Combination treatment with medium dose THC and CBD had no therapeutic effect in a transgenic mouse model for Alzheimer's disease but affected other domains including anxiety-related behaviours and object recognition memory

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that effects memory and behaviour. The phytocannabinoid cannabidiol (CBD) has been found to reverse impairments of recognition as well as spatial memory deficits of AD transgenic mice but had only limited effects on disease-relevant brain pathologies. Recent evidence suggests that combining CBD with other cannabinoids including delta-9-tetrahydrocannabinol (THC) may lead to improved therapeutic outcomes. Thus, this study evaluated the chronic effects of combined treatment with 3 mg/kg THC and 20 mg/kg CBD on 14.5-month-old APPSwe/PS1ΔE9 (APP/PS1) transgenic females and control littermates. Mice were treated with THCxCBD or vehicle (VEH) daily via intraperitoneal injections for 3 weeks before behavioural testing commenced. AD-relevant behavioural domains were analysed utilising Elevated Plus Maze (EPM), open field (OF), novel object recognition test (NORT), social interaction (SI), Y-maze (YM), and prepulse inhibition test (PPI). APP/PS1 females showed an anxiety-like phenotype and object recognition deficits that remained unchanged by cannabinoid treatment. Interestingly, some effects of THCxCBD appeared genotype-dependent with cannabinoid treatment causing an anxiogenic EPM response in APP/PS1 mice but having an anxiolytic-like effect in WT females. Moreover, THCxCBD administration disrupted the novel object preference of control females. Noteworthy, THCxCBD significantly decreased different fat depots and bodyweight of all mice across genotype. No other differences between genotypes or treatment groups were detected. In conclusion, the particular cannabinoid combination strategy utilised had no prominent therapeutic-like effect in 14.5-month-old APP/PS1 females.