Table 2.

Effects of pharmacological agents on neuronal activity and synaptic plasticity implicated in fear extinction (Ext).

Target, mechanism of action & agent	Pathway	Effects on neuronal activity and synaptic Plasticity	Site	Time	Effect on fear extinction
NMDA receptor
Antagonist  AP-5	THAL-LA CTX-LA	Blocks ex vivo depotentiation induced by LFS in fear-conditioned animals (Kim et al. 2007b; Hong et al. 2009)	LA BLA	Pre-Ext	Blocks extinction (Falls et al. 1992; Lin et al. 2003c; Mao et al. 2006)
	CTX-LA	Blocks LFS-induced depotentiation in slices from naïve animals, following LTP induction in vitro (Lin et al. 2003a)
	THAL-LA	Blocks LFS and pairing- induced (−50 mV) LTD (Clem and Huganir 2010)
	BLA- mITC	Blocks LTD and LTP (Royer and Paré 2002)
Antagonist CPP		Reduces burst firing in mPFC (Burgos-Robles et al. 2007)	mPFC	Pre-Ext Post-Ext	Impairs consolidation (Burgos-Robles et al. 2007)
GluN2B Antagonist Ifenprodil	THAL-LA		LA	Pre-Ext Post-Ext	Impairs acquisition, but not consolidation (Sotres-Bayon et al. 2007; Sotres-Bayon et al. 2009)
			mPFC	Pre-Ext Post-Ext	Impairs consolidation, but not acquisition (Sotres-Bayon et al. 2009)
Partial agonist DCS (Gly site)	CTX-LA	Facilitates LFS-induced depotentiation applied 60 min after tetanus stimulation and reduction in surface GluA1 (Mao et al. 2006)	LA BLA	Pre-Ext Post-Ext	Augments consolidation (Walker et al. 2002; Ledgerwood et al. 2003; Mao et al. 2006)
L-type VGCC
Blockers Nifedipine Nimodipine	CTX-LA	Partially/fully blocks LFS- induced depotentiation in slices from naïve animals, following LTP induction in vitro (Lin et al. 2003a)	Sys	Pre-Ext	Blocks extinction conducted 1 or 3 h post-acquisition (Cain et al. 2005)
Group I mGluR
mGluR5 antagonist MPEP	THAL-LA	No impact on LFS and pairing-induced (−50 mV) LTD (Clem and Huganir 2010)	IL	Pre-Ext	Impairs extinction recall (Fontanez-Nuin et al. 2011)
mGluR5 agonist CHPG	IL	Increases intrinsic excitability of IL neurons, decreases the slow AHP (Fontanez-Nuin et al. 2011)
mGluR1 antagonist CPCCOEt	THAL-LA	Blocks ex vivo depotentiation induced by LFS in fear-conditioned animals (Kim et al. 2007b)	LA	Pre-Ext	Impairs extinction initiated 48 h (but not 2 h) after FC (Kim et al. 2007a)
mGluR1 antagonist LY367385	THAL-LA	Blocks LFS and pairing- induced (−50 mV) LTD (Clem and Huganir 2010)
Group II mGluR
Antagonist EGLU	CTX-LA	No effect on LFS-induced depotentiation in slices  from naïve animals, following LTP induction in vitro (Lin et al. 2003a)
Antagonist LY341495	CTX-LA	Blocks ex vivo depotentiation induced by LFS in fear-conditioned animals (Hong et al. 2009)	LA, not CeA	Pre-Ext	Impairs retention, no effect on acquisition (Kim et al. 2015)
Agonist DCG-IV	CTX-LA	Elicits in vitro depotentiation following LTP induction by tetanus stimulation (Lin et al. 2005)	LA & BLA	Post-FC	Reduces a conditioned response (Lin et al. 2005)
Protein synthesis
Inhibitor Anisomycin			LA BLA	Pre-Ext	Blocks extinction (Lin et al. 2003c)
			mPFC	Pre-Ext	Blocks retention, but not acquisition (Santini et al. 2004)
PI-3 kinase
Inhibitor Wortmannin	AMY	Blocks extinction-induced changes in phosphorylation of CREB (Lin et al. 2003c)	LA BLA	Pre-Ext	Blocks extinction (Lin et al. 2003c; Mao et al. 2006)
PP2B (CaN)
Inhibitors Cyclosporin A FK-506	CTX-LA	Blocks LFS-induced depotentiation in slices  from naïve animals, following LTP induction in vitro (Lin et al. 2003a)	LA BLA	Pre-Ext	FK-506 blocks extinction (Lin et al. 2003b)
GABAA
Agonist Muscimol	LA BLA	Silences neuronal activity (Herry et al., 2008; Ghosh and Chattarji 2015)	BLA	Pre-Ext	Impairs extinction (Herry et al. 2008; Sierra-Mercado et al. 2011)
			mPFC	Pre-Ext	Long-term enhancement of extinction (Akirav et al. 2006)
			IL	Pre-Ext	Impairs acquisition of extinction and extinction memory (Sierra-Mercado et al. 2011)
			LA &BLA	Ext (after 5 CSs)	Facilitates the consolidation (Akirav et al. 2006)

List of abbreviations used:

AC - adenylyl cyclase, AHP – afterhyperpolarization, AMY – amygdala, BLA – basolateral amygdala, CaMKII - Ca2+/calmodulin-dependent protein kinase II, CeA – central amygdala, CHPG – (RS)-2-chloro-5-hydroxyphenylglycine, CREB - cAMP response element-binding protein, CTX-LA – cortical pathway to the LA, DCS - D-cycloserine, E-LTP – early phase of LTP, FC – fear conditioning, Gly site - glycine site of the NMDA receptor, IL - infralimbic division of medial prefrontal cortex, LA – lateral anygdala, LFS – low-frequency stimulation, List of abbreviations used: L-LTP – late phase of LTP, LTP – long-term potentiation, mGluR - metabotropic glutamate receptor, mITC – medial cluster of intercalated cells, MPEP - 2-methyl-6-(phenylethynyl)-pyridine, PI-3 - Phosphatidyl inositol 3, PKA – protein kinase A or cAMP-dependent protein kinase, PL – prelimbic medial prefrontal cortex (mPFC), PP2B (CaN) - serine/threonine-protein phosphatase 2B or calcineurin, Sys – systemic (injection), THAL-LA – thalamic input to the LA, VGCC – voltage-gated calcium channel.