Preclinical assessment for selectively disrupting a traumatic memory via postretrieval inhibition of glucocorticoid receptors

Abstract

Background: Traumatic experiences may lead to debilitating psychiatric disorders including acute stress disorder and posttraumatic stress disorder. Current treatments for these conditions are largely ineffective, and novel therapies are needed. A cardinal symptom of these pathologies is the reexperiencing of the trauma through intrusive memories and nightmares. Studies in animal models indicate that memories can be weakened by interfering with the postretrieval restabilization process known as memory reconsolidation. We previously reported that, in rats, intraamygdala injection of the glucocorticoid receptor antagonist RU38486 disrupts the reconsolidation of a traumatic memory. Here we tested parameters important for designing novel clinical protocols targeting the reconsolidation of a traumatic memory with RU38486.

Methods: Using rat inhibitory avoidance, we tested the efficacy of postretrieval systemic administration of RU38486 on subsequent memory retention and evaluated several key preclinical parameters.

Results: Systemic administration of RU38486 before or after retrieval persistently weakens inhibitory avoidance memory retention in a dose-dependent manner, and memory does not reemerge following a footshock reminder. The efficacy of treatment is a function of the intensity of the initial trauma, and intense traumatic memories can be disrupted by changing the time and number of interventions. Furthermore, one or two treatments are sufficient to disrupt the memory maximally. The treatment selectively targets the reactivated memory without interfering with the retention of another nonreactivated memory.

Conclusions: RU38486 is a potential novel treatment for psychiatric disorders linked to traumatic memories. Our data provide the parameters for designing promising clinical trials for the treatment of flashback-type symptoms of PTSD.

Figure 1

RU38486 administered following memory reactivation disrupts the retention of a traumatic memory in a dose-dependent manner. (A) IA training/testing and drug administration schedule. (B) Mean latencies ± s.e.m. of groups of rats systemically injected (↑) with 3 mg/Kg of RU38486 (n = 8) or vehicle (Veh, n = 7) immediately after Test 1 and re-tested 48 hours later (Test 2). (C) Mean latencies ± s.e.m. of groups of rats systemically injected with 30 mg/Kg of RU38486 (n = 11) or Veh (n = 11) immediately after Test 1 and re-tested 48 hours later (Test 2), 1 week later (Test 3) and after a reminder shock (Test 4). RU38486 NR: rats that received RU38486 in the absence of reactivation (n = 7). (**p < 0.01). (D) Identical to C, except that rats were injected with 60 mg/Kg of RU38486 (n = 9) or Veh (n = 12); NR, n = 7 (*p < 0.05; **p < 0.01). (E) Identical to C and D, except that animals were injected with 120 mg/Kg of RU38486 (n = 8) or Veh (n = 8); NR, n = 6 (*p < 0.05; **p < 0.01). (F) Identical to C, except that rats were tested 3 weeks after Test 1 (Test 2); RU38486 (n = 9); Veh (n = 8) (*p < 0.05). (G) Mean ± s.e.m. time spent exploring the inner arena. No significant difference was found between RU38486- and vehicle-treated groups (n=5 per group). (H) Mean ± s.e.m. locomotor activity in the arena (center). No significant difference was found between RU38486- and vehicle-treated groups (n=5 per group).

Figure 2

One-two post-retrieval RU38486 treatments are sufficient to maximally disrupt the retention of a traumatic memory. Mean latencies ± s.e.m. of groups of rats systemically injected (↑) with 30 mg/Kg of RU38486 (n = 8) or Veh (n = 7) immediately after Tests 1 through 4, and then re-tested 48 hours later (Test 5). (***p < 0.001). RU38486 NR: rats that received RU38486 in the absence of reactivation (n = 6). (*p < 0.05)

Figure 3

RU38486 disrupts a traumatic memory when administered prior to memory reactivation. Animals were trained using a 0.6 mA (mild) foot shock. Mean latencies ± s.e.m. of groups of rats systemically injected (↑) with 30 mg/Kg of RU38486 (n = 13) or Veh (n = 11) 45 minutes prior to Test 1 and re-tested 48 hours later (Test 2). (**p < 0.01).

Figure 4

RU38486-mediated disruption of a traumatic memory is selective for the reactivated memory and does not interfere with the stability of another established memory. Groups of rats were trained in both IA and in FC. IA retention is expressed as mean latencies ± s.e.m., FC retention is expressed as mean % freezing ± s.e.m.. (A) Rats underwent reactivation of IA but not FC: Groups of rats systemically injected (↑) with 30 mg/Kg of RU38486 (n = 8) or Veh (n = 6) immediately after IA reactivation (Test 1) and re-tested 48 hours later for both IA (IA Test 2; *p < 0.05) and FC (no effect) retentions. (B) Rats underwent reactivation of FC but not IA: Groups of rats systemically injected (↑) with 30 mg/Kg of RU38486 (n = 8) or Veh (n = 8) immediately after FC Test 1 and tested 48 hours later for both IA (no effect) and FC (FC Test 2, *p < 0.05).

Figure 5

The efficacy of post-retrieval RU38486 treatmment is a function of the intensity of the initial trauma. (A) IA training/testing and drug administration schedule. (B) Animals were trained using a 0.9 mA (moderate) foot shock. Mean latencies ± s.e.m. of groups of rats systemically injected (↑) with 30 mg/Kg of RU38486 (n = 8) or Veh (n = 10) immediately after Test 1 and re-tested 48 hours later (Test 2), 1 week later (Test 3) and after a reminder shock (Test 4). NR, n = 7. (***p < 0.001). (C) Animals were trained using a 1.2 mA (high) foot shock. Mean latencies ± s.e.m. at Test 2 of groups of rats systemically injected with 3 (n = 8), 30 (n = 7) or 120 (n = 8) mg/Kg of RU38486 or Veh (n = 8) immediately after Test 1. (D) Animals were trained using a 1.2 mA (high) foot shock. Mean latencies ± s.e.m. of groups of rats systemically injected twice, 5 hours apart, with 2.2 mg/Kg of cycloheximide (CXM) (n = 7) or Veh (n = 7) immediately after Test 1 and re-tested 48 hours later (Test 2). (***p < 0.001).

Figure 6

Time and number of interventions are critical parameters for RU38486 efficacy in disrupting a high intensity traumatic memory. (A) Mean latencies ± s.e.m. of groups of rats systemically injected (↑) with 30 mg/Kg of RU38486 (n = 12) or Veh (n = 9) immediately after Test 1 and Test 2, and then re-tested 48 hours later (Test 3). (B) Mean latencies ± s.e.m. of groups of rats systemically injected with 30 mg/Kg of RU38486 (n = 11) or Veh (n = 11) immediately after both Tests 1 and 2, and then re-tested 48 hours later (Test 3), 1 week later (Test 4) and after a reminder shock (Test 5). (*p < 0.05; **p < 0.01). RU38486 NR: rats that received RU38486 in the absence of reactivation (n = 6). (*p < 0.05).