August 1, 2009, 76 (2) 369-378; DOI: https://doi.org/10.1124/mol.108.053728
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