GABAC receptors in the lateral amygdala: a possible novel target for the treatment of fear and anxiety disorders?

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.

Differentiating Enantioselective Actions of GABOB: A Possible Role for Threonine 244 in the Binding Site of GABAC ρ1 Receptors

“…17,18 They are highly expressed in retina and in distinct areas of the brain: cerebellum, 19 hippocampus, 20 superior colliculus, 21 and lateral amygdala. 22 Experimental evidence suggests that GABA C receptors are potential therapeutic targets for the treatment of myopia, 23 anxiety, 22 memory, 24 and sleep-related disorders. 25 The orthosteric binding sites of GABA C receptors are located at the interface of two ρ subunits within the N-terminal domain.…”

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

“…Rats administered TPMPA via bilateral cannulae injections into the lateral amygdala showed reduced freezing in a foot shock conditioned fear task. This reduction in fear learning and memory is likely mediated by presynaptically located GABA C receptors in the lateral amygdala [54].…”

“…Injection of bicuculline caused the opposite efect. TPMPA has also been used to demonstrate a role for GABA C receptors in fear learning and memory in rats [54]. Rats administered TPMPA via bilateral cannulae injections into the lateral amygdala showed reduced freezing in a foot shock conditioned fear task.…”

“…GABA C receptor antagonists have also been useful experimental tools for demonstrating a role for these receptors in learning and memory [49,50,54]. TPMPA and the structural analog P4MPA ((piperidin-4-yl)methylphosphinic acid) were shown to enhance short-term memory in a bead discrimination task following injection into the multimodal association forebrain area in chicks [49].…”

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

“…Thus, GABA C receptors may be of clinical and pharmacological interest as potential therapeutic targets for myopia, in enhancing cognition and managing memory-related disorders, and its presence in the amygdala might be an alternative target for the development of antianxiety drugs. 16 To date, the structural manipulations made in developing GABA analogues for the GABA C receptor have mainly been confined to the carboxylic acid end of the molecule or restricting the conformations of the flexible GABA backbone. As the structure-activity-relationship (SAR) profile of selective GABA C receptor ligands is limited, there is a need to develop more structurally diverse GABA C receptor ligands to understand the physiological role of these receptors.…”