Lack of drug-induced post-retrieval amnesia for auditory fear memories in rats

Abstract

Background Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia. Results In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide). Conclusions In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.

Interfering with contextual fear memories by post-reactivation administration of propranolol in mice: a series of null findings

“…Finally, we found no effects of memory reactivation on expression of the glutamate receptor subunit GluA2 (i.e., a marker of memory destabilization, Rao-Ruiz et al, 2011;Bhattacharya et al, 2017). This is in line with recent research showing similar null findings in rats using cued fear conditioning and Shank protein as a marker of memory destabilization (Rotondo et al, 2022, see also Luyten et al (2021) for more behavioral data).…”

Targeting the Reconsolidation of Licit Drug Memories to Prevent Relapse: Focus on Alcohol and Nicotine

“…The vast majority of studies on memory reconsolidation in animal models have been conducted on Pavlovian fear conditioning memories, where a context or a cue (typically a tone or a light) is paired with a foot shock, and subsequently the memory is retrieved by the presentation of the context/cue alone [9,10]. Despite this relatively standard and simple classical conditioning paradigm, methodological variability might account for inconsistent findings in the fear-memories reconsolidation field, e.g., [61,89,90]. In drug-related studies on memory reconsolidation, methodological variability is potentially even greater, due to the mosaic nature of these studies.…”

Covert capture and attenuation of a hippocampus-dependent fear memory

“…Although we found that intra-hippocampal rapamycin impaired reconsolidation of a covertly retrieved context memory, it is possible that this reflects a retrieval deficit, as opposed to memory erasure. Indeed, recent reports have challenged the idea that contextual and auditory fear memories in rats undergo protein synthesis-dependent reconsolidation 33 , 34 . Indeed, we observed spared freezing in rapamycin-treated rats during the early portions of the context test in the current study ( Fig.…”