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.

Figure 1

Influence of earlier stress on the effect of MDZ (1.5 or 3 mg/kg) on the reconsolidation of 1 day fear contextual memory. (a) Experimental design used with data presented below. (b) MDZ 1.5 or 3 mg/kg administration after a 3 min re-exposure has no effect on the reconsolidation process in STRESS group (n=7/10 per group). (c) Reconsolidation after 5 min re-exposure is disrupted by MDZ administration (1.5 and 3 mg/kg) in both groups (NO STRESS and STRESS) (n=9/10 per group). Data are the mean±SEM percentage of time spent freezing during re-exposure to A (3 or 5 min) and during the test. ^*Significantly different than SAL group during the test (P⩽0.02).

Figure 2

Effect of MDZ 1.5 mg/kg administration after 5 min exposure session to B (NO reactivation-B exposure). (a) Experimental design used with data presented below. (b) MDZ administration after exposure to a novel environment did not affect memory when tested in the associated context (a). Similar levels of freezing were observed between SAL- and MDZ-treated rats (1.5 mg/kg) in both groups (NO STRESS and STRESS) during the test. Data are the mean±SEM percentage of time spent freezing during exposure to B and during the test (n=6/9 per group). ^*Significantly different than the rest of the groups during exposure to B and during the test (P<0.01).

Figure 3

Influence of stress on the effect of MDZ on the reconsolidation of a 7 days fear contextual memory. (a) Experimental design used with data presented below. (b) and (c) MDZ 1.5 or 3 mg/kg does not affect reconsolidation of a 7-day fear memory regardless of the duration of the re-exposure period (3 or 5 min) in previously stressed animals. Data are the mean±SEM percentage of time spent freezing during re-exposure to A (3 or 5 min) and during the test (n=7/12 per group). ^*Significantly different than SAL group during the test (P<0.01).

Figure 4

Influence of stress on the effect of MDZ on reconsolidation of a 21-day fear contextual memory. (a) Experimental design used with data presented below. (b) MDZ 1.5 or 3 mg/kg administered after 5 min re-exposure does not affect reconsolidation of a 21-day fear memory in previously stressed animals. Data are the mean±SEM percentage of time spent freezing during re-exposure to A and during the test (n=7/10 per group). ^*Significantly different than SAL group during the test (P<0.01).

Figure 5

Influence of pre-reactivation DCS administration on MDZ's disruptive effect on reconsolidation of a 7-day-old fear memory in previously stressed animals. (a) The behavioral procedures used in the experiment. (b) DCS pre-reactivation facilitates MDZ's disruptive effect on the reconsolidation of a 7-day contextual fear memory in previously stressed animals. Data are the mean±SEM percentage of time spent freezing during tests 1 and 2 (n=10/14 per group). ^*Significantly different than SAL-SAL group (P<0.01). ⁺Significantly different than DCS-SAL group (P<0.01).

Figure 6

Influence of DCS administration before the exposure to a novel environment (B—no reactivation session) on MDZ's influence on a 7-day fear memory reconsolidation. (a) Experimental design used with data presented below. (b) Neither DCS nor MDZ affects memory reconsolidation during testing. Data are the mean±SEM percentage of time spent freezing during exposure to B (3 min) and during the test (A re-exposure) (n=8/10 per group). ^*Significantly different than the rest of the groups during exposure to B and during the test (P<0.01).