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. Author manuscript; available in PMC: 2015 May 1.
Published in final edited form as: Pharmacol Ther. 2014 Dec 27;149:150–190. doi: 10.1016/j.pharmthera.2014.12.004

Table 4.

Glutamatergic signaling in fear extinction (preclinical studies).

Drug/manipulation Extinction
training		 Extinction
retrieval		 Longterm
extinction		 Route Reference
Facilitating AMPA signaling
PEPA (AMPA potentiator) No effect* No effect* ns ip (Whittle et al., 2013)
No effect* +* ns ip (Yamada et al., 2011)
+# + + (Re-in) ip (Yamada et al., 2009)
+ + ns ip (Zushida et al., 2007)
PEPA + NBQX (AMPA ant) No effect No effect ns ip (Zushida et al., 2007)
PEPA (AMPA potentiator) (+) (+) ns PL (Zushida et al. 2007)
+ + ns BLA/ceA (Zushida et al., 2007)
Inhibiting AMPA signaling
CNQX (AMPA ant) ns No effect ns BLA (Falls et al. 1992; Lin et al. 2003b; Zimmerman and Maren 2010)
Facilitating NMDA signaling
D-Cycloserine ns + ns ip (Walker et al., 2002)
ns +1 ns Systemic (Ledgerwood et al., 2003)
ns +1 + (Re-in) Systemic (Ledgerwood et al., 2004)
ns +1 ns Systemic (Ledgerwood et al., 2005)
ns +1 ns ip (Parnas et al., 2005)
ns + ns ip (Yang and Lu, 2005)
ns + ns ip (Lee et al., 2006)
ns + No effect sc (Woods and Bouton 2006)
ns + ns sc (Werner-Seidler and Richardson, 2007)
ns + ns Systemic (Weber et al., 2007)
ns + ns ip (Yang et al., 2007)
ns + ns ip (Yang et al., 2007)
ns + ns ip (Hefner et al., 2008)
ns + ns po (Yamamoto et al. 2008)
ns + ns ip (Matsumoto et al., 2008)
+ + ns ip (Silvestri and Root, 2008)
ns + ns sc (Langton and Richardson, 2008)
ns + No effect sc (Bouton et al., 2008)
ns + ns ip (Lin et al., 2010)
+# + + (Re-in) ip (Yamada et al., 2009)
+ ns ns ip (Lehner et al., 2010)
ns +1 ns Systemic (Langton and Richardson, 2010)
No effect* +* ns ip (Yamada et al., 2011)
No effect + ns ip (Toth et al., 2012b)
ns +1 ns ip (Toth et al., 2012b)
ns + ns Systemic (Gupta et al., 2013)
ns + ns ip (Matsuda et al., 2010)
+ + ns ip (Bai et al., 2014)
ns +1* ns ip (Whittle et al., 2013)
ns + ns BLA (Walker et al., 2002)
ns +1 ns BLA (Ledgerwood et al., 2003)
ns + ns BLA (Lee et al., 2006)
ns + ns BLA (Mao et al., 2008)
ns + ns BLA (Lee et al., 2006)
ns + ns BLA (Akirav et al., 2009)
ns No effect ns BLA (Bolkan & Lattal, 2014)
ns + ns HPC (Bolkan & Lattal, 2014)
ns + ns HPC (Ren et al., 2013)
Spermidine ns +1 ns HPC (Gomes et al., 2010)
Inhibiting NMDA signaling
MK-801 (non-competitive NMDA ant) ns − ns Systemic (Baker & Azorlosa, 1996); (Storsve et al., 2010)
ns ns + (Re-in) sc (Johnson et al., 2000)
ns −1 ns ip (Lee et al., 2006); (Liu et al., 2009)
ns − ns Systemic (Langton et al., 2007); (Chan & McNally, 2009)
CPP (competitive NMDA ant) No effect −5 ns ip (Santini et al., 2001); (Sotres-Bayon et al., 2007)
No effect − ns mPFC (Burgos-Robles et al., 2007)
ns −1 ns mPFC (Burgos-Robles et al., 2007)
− − ns BLA (Parsons et al., 2010)
