Abstract
Cannabis is the most-used recreational drug worldwide, with a high prevalence of use among adolescents. In animal models, long-term adverse effects were reported following chronic adolescent exposure to the main psychotomimetic component of the plant, delta-9-tetrahydrocannabinol (THC). However, these studies investigated the effects of pure THC, without taking into account other cannabinoids present in the cannabis plant. Interestingly, cannabidiol (CBD) content seems to mitigate some of the side effects of THC, at least in adult animals. Thus, in female rats, we evaluated the long-term consequences of a co-administration of THC and CBD at a 3:1 ratio, chosen based on the analysis of recently confiscated illegal cannabis samples in Europe. CBD content is able to mitigate some of the long-term behavioral alterations induced by adolescent THC exposure as well as long-term changes in CB1 receptor and microglia activation in the prefrontal cortex (PFC). We also investigated, for the first time, possible long-term effects of chronic administration of a THC/CBD combination reminiscent of “light cannabis” (CBD:THC in a 33:1 ratio; total THC 0.3%). Repeated administration of this CBD:THC combination has long-term adverse effects on cognition and leads to anhedonia. Concomitantly, it boosts Glutamic Acid Decarboxylase-67 (GAD67) levels in the PFC, suggesting a possible lasting effect on GABAergic neurotransmission.
Highlights
Cannabis is consumed by more than 182 million people worldwide, with a high prevalence of use among adolescents [1]
In this study, we investigated the possible protective role of CBD when administered in a 1:3 ratio relative to THC, resembling THC-rich/CBD-poor cannabis, during adolescence by comparing the long-term behavioral and neurochemical effects with the ones triggered by pure THC in female rats [14,15,16,17]
This study demonstrates that CBD content is able to modulate some of the long-term behavioral alterations induced by adolescent exposure to THC in female rats, especially when anxiety-like behaviors are considered
Summary
Cannabis is consumed by more than 182 million people worldwide, with a high prevalence of use among adolescents [1]. Exposure to cannabinoids during adolescence has been shown to exert long-term detrimental effects on emotional and cognitive functions in both animal models and humans [4]. In rodents, significant sexual divergence has been reported for both molecular and behavioral outcomes related to cannabis exposure, mainly on domains of function pertaining to the emotional sphere [9]. Another factor that could increase the risk of long-term adverse impact of cannabis on adolescent brain development is related to cannabis potency levels, which seem to depend on the delta-9-tetrahydrocannabinol (THC): cannabidiol (CBD) ratio in cannabis products. The investigation of a possible protective effect of CBD towards the adverse effects of THC has focused on the adult population, whereas, to the best of our knowledge, no specific study has addressed this issue in adolescent rodent models using
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