Table 1.

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

Target, mechanism of action & agent	Pathway	Effects on neuronal activity and synaptic plasticity	Site	Time	Effect on FC
NMDA receptor
Antagonist AP-5	CTX-LA THAL-LA	Blocks tetanus-induced, but not pairing-induced LTP (Huang and Kandel 1998; Weisskopf et al. 1999; Bauer et al. 2002)	AMY (LA)	Pre-FC Post-FC	Blocks the acquisition, but not expression (Miserendino et al. 1990; Campeau et al. 1992)
GluN2B antagonist Ifenprodil	THAL-LA	Impairs tetanus-induced LTP (Bauer et al. 2002)	LA	Pre-FC Pre-Test	Disrupts the acquisition, but not expression (Rodrigues et al. 2001)
L-type VGCC
Blocker Verapamil Nifedipine	THAL-LA	Blocks pairing-induced, but not tetanus-induced LTP (Weisskopf et al. 1999; Bauer et al. 2002)	LA	Pre-FC	Impairs long-term (24 h) fear memory (Bauer et al. 2002)
Group I mGluR
mGluR5 antagonist MPEP	THAL-LA	Impairs tetanus-induced LTP (Rodrigues et al. 2002)	LA	Pre-FC Post-FC Pre-Test	Impairs the acquisition, but not expression or consolidation (Rodrigues et al. 2002)
mGluR1 antagonist CPCCOEt			LA	Pre-FC	No effect on fear memory acquisition (Kim et al. 2007a)
CaMKII
Inhibitor KN-62	THAL-LA	Impairs tetanus-induced LTP (Rodrigues et al. 2004)	LA	Pre-FC Pre-Test	Impairs the acquisition, but not the expression (Rodrigues et al. 2004)
PKA & AC
PKA inhibitor Rp-cAMPS KT5720	CTX-LA THAL-LA	Blocks tetanus-induced E-LTP (Huang and Kandel 1998) and L-LTP (Huang et al. 2000)	LA	Post-FC	(RP)-cAMPS impairs fear memory consolidation (Schafe and LeDoux 2000)
Rp-cAMPS H-89	CTX-LA	Blocks heterosynaptic associative presynaptic LTP (Fourcaudot et al. 2008)
AC activator Forskolin	LA	Enhances tone-induced firing at lower shock intensities (Ghosh and Chattarji 2015)	LA		Increases freezing to CS−, leads to generalized fear (Ghosh and Chattarji 2015)
PKA & PKC
Inhibitor H7			BLA Not CEA	Pre-FC	Impairs acquisition of long-term fear memories (Goosens et al. 2000)
Protein synthesis
Inhibitor Anisomycin	CTX-LA	Blocks tetanus-induced L-LTP, but not E-LTP (Huang et al. 2000)	LA	Post-FC	Impairs fear memory consolidation (Schafe and LeDoux 2000)
	CTX-LA	Blocks slow onset L-LTP induced by LFS in CTX- LA, but not THAL-LA (Huang and Kandel 2007)	CeA	Post-FC	Impairs fear memory consolidation (Wilensky et al. 2006)
PI-3 kinase
Inhibitor Wortmannin	AMY	Blocks FC-induced changes in phosphorylation of CREB (Lin et al. 2003c)	LA BLA	Pre-FC	Blocks long-term (24 h) but not short-term memory (1h) (Lin et al. 2001)
Inhibitors Wortmannin LY294002	CTX-LA	Blocks tetanus-induced LTP (Lin et al. 2001)
GABAA
Agonist Muscimol	LA BLA	Silences neuronal activity (Herry et al., 2008; Ghosh and Chattarji 2015)	LA	Pre-FC	Blocks fear generalization in animals conditioned to a strong US (Ghosh and Chattarji 2015)
			LA BLA	Pre-FC Post-FC	Impairs acquisition, but not expression (Wilensky et al. 2000; Wilensky et al. 2006, but see Sierra-Mercado et al. 2011)
			CeA	Pre-FC Pre-Test	Impairs both fear acquisition and fear expression (Wilensky et al. 2006)
			PL	Post-FC	Affects fear expression (Sierra-Mercado et al. 2011)
Antagonist Picrotoxin	THAL-LA CTX-LA	Facilitates in vitro LTP induction (Bissière et al. 2003; Shin et al. 2006; Tully et al. 2007)

List of abbreviations used:

AC - adenylyl cyclase, AMY – amygdala, BLA – basolateral amygdala, CaMKII - Ca2+/calmodulin-dependent protein kinase II, CeA – central amygdala, CREB - cAMP response element-binding protein, CTX-LA – cortical pathway to the LA, E-LTP – early phase of LTP, FC – fear conditioning, H7– 1-(5’-isoquinolinesulfonyl)-2-methylpiperazine, LA – lateral anygdala, LFS – low-frequency stimulation, L-LTP – late phase of LTP, LTP – long-term potentiation, mGluR - metabotropic glutamate receptor, MPEP - 2-methyl-6-(phenylethynyl)-pyridine, PI-3 - Phosphatidyl inositol 3, PKA – protein kinase A or cAMP-dependent protein kinase, PKC – protein kinase C, PL - prelimbicmedial prefrontal cortex (mPFC), THAL-LA – thalamic input to the LA, VGCC – voltage-gated calcium channel.