Medium-Dose Chronic Cannabidiol Treatment Reverses Object Recognition Memory Deficits of APP Swe /PS1ΔE9 Transgenic Female Mice.

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. 2020 Dec 4;11:587604.

doi: 10.3389/fphar.2020.587604. eCollection 2020.

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Madilyn Coles et al. Front Pharmacol. .

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that causes behavioral and cognitive impairments. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory, antioxidant, and neuroprotective properties, and in vitro and limited in vivo evidence suggests that CBD possesses therapeutic-like properties for the treatment of AD. Cannabinoids are known to have dose-dependent effects and the therapeutic potential of medium-dose CBD for AD transgenic mice has not been assessed in great detail yet. 12-month-old control and APP Swe/PS1ΔE9 (APPxPS1) transgenic female mice were treated daily via intraperitoneal injection with 5 mg/kg bodyweight CBD (or vehicle) commencing three weeks prior to the assessment of behavioral domains including anxiety, exploration, locomotion, motor functions, cognition, and sensorimotor gating. APPxPS1 mice exhibited a hyperlocomotive and anxiogenic-like phenotype and had wild type-like motor and spatial learning abilities, although AD transgenic mice took generally longer to complete the cheeseboard training (due to a lower locomotion speed). Furthermore spatial learning and reversal learning was delayed by one day in APPxPS1 mice compared to control mice. All mice displayed intact spatial memory and retrieval memory, but APPxPS1 mice showed reduced levels of perseverance in the cheeseboard probe trial. Importantly, vehicle-treated APPxPS1 mice were characterized by object recognition deficits and delayed spatial learning, which were reversed by CBD treatment. Finally, impairments in sensorimotor gating of APPxPS1 mice were not affected by CBD. In conclusion, medium-dose CBD appears to have therapeutic value for the treatment of particular behavioral impairments present in AD patients. Future research should consider the molecular mechanisms behind CBD’s beneficial properties for AD transgenic mice.

Keywords: APPSwe/PS1ΔE9; Alzheimer’s disease; behavior; cannabidiol; transgenic mouse model; treatment.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1

FIGURE 1

Novel object recognition. The percentage of time spent nosing the novel object in the NORT. Data for wild type-like (WT) control and double transgenic APP
Swe/PS1ΔE9 (APPxPS1) female mice treated with either vehicle (VEH) or cannabidiol (CBD) are shown as means + SEM. Significant t-test results against chance levels (i.e., 50%) are indicated with “+” (+p < .05 and ++p < .01).

FIGURE 2

FIGURE 2

Spatial learning in the cheeseboard (CB). (A, C, and E) Latency (s) to find the food reward and (B, D, and F) distance traveled (m) during CB training (A and B) averaged across all three trials, (C and D) for intermediate-term memory and (E and F) for reference memory. Data for wild type-like (WT) control and double transgenic APP
Swe/PS1ΔE9 (APPxPS1) female mice treated with either vehicle (VEH) or cannabidiol (CBD) are shown as means ± SEM. Significant “genotype” effects are indicated by “*” (*p < .05 and **p < .01) and successful learning is indicated by ‘ ^ ’ (^ ^ ^ p < .001).

FIGURE 3

FIGURE 3

Spatial learning in the reversal cheeseboard (reversal CB). (A, C, and E) Latency (s) to find the food reward and (B, D, and F) distance traveled (m) during reversal CB training (A and B) averaged across all three trials, (C and D) for intermediate-term memory and (E and F) for reference memory. Data for wild type-like (WT) control and double transgenic APP
Swe/PS1ΔE9 (APPxPS1) female mice treated with either vehicle (VEH) or cannabidiol (CBD) are shown as means ± SEM. Significant “genotype” effects are indicated by “*” (**p < .01 and ***p < .001) and successful learning is indicated by ‘ ^ ’ (^ ^ ^ p < .001). There was a “time” by “genotype” by “treatment” interaction for distance traveled across all three trials (p = .004) and for intermediate-term memory (p = .04). The “time” by “treatment” interactions for APPxPS1 mice are indicated by “” (p < .05) or the exact trend level has been indicated by “p = .06.”

FIGURE 4

FIGURE 4

Spatial memory in the cheeseboard (CB) probe and reversal cheeseboard (reversal CB) probe. (A) Percentage of time spent (%) in the target zone for the CB probe and (B) for the reversal CB probe. Data for wild type-like (WT) control and double transgenic APP
Swe/PS1ΔE9 (APPxPS1) female mice treated with either vehicle (VEH) or cannabidiol (CBD) are shown as means + SEM. Significant t-test results against chance levels (i.e., 12.5%) are indicated by “+” (+p < .05,++p < .01, and +++p < .001).

FIGURE 5

FIGURE 5

Acoustic startle response (ASR) and sensorimotor gating (PPI). (A) ASR to increasing startle pulse intensity (70/100/120 dB), (B) percentage prepulse inhibition (%PPI) averaged over trials for increasing prepulse intensities (74/82/86 dB), and (C) %PPI averaged over prepulse intensity and interstimulus interval (ISI). Data for wild type-like (WT) control and double transgenic APP
Swe/PS1ΔE9 (APPxPS1) female mice treated with either vehicle (VEH) or cannabidiol (CBD) are shown as means + SEM. Significant “genotype” effects are indicated with “*” (*p < .05 and **p < .01) and RM effects are indicated by ‘ ^ ’ ( ^ ^ ^ p < .001). There was a “genotype” by “prepulse intensity” interaction for average %PPI for increasing prepulse intensities (p < .001).

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