Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats--a possible mechanism for the persistence of traumatic memories in PTSD

Abstract

Background: Posttraumatic stress disorder (PTSD) is associated with enhanced noradrenergic activity. Animal and human studies demonstrate that noradrenergic stimulation augments consolidation of fear learning. Retrieval of well-established memories by presenting a learned fear cue triggers reconsolidation processes during which memories may be updated, weakened, or strengthened. We previously reported that noradrenergic blockade in the rat amygdala impairs reconsolidation of fear memories. Here we investigated the effects of noradrenergic enhancement on reconsolidation of learned fear.

Methods: Using auditory fear conditioning in rats, we tested the effects of postretrieval intraamygdala infusion of the β-adrenergic receptor agonist isoproterenol or the antagonist propranolol on conditioned fear in the amygdala.

Results: A single intraamygdala infusion of isoproterenol following a retrieval of a well-consolidated memory enhanced fear memory elicited by the learned fear stimulus and impaired extinction of this memory 48 hr later. Intraamygdala infusion of the β-adrenergic receptor antagonist propranolol following a consecutive retrieval trial blocked the enhancing effects of isoproterenol on fear memory.

Conclusions: Postretrieval β-adrenergic stimulation in the amygdala enhances reconsolidation of fear memories, making them resistant to extinction. Noradrenergic augmentation during retrieval of fear memories may thus contribute to persistence and severity of traumatic memories. Reconsolidation may be a useful tool in understanding the pathology of PTSD and may thus help in developing new and in modifying existing treatments of traumatic memories.

Figure 1. Cannualae placements in the lateral nucleus of the amygdala

Images show cannulae placements for rats included in Experiments 1, 3 and 4. Symbols indicate injection sites. White squares indicate saline (SAL) groups and grey circles indicate isoproterenol (ISO) groups in Experiments 1 and 3. White triangles indicate saline-saline (SAL-SAL) group, white circles indicate isoproterenol-saline (ISO-SAL) group, black squares indicate propranolol-saline (PRO-SAL), grey triangles indicate isoproterenol-saline (ISO-SAL) group and black triangles indicate propranolol-isoproterenol (PRO-ISO) group in Experiment 4. LA – lateral nucleus of the amygdala; B – basal nucleus of the amygdala. All sections depicted at around 3.8 mm posterior to Bregma.

Figure 2. Isoproterenol enhances reconsolidation of cue conditioned fear

(A) Post-reactivation isoproterenol infusions into the lateral nucleus of the amygdala (LA) enhance fear memory and impair extinction processes forty-eight hours later. The behavioral procedure (top) and freezing to the CS (bottom) during extinction test. (B) Post-reactivation isoproterenol infusions two millimeters dorsal to the LA have no effect on fear memory. The behavioral procedure (top) and freezing to the CS (bottom) during extinction test. (C) Post-reactivation isoproterenol infusions into the lateral nucleus of the amygdala (LA) have no effect on memory three hours later. The behavioral procedure (top) and freezing to the CS (bottom) during extinction test. (ISO: isoproterenol; SAL: saline; ** indicates different from all other groups Tukey’s HSD p < .01)

Figure 3. Noradrenergic-dependent reconsolidation of conditioned fear occurs more than once

The behavioral procedure (top) and freezing to the CS (bottom) during extinction test forty-eight hours following the second reactivation trial. (SAL-SAL: saline-saline; PRO-SAL: propranolol-saline; PRO-ISO: propranolol-isoproterenol; ISO-SAL: isoproterenol-saline; ISO-PRO: isoproterenol-propranolol; * indicates Tukey’s HSD p < .05, ** indicates Tukey’s HSD p < .01)