AP-5 (competitive NMDA ant) ns − ns BLA (Falls et al., 1992)
−## − ns BLA (Lee & Kim, 1998)
ns −1 ns BLA (Lin et al., 2003a); (Laurent et al., 2008); (Fiorenza et al., 2012)
No effect − ns BLA (Lin et al., 2003a); (Zimmerman & Maren, 2010)
ns − ns CA1 (Szapiro et al., 2003)
ns −1 ns CA1 (Fiorenza et al., 2012)
ns −1 ns mPFC (Fiorenza et al., 2012)
Inhibiting NMDA signaling
ifenprodil (non-comp NR2B–NMDA ant) − − ns ip (Sotres-Bayon et al., 2007)
ns −1 ns Systemic (Sotres-Bayon et al., 2009)
− − ns BLA (Sotres-Bayon et al., 2007); (Laurent & Westbrook, 2008);
(Laurent et al., 2008)
ns No effect1 ns BLA (Laurent et al., 2008); (Laurent & Westbrook, 2008); (Sotres-Bayon et al., 2009)
No effect − ns mPFC (Laurent & Westbrook, 2008)
No effect No effect ns mPFC (Sotres-Bayon et al., 2009)
No effect −1 ns mPFC (Laurent & Westbrook, 2008); (Sotres-Bayon et al., 2009)
ns −1 ns HPC (Gomes et al., 2010)
Ro25–6981 (non-comp NR2B–NMDA ant) − No effect ns ip (Dalton et al., 2008, 2012)
Facilitating mGluR signaling
CDPPB (mGluR5 pos modulator) +3 ns ns sc (Gass & Olive, 2009)
AMN082 (mGluR7 ag) +* +* ns ip (Whittle et al., 2013)
ns + ns po (Fendt et al., 2008)
− No effect ns ip (Toth et al., 2012b)
ns −1 ns ip (Toth et al., 2012b)
(+) No effect ns BLA (Dobi et al., 2013)
− − ns mPFC (Morawska & Fendt, 2012)
Inhibiting mGluR signaling
CPCCOEt (non-comp mGluR1 ant) − − ns BLA (Kim et al., 2007)
No effect No effect No effect (SR) ip (Mao et al., 2013)
mGluR4 KO ns + ns No drug (Davis et al., 2013)
mGluR5 KO − − ns No drug (Xu et al., 2009)
MTEP (mGluR5 ant) No effect − − (SR) ip (Mao et al., 2013)
ns ns − (SR) BLA (Mao et al., 2013)
MPEP (allosteric mGluR5 ant) No effect No effect ns ip (Toth et al., 2012b)
ns No effect1 ns ip (Toth et al., 2012b)
No effect − ns ip (Fontanez-Nuin et al., 2011)
No effect − ns IL (Fontanez-Nuin et al., 2011)
− − ns IL (Sepulveda-Orengo et al., 2013)
mGluR7 KO −4 ns ns No drug (Callaerts-Vegh et al., 2006);
(Goddyn et al., 2008)
+ + ns No drug (Fendt et al., 2013)
siRNA knock-down of mGluR7 −2 ns ns No drug (Fendt et al., 2008)
mGluR8 KO No effect# No effect ns No drug (Fendt et al., 2013)
(S)-3,4-DCPG (mGluR8 ag) − No effect ns BLA (Dobi et al., 2013)
1

Drug administration following extinction training;

2

conditioned taste aversion;

3

cocaine conditioned place preference;

4

food-rewarded operant conditioning,

5

reduced locomotion.

*

Facilitates rescue of impaired fear extinction;

#

reduced fear expression at the beginning of extinction training;

##

enhanced fear expression at the beginning of extinction training.

+, Improved; -, impaired; (+) or (−), only minor effects; po, peroral administration; ip, intraperitoneal injection; sc, subcutaneous injection; ns, not studied; BLA, intra-basolateral amygdala administration; HPC, hippocampus; IL, infralimbic cortex; SR, spontaneous recovery; Re-in, reinstatement; ag, agonist; ant, antagonist, KO, knock-out;