Baclofen acts in the central amygdala to reduce synaptic transmission and impair context fear conditioning

Abstract

The two main sub-divisions of the Central amygdala (CeA), the lateral-capsular (CeA-LC) and the medial (CeA-M), contain extensive networks of inhibitory interneurons. We have previously shown that activation of GABAB-receptors reduces excitatory transmission between axons of the pontine parabrachial nucleus and neurons of the CeA-LC by inhibiting glutamate release from presynaptic terminals13. Here we have characterised GABAB-receptor activation on other excitatory and inhibitory projections within the CeA. Using whole-cell, patch-clamp recordings, we found that the GABAB-receptor agonist baclofen significantly reduced excitatory and inhibitory transmission from all tested inputs into the CeA-LC and CeA-M. In all but one of the inputs, reductions in transmission were accompanied by an increase in paired pulse ratio, indicating that presynaptic GABAB-receptors acted to reduce the release probability of synaptic vesicles. To examine the impact of GABAB-receptors in the CeA on contextual fear-conditioning, we infused baclofen into the CeA immediately prior to training. Compared to vehicle-infused rats, baclofen-infused rats displayed significantly less freezing both during the final stages of the training period and at test 24 hours later. The results of this study demonstrate that, by suppressing excitatory and inhibitory transmission, activation of presynaptic GABAB-receptors in the CeA inhibits the development of context conditioned fear.

Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala

“…Indeed, down-regulation of GAT-3 in rats showing addiction-like behaviours results in an increased GABAergic tone in the CeA, presumably as the result of decreased GABA clearance by these GABA transporters in the synaptic cleft 17 . Pharmacological activation of GABA B receptors by the agonist baclofen decreases the extracellular release of GABA 23,24 , and results in a dose-dependent decrease in alcohol intake at the population level, as shown in this and in previous studies 6 . Furthermore, as shown in the present study, baclofen selectively decreased the compulsive drinking of alcohol by AAR rats when challenged by adulteration with quinine.…”

“…This indicates that restoring the putatively altered extracellular GABA levels triggered by reduced GAT-3 expression may decrease persistent alcohol drinking in compulsive individuals 17,22 . For example, GABA receptor agonists such as baclofen may restore extrasynaptic GABA levels by acting at presynaptic GABA B receptors that control GABA release in the synaptic cleft [22][23][24] and hence decrease alcohol drinking.…”

Presynaptic inhibition rapidly stabilises recurrent excitation in the face of plasticity

“…The system described by Eqs (22) and 23is in the stationary state if the rate estimate and excitatory firing rate are at the target (� r E ¼ r E ¼ k). To obtain the Jacobian of the system, we calculate the partial derivates of the right hand side of Eqs (22) and (23) with respect to r E and � r E and evaluate it at the fixed point ðr E ; � r E Þ ¼ ðk; kÞ:…”

Oxytocin increases inhibitory synaptic transmission and blocks development of long-term potentiation in the lateral amygdala

“…In this study, we demonstrate that an OT-induced increase in GABA release can, through the activation of presynaptic GABA B receptors, attenuate excitatory and inhibitory synaptic transmission in the LA. Since the activation of presynaptic GABA B receptors also inhibits excitatory and inhibitory transmission in the central amygdala (Delaney and Crane 2016;Delaney et al 2018), it is possible that OT, by enhancing inhibitory transmission and the activation of presynaptic GABA B receptors in the central amygdala, could reduce excitatory neurotransmission and synaptic plasticity within the central amygdala. However, this possibility remains to be investigated.…”