Abstract
Activation of GABAARs in the lateral nucleus of the amygdala (LA), a key site of plasticity underlying fear learning, impairs fear learning. The role of GABACRs in the LA and other brain areas is poorly understood. GABACRs could be an important novel target for pharmacological treatments of anxiety-related disorders since, unlike GABAARs, GABACRs do not desensitize. To detect functional GABACRs in the LA we performed whole cell patch clamp recordings in vitro. We found that GABAARs and GABABRs blockade lead to a reduction of evoked inhibition and an increase increment of excitation, but activation of GABACRs caused elevations of evoked excitation, while blocking GABACRs reduced evoked excitation. Based on this evidence we tested whether GABACRs in LA contribute to fear learning in vivo. It is established that activation of GABAARs leads to blockage of fear learning. Application of GABAC drugs had a very different effect; fear learning was enhanced by activating and attenuated by blocking GABACRs in the LA. Our results suggest that GABAC and GABAARs play opposing roles in modulation of associative plasticity in LA neurons of rats. This novel role of GABACRs furthers our understanding of GABA receptors in fear memory acquisition and storage and suggests a possible novel target for the treatment of fear and anxiety disorders.
Highlights
The lateral nucleus of the amygdala (LA) is a key site of plasticity underlying fear learning (LeDoux, 2000; Blair et al, 2001; Maren and Quirk, 2004), and inhibitory circuits in that structure play an important role in the regulation of fear memory and its extinction (Wilensky et al, 1999; Akirav and Richter-Levin, 2006; Zhang and Cranney, 2008)
The effects of the 1 μM muscimol, the GABA agonist, on the electrically evoked responses was assessed since this concentration has been reported to selectively activate GABACRs as opposed to GABAARs (Pasternack et al, 1999; Boller and Schmidt, 2001; Schmidt et al, 2001)
To determine whether this 1 μM muscimol primarily activated GABACRs we examined the effects of blockade of GABAARs and GABAB receptor (GABABR) on the electrically evoked responses by adding the GABAAR antagonist bicuculline and the GABABR antagonist CGP 52432 separately to the bath during recordings
Summary
The lateral nucleus of the amygdala (LA) is a key site of plasticity underlying fear learning (LeDoux, 2000; Blair et al, 2001; Maren and Quirk, 2004), and inhibitory circuits in that structure play an important role in the regulation of fear memory and its extinction (Wilensky et al, 1999; Akirav and Richter-Levin, 2006; Zhang and Cranney, 2008). Γ-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter (Nicoll et al, 1990). It acts through different receptor types, including the ionotropic GABAA (GABAAR) and GABAC (GABACR) receptors (both of which activate Cl− currents), and the metabotropic GABAB receptor (GABABR). Most studies that have examined the role of GABA receptors in the LA have focused on GABAARs. GABAARs and GABACRs are activated by the same ligands (GABA or GABAA agonists; Lukasiewicz et al, 1994), but GABACRs are many times more sensitive than GABAARs to these. If GABACRs are present in the LA, they should contribute to amygdala functions under different conditions than GABAARs. To test this, we used different concentrations of the GABA agonist muscimol since low concentrations should activate GABACRs and high concentrations GABAARs
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