Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

Abstract

It is well known that, under certain boundary conditions, the retrieval of a stable consolidated memory results into a labile one. During this unstable phase, memory can be vulnerable to interference by a number of pharmacological agents, including benzodiazepines. One of the goals of this study was to evaluate the vulnerability to midazolam (MDZ) after reactivation of recent and remote contextual fear memories in animals that experienced a stressful situation before learning. Animals were subjected to a restraint session and trained in a contextual fear paradigm the following day; consolidated memories were reactivated at different times after learning and different MDZ doses (1.5, 3.0 mg/kg) were administered to rats after reactivation. Our results show that MDZ did not affect memory reconsolidation in older-than-one-day memories of stressed animals, even after the administration of a higher MDZ dose and a longer reactivation session (5 min). In contrast, MDZ was effective in blocking reconsolidation at all memory ages in unstressed animals. In addition, the current research investigated whether activating NMDA sites before reactivation promotes the destabilization of resistant memories such as those of stressed animals. We tested the influence of pre-reactivation D-cycloserine (DCS), a partial NMDA agonist, on MDZ's effect on fear memory reconsolidation in stressed animals. Our findings indicate that DCS before reactivation promotes retrieval-induced lability in resistant memory traces, as MDZ-induced memory impairment in stressed rats became evident with pre-reactivation DCS but not after pre-reactivation sterile isotonic saline.

d-cycloserine in the basolateral amygdala prevents extinction and enhances reconsolidation of odor-reward associative learning in rats

“…However, the observation of the animals' behavior during reactivation by the experimenters showed comparable olfactory bouts or motor activity between DCS-and VEHtreated animals. Such observations agree with findings from other studies showing that DCS injected before reactivation did not influence freezing behavior during the reactivation session of fear conditioning (Bustos et al, 2010;Lee et al, 2006). Nevertheless, post-session injections would have better isolated retrieval-induced memory processes, and the possibility that postreactivation DCS affect ODT reconsolidation should be addressed in future studies.…”

“…Although these data suggest that DCS is able to potentiate memory consolidation after reactivation, namely reconsolidation, such an interpretation may be complicated by the fact that the injections were administered pre-reactivation (as in other reconsolidation studies, see Bustos et al, 2010;Lee et al, 2009;Lee et al, 2006;Yamada et al, 2009). Thus, it is possible that the effects found in the reconsolidation test may be due to performance effects on the actual reactivation trial.…”

“…More specifically, NMDA receptors (NMDARs) agonists have been regarded as pharmacological treatments that enhance learning, and as such, have been considered potential cognitive enhancers (see Villarejo-Rodríguez, Vale-Martínez, GuillazoBlanch, & Martí-Nicolovius, 2010). D-cycloserine (DCS) is a partial agonist at the glycine recognition site of the NMDARs and has been shown to enhance acquisition, consolidation, relearning, extinction and reconsolidation in several associative learning paradigms (Bustos, Giachero, Maldonado & Molina, 2010;Curlik & Shors, 2011;Davis, 2002;Ledgerwood, Richardson & Cranney, 2005;Lee, Milton & Everitt, 2006;Rodgers, Harvest, Hassall & Kaddour, 2011;Villarejo-Rodriguez et al, 2010). The majority of studies have focused on the role of DCS in extinction and reconsolidation, as the modulation of such processes may be useful as a treatment strategy for maladaptive memory or anxiety disorders (Davis, Ressler, Rothbaum & Richardson, 2006;Hofmann, 2007).…”

A BDNF sensitive mechanism is involved in the fear memory resulting from the interaction between stress and the retrieval of an established trace

“…Hence, these findings suggest that fear memory from stressed rats is less likely to become destabilized and vulnerable to disruption upon reactivation. Accordingly, retrieval-induced fragility of a contextual fear memory trace was constrained in animals subjected to a stressful situation similar to that used in the current study (Bustos et al 2010).…”

“…No other subjects were present in the experimental room during stress exposure. This procedure was selected based on previous findings from our laboratory using a similar stress protocol to that used in the current study (Rodriguez Manzanares et al 2005;Isoardi et al 2007;Bustos et al 2010). Retrieval was performed 1 d after stress exposure.…”