Exploring pharmacological options for adolescent depression: a preclinical evaluation with a sex perspective

Abstract

There is an urgent need for developing novel pharmacological treatment options for adolescent depression, and to ensure an optimal translational outcome to the clinic, sex should be included as a biological variable in preclinical studies. In this context, the present study compared the antidepressant-like potential of ketamine and cannabidiol, with the clinical standard fluoxetine, in adolescent rats exposed to maternal deprivation (as a model of early-life stress), while including a sex perspective. Moreover, changes in drug efficacy over time were evaluated by re-exposing rats to the same dose regimens during adulthood. Antidepressant-like responses were scored through a battery of distinctive tests (forced-swim, novelty-suppressed feeding, and sucrose preference) across time. The main results proved an antidepressant-like potential for ketamine and cannabidiol in adolescent rats, although their efficacy was dependent on sex and prior stress exposure, as well as on treatment length and the behavioral feature analyzed. In general, while all tested antidepressants in male rats improved certain affective-like features, female rats were mainly unresponsive to the treatments performed (except for certain benefits induced by ketamine), demonstrating the need for further characterizing proper treatments for this particular sex. Moreover, when rats were re-exposed in adulthood to the same drug regimens as in adolescence, a drop in efficacy was observed. These findings may have translational ramifications in that ketamine or cannabidiol could be moved forward as antidepressants for the adolescent depressed population, but not before further characterizing their potential long-term safety and/or beneficial vs. harmful effects for both sexes.

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

“…Four studies assessed the behavioural effects of acute or repeated exposure to CBD in adolescent or adult rodents. Two of these studies focused on the potential of CBD to modulate addiction-related effects of THC [ 53 , 54 ] and the other two focused on antidepressant-like effects of CBD [ 55 , 56 ].…”

“…Ledesma-Corvi et al (2022) administered daily 10 mg/kg CBD intraperitoneal injections for seven days during adolescence in Sprague-Dawley rats, then re-exposed the rats for another seven days in adulthood, and tested antidepressant-like effects during both treatment phases on day 1 of CBD treatment (acute effects) and immediately after treatment (repeated effects) [ 55 ]. Approximately half of the rats were exposed to maternal deprivation, and there were also cohorts who received vehicle, fluoxetine, or ketamine, which led to complex three-way interactions of sex, treatment group, and early-life condition.…”

“…Similar effects on immobility time and climbing were observed in male adults, though only after repeated exposure to CBD (no acute effect). CBD did not have effects on the novelty-suppressed feeding or sucrose preference tests in either adolescence or adulthood, regardless of early-life condition, with the exception of a small decrease in distance travelled in the novelty-suppressed feeding test in male maternally-deprived rats [ 55 ]. Silote et al (2021) administered a single intraperitoneal injection of 3, 10, or 30 mg/kg CBD to both Swiss and C57BL/6 mice and Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats (who were additionally administered a 60 mg/kg dose), and then tested antidepressant-like effects [ 56 ].…”

“…Second, two studies found evidence of antidepressant-like effects of CBD in male (but not female) rats and mice [ 55 , 56 ]. Of note, these studies found that the antidepressant-like effects of CBD were also influenced by species, strain, early life exposure to maternal deprivation, CBD exposure paradigm (acute vs. repeated), and age of the rodents [ 55 , 56 ], which speaks to the difficulty of assessing sex differences against a backdrop of multiple other potential moderating factors.…”

“…Second, two studies found evidence of antidepressant-like effects of CBD in male (but not female) rats and mice [ 55 , 56 ]. Of note, these studies found that the antidepressant-like effects of CBD were also influenced by species, strain, early life exposure to maternal deprivation, CBD exposure paradigm (acute vs. repeated), and age of the rodents [ 55 , 56 ], which speaks to the difficulty of assessing sex differences against a backdrop of multiple other potential moderating factors. These results are consistent with one previous study that found antidepressant-like effects of CBD across males of two different genetic models of depression [Wistar Kyoto (WKY) and Flinders Sensitive Line (FSL) rats], while CBD had antidepressant-like effects in females of only one genetic model (WKY rats) [ 74 ].…”