Antagonism of lateral amygdala alpha1-adrenergic receptors facilitates fear conditioning and long-term potentiation

Abstract

Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala terazosin delivered before conditioning enhanced short-and long-term memory. Terazosin delivered after conditioning did not affect consolidation. In vitro, terazosin impaired lateral amygdala inhibitory postsynaptic currents leading to facilitation of excitatory postsynaptic currents and long-term potentiation. Since alpha1 blockers are prescribed for hypertension and posttraumatic stress disorder, these results may have important clinical implications.Although norepinephrine (NE) has been widely studied as an important modulator of memory and emotion, comparatively little is known about the role of NE in amygdala-dependent Pavlovian fear conditioning, a major model for understanding the neural basis of fear learning and memory. In fear conditioning, an emotionally neutral conditioned stimulus (CS; i.e., tone) is temporally paired with an aversive unconditioned stimulus (US; i.e., footshock). After very few pairings, a lasting, robust CS-US association is acquired, and the CS elicits stereotypical defensive responses, including behavioral freezing (Blanchard and Blanchard 1969;Bolles and Fanselow 1980). The lateral nucleus of the amygdala (LA) is a key structure underlying fear conditioning (LeDoux 2000). Convergence of CS and US information in LA is believed to play an important role in initiating synaptic plasticity. Long-term potentiation (LTP)-like changes in LA CS processing are critical for fear memory storage (LeDoux 2000;Blair et al. 2001;Maren 2001;Walker and Davis 2002). LA receives auditory CS inputs from the thalamus and cortex and connects directly and indirectly with the central nucleus of the amygdala to control expression of Pavlovian fear responses.Of the noradrenergic receptor subtypes, alpha1 receptors have received the least attention in fear conditioning. LA receives NE-containing inputs from the locus coeruleus that fire tonically and phasically in response to aversive stimuli like footshock (Pitkänen 2000;Tanaka et al. 2000;Aston-Jones and Cohen 2005). Alpha1-adrenergic receptors are expressed in LA, most likely on both excitatory and inhibitory neurons (Jones et al. 1985;Domyancic and Morilak 1997). Alpha1 receptor activation stimulates GABA-mediated miniature inhibitory postsynaptic currents in LA (Braga et al. 2004), suggesting that alpha1 receptors contribute to inhibition in fear conditioning pathways. Several elegant experiments recently demonstrated that LA inhibition gates synaptic plasticity necessary for fear conditioning, and this inhibitory gate can be influenced by neuromodulators including NE (Stutzmann and LeDoux 1999;Shumyatsky et al. 2002;Bissière et al. 2003;Shaban et al. 2006;Shin et al. 2006;Tully et al. 2007). However, the rol...

Animal model of methylphenidate's long-term memory-enhancing effects

“…MPH, a high affinity dopamine transporter (DAT) and norepinephrine transporter (NET) inhibitor (Han and Gu 2006), modulates behavior via increased monoamine neurotransmission Segal 1997, 2002;Lazzaro et al 2010;de Oliveira et al 2011;Johansen et al 2011). We also tested diverse monoamine transporter inhibitors that have been used to treat ADHD, atomoxetine (ATM, NET inhibitor), bupropion (BPN, DAT inhibitor), and citalopram (CIT, SERT inhibitor), on fear learning (Fone and Nutt 2005).…”

The Role of Norepinephrine in Amygdala Dependent Fear Learning and Memory

“…At thalamic inputs, terazosin decreased the amplitude of disynaptically induced inhibitory currents at 10 μM concentration, which did not alter the excitatory ones that were evoked in response to the first pulse (Lazzaro et al, 2010). The sequence of dysynaptic excitatory and inhibitory currents/potentials can be also evoked by stimulating the cortical inputs and adjusting the holding potential to between 30 and 40 mV (Kodirov et al, 2006).…”

“…The sequence of dysynaptic excitatory and inhibitory currents/potentials can be also evoked by stimulating the cortical inputs and adjusting the holding potential to between 30 and 40 mV (Kodirov et al, 2006). Interestingly, the amplitude of excitatory currents evoked during application of second pulse was increased by terazosin (Lazzaro et al, 2010), thus resulting in paired-pulse facilitation (PPF). Note that no PPF at both synapses was observed under control conditions, although employing the ISI of 50 ms usually results in PPF when the single pulses are applied.…”

Catecholamines in Post-Traumatic Stress Disorder

“…Pharmacologically, there is evidence for and against mGluR5 signaling being required for cued fear memory (Nielsen et al, 1997;Rodrigues et al, 2002;Gravius et al, 2006), although stimulating mGluR1/5 receptors can enhance fear memory (Rudy and Matus-Amat, 2009). For NE/E, antagonist treatment suggests that ␣ 1 -adrenergic signaling is not required for fear memory (Lazzaro et al, 2010). On the other hand, mice with a targeted disruption of the gene for PLC-␤1 exhibit greatly reduced contextual fear, although this could be due to a deficit in hippocampus-dependent memory rather than BLA-dependent fear memory per se (McOmish et al, 2008a,b).…”