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.
Keywords: Cannabidiol (CBD); Citalopram; Extinction; Fear learning and memory; Female; Selective serotonin reuptake inhibitor (SSRI); Sexual dimorphism.