Comparison of cannabidiol to citalopram in targeting fear memory in female mice

Abstract

Background Cannabidiol (CBD) and selective serotonin reuptake inhibitors (SSRIs) are currently used to treat post-traumatic stress disorder (PTSD). However, these drugs are commonly studied after dosing just prior to extinction training, and there are gaps in our understanding of how they affect fear memory formation, their comparative effects on various types of memory, and of sexual dimorphisms in effects. Also, more studies involving female subjects are needed to balance the gender-inequality in the literature. Therefore, the purpose of this study was to directly compare the effects of CBD to citalopram in affecting the formation of auditory cued, contextual, and generalized fear memory, and to evaluate how extinction of these different memories was altered by pre-acquisition treatment in female mice. We also evaluated the impact of the estrous cycle on each of these. Methods Auditory-cued trace fear conditioning was conducted shortly after dosing female C57BL/6 mice, with either CBD or citalopram (10 mg/kg each), by pairing auditory tones with mild foot shocks. Auditory-cued, contextual, and generalized fear memory was assessed by measuring freezing responses, with an automated fear conditioning system, 24 h after conditioning. Each memory type was then evaluated every 24 h, over a 4-day period in total, to create an extinction profile. Freezing outcomes were statistically compared by ANOVA with Tukey HSD post hoc analysis, N = 12 mice per experimental group. Evaluation of sexual dimorphism was by comparison to historical data from male mice. Results Auditory cue-associated fear memory was not affected with CBD or citalopram; however, contextual memory was reduced with CBD by 11%, p < 0.05, but not citalopram, and generalized fear memory was reduced with CBD and citalopram, 20% and 22%, respectively, p < 0.05. Extinction learning was enhanced with CBD and citalopram, but, there was considerable memory-type variability between drug effects, with freezing levels reduced at the end of training by 9 to 17% for CBD, and 10 to 12% with citalopram. The estrous cycle did not affect any outcomes. Conclusions Both drugs are potent modifiers of fear memory formation; however, there is considerable divergence in their targeting of different memory types which, overall, could support the use of CBD as an alternative to SSRIs for treating PTSD in females, but not males. A limitation of the study was that it compared data from experiments done at different times to evaluate sexual dimorphism. Overall, this suggests that more research is necessary to guide any therapeutic approach involving CBD.

Long-Term Exposure to SSRI Citalopram Induces Neurotoxic Effects in Zebrafish

“…Recent data on the impacts of citalopram on learning and memory processes are inconsistent, as studies in mammals have shown contradictory results. Intriguingly, the memory impairments induced by citalopram are more likely to occur in normal or healthy mammalian models ,, but are conversely also present in disease models. − Given our results (Figure S2) in the “”-maze and previous reports in the plus maze that demonstrated that zebrafish perform well in complex associative learning tasks, we investigated whether long-term exposure to citalopram resulted in decreased learning and memory in adult zebrafish. A significant decline in learning and memory performance was noted in citalopram-exposed adult zebrafish, with males and groups that received higher concentrations (10 and 100 μg/L) appearing relatively more vulnerable to impairment induced by long-term citalopram exposure.…”

Effect of long-term cannabidiol on learning and anxiety in a female Alzheimer’s disease mouse model

“…Long-term oral CBD treatment reduced freezing in the cue test of all females, regardless of the genotype. Although it is well established that acute systemic CBD can impair fear memory consolidation ( Han et al, 2022 ; Shallcross et al, 2019 ; review: Stern et al, 2018 ), including in female mice ( Montoya et al, 2020 ), effects of chronic CBD on fear memory have had limited investigation, and chronic CBD does not affect fear memory acquisition ( Cheng et al, 2014a ; 2014c ). Considering CBD-induced differences in freezing were very limited in this study, future research should consider evaluating the effects of long-term CBD on fear learning in female mice.…”

Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction

“…Evidence for serotonin's involvement in FE processes comes mainly from studies investigating the relationship between different SSRIs and FE learning. Most commonly prescribed antidepressants—fluoxetine, paroxetine, sertraline, and citalopram—have the ability to facilitate the extinction of conditioned fear (Karpova et al, 2011; Montoya et al, 2020; Pedraza et al, 2019; Popova et al, 2014) and restore impaired extinction learning induced by different stressors (Pereira‐Figueiredo et al, 2017; Regue et al, 2019; Uniyal et al, 2019). SSRI‐induced augmentation of FE was associated with enhanced NMDAR expression in the amygdala and hippocampus (Popova et al, 2014), increased AMPAR hippocampal signaling (Gottschalk et al, 2018), and altered levels of BDNF mRNA and protein in the amygdala (Karpova et al, 2011; Regue et al, 2019), cortex (Uniyal et al, 2019), and hippocampus (Karpova et al, 2011; Regue et al, 2019; Uniyal et al, 2019).…”