Differential effects of cannabidiol on inhibitory avoidance memory reconsolidation and consolidation are associated with distinct hippocampal proBDNF and BDNF signaling profiles

Abstract

Introduction Cannabidiol (CBD), a major non-psychoactive constituent of Cannabis sativa, exerts pleiotropic effects, including antipsychotic, anxiolytic, and neuroprotective properties, with low toxicity and minimal euphoric effects. Previous studies have demonstrated that CBD alleviates memory impairments associated with pathological conditions such as seizures, reserpine exposure, pneumococcal meningitis, and sepsis. However, its effects on memory processes, particularly inhibitory avoidance (IA) memory reconsolidation and consolidation, remain incompletely understood and inconsistently reported. Therefore, this study investigated the effects of CBD on IA memory reconsolidation and consolidation in mice and explored the underlying neurotrophic mechanisms. Methods Mice were subjected to the IA task and administered CBD at different doses during either the reconsolidation or consolidation phase. To examine the involvement of tropomyosin receptor kinase (Trk) signaling, the Trk receptor antagonist K252a was co-administered with CBD. In addition, anisomycin (ANI) was used to induce impairments in IA memory consolidation. Hippocampal levels of pro-brain-derived neurotrophic factor (proBDNF) and mature brain-derived neurotrophic factor (BDNF) were measured to investigate the molecular mechanisms underlying CBD-mediated effects. Results CBD impaired IA memory reconsolidation in a dose-dependent manner, and this effect was abolished by K252a. During reconsolidation, CBD selectively reduced hippocampal proBDNF levels without altering mature BDNF expression. In contrast, the same dose of CBD did not affect IA memory consolidation under baseline conditions. However, CBD attenuated ANI-induced impairments in IA memory consolidation, and this protective effect was also blocked by K252a. Biochemical analyses further showed that ANI treatment reduced hippocampal mature BDNF levels, whereas CBD administration prevented this reduction. Discussion These findings demonstrate that CBD differentially modulates IA memory reconsolidation and consolidation through distinct neurotrophic mechanisms. Specifically, the CBD-induced impairment of memory reconsolidation was associated with reduced hippocampal proBDNF levels, whereas the protective effect of CBD against ANI-induced deficits in memory consolidation was accompanied by restoration of mature BDNF expression relative to the vehicle control group. Collectively, these findings provide novel mechanistic insights into the bidirectional effects of CBD on memory processes and underscore the importance of carefully evaluating its therapeutic potential and associated neurobiological mechanisms in the context of memory-related disorders.