Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression

Zsolt Gáll, Szidónia Farkas, Ákos Albert, Elek Ferencz, Szende Vancea, Melinda Urkon, Melinda Kolcsár, Zsolt Gáll, Szidónia Farkas, Ákos Albert, Elek Ferencz, Szende Vancea, Melinda Urkon, Melinda Kolcsár

Abstract

Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified. The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression. Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography-mass spectrometry. At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. -45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment. The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.

Keywords: animal model; cannabidiol; chronic mild stress; depression; hair corticosterone.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Study timeline to illustrate the design of the acute and chronic experiments, the application of the chronic unpredictable mild stress (CUMS) protocol, and the timing of the behavioral assays and hair sampling. The diagonally striped box shows the 28-day stressing period preceded by a 21-day habituation to single housing. Stressors were applied twice daily starting at 10:00 and 17:00. Cannabidiol was administered in a single dose of 10 mg/kg by intraperitoneal injections in the acute experiment and daily, starting at day 0 until day 32, in the chronic experiment. Abbreviations: OF, open field test; EPM, elevated plus maze test.
Figure 2
Figure 2
Representative HPLC chromatograms obtained: A. blank solution (20 μL 0.1% formic acid (v/v) in deionized water in 150 μL methanol); B. standard solution (15 ng/mL), C. real sample (10.48 ng/mL).
Figure 3
Figure 3
Results of body weight measurements during a four-week CUMS procedure with or without concomitant cannabidiol (10 mg/kg body weight) treatment. Data are expressed as mean ± 95% confidence interval; * p < 0.05 vs. control.
Figure 4
Figure 4
Results of the sucrose preference test for rats submitted to a four-week CUMS treatment with or without cannabidiol administration (mean ± SEM, n = 18). (A.) Sucrose preference measured as % preference for sucrose; (B.) sucrose (mL of 1.0% sucrose solution ingested) and water intake on each testing day. CBD, cannabidiol; * p < 0.05 vs baseline.
Figure 5
Figure 5
Results of the open field test in the two experiments. The first column represents the acute experiment, where non-stressed animals received a single dose of vehicle or 10 mg/kg of CBD. The second column shows the chronic experiment, where the animals were treated for 32 days with vehicle or 10 mg/kg of CBD and were subjected to the CUMS protocol. Means ± SEM (n = 8–10) are presented. Data were analyzed with unpaired t-test or Mann–Whitney test. The dots represent individual values, * p < 0.05.
Figure 6
Figure 6
Hair corticosterone (CORT) levels in rats subjected to a four-week CUMS procedure and CBD treatment (10 mg/kg body weight) for 32 days. Samples were taken at day 0 and at day 32 (before and after CUMS). Means ± SEM (n = 8–10 per group) are presented. Data were analyzed by two-way ANOVA with repeated measures for the factors time and treatment. (A) Hair corticosterone change expressed as percentage with respect to baseline value; (B,C) hair corticosterone levels before and after CUMS. The dots represent individual values; * p < 0.05, ** p < 0.01.

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