Chronic Adolescent D9-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment
Michelle Murphy,Sierra Mills, Joanna Winstone, Emma Leishman, Jim Wager-Miller, Heather Bradshaw, and Ken Mackie
Cannabis and Cannabinoid Research, Volume 2.1, 2017
Introduction : The high prevalence of adolescent cannabis use, the association between this use and later psychiatric disease, and increased access to high-potency cannabis highlight the need for a better understanding of the long-term effects of adolescent cannabis use on cognitive and behavioral outcomes. Furthermore, increasing Δ9-tetrahydrocannabinol (THC) in high-potency cannabis is accompanied by a decrease in cannabidiol (CBD), thus an understanding of the interactions between CBD and THC in the neurodevelopmental effects of THC is also important. The current study examined the immediate and long-term behavioral consequences of THC, CBD, and their combination in a mouse model of adolescent cannabis use.
Materials and Methods : Male CD1 mice received daily injections of THC (3 mg/kg), CBD (3 mg/kg), CBD+THC (3 mg/kg each), vehicle, or remained undisturbed in their home cage (no handling/injections), either during adolescence (postnatal day [PND] 28–48) or during early adulthood (PND 69–89). Animals were then evaluated with a battery of behavioral tests 1 day after drug treatment, and again after 42 drug-free days. The tests included the following: open field (day 1), novel object recognition (NOR; day 2), marble burying (day 3), elevated plus maze (EPM; day 4), and Nestlet shredding (day 5).
Results : Chronic administration of THC during adolescence led to immediate and long-term impairments in object recognition/working memory, as measured by the NOR task. In contrast, adult administration of THC caused immediate, but not long term, impairment of object/working memory. Adolescent chronic exposure to THC increased repetitive and compulsive-like behaviors, as measured by the Nestlet shredding task. Chronic administration of THC, either during adolescence or during adulthood, led to a delayed increase in anxiety as measured by the EPM. All THC-induced behavioral abnormalities were prevented by the coadministration of CBD+THC, whereas CBD alone did not influence behavioral outcomes.
Conclusion : These data suggest that chronic exposure to THC during adolescence leads to some of the behavioral abnormalities common in schizophrenia. Interestingly, CBD appeared to antagonize all THC-induced behavioral abnormalities. These findings support the hypothesis that adolescent THC use can impart long-term behavioral deficits; however, cotreatment with CBD prevents these deficits.
Cannabis contains more than 60 cannabinoids.1–3 Of these, tetrahydrocannabinol (THC) is the major psychoactive and cannabidiol (CBD) is the main nonpsychoactive component of cannabis. Through genetic interactions, breeding for high-THC content (to create high-potency cannabis) results in very low-CBD levels. The market demand for high-potency cannabis has seen the average THC content of U.S. cannabis increasing from ∼4% to 12% in the past 20 years. This has been accompanied by a corresponding decrease in CBD content, increasing the average THC/CBD ratio ∼20-fold over the same period.4
Cannabis is the most widely used illicit drug among adolescents in the United States.5 In 2016, 12.8% of 8th graders have used cannabis in their lifetime, and by 12th grade 44.5% have tried cannabis.5 Furthermore, daily use increases from 0.7% among 8th graders to 6% among 12th graders.5 The high prevalence of frequent adolescent cannabis use, and the increased presence of high-THC/low-CBD cannabis, emphasizes a need for research examining the long-lasting effects of chronic adolescent exposure to major cannabis constituents on neurobehavioral outcomes.
During human adolescence (age ∼10–25), neuroanatomical and functional changes lead to increased neural and cognitive efficiency.6–8 As the prefrontal cortex (PFC) matures during adolescence, it undergoes significant synaptic remodeling and changes in myelination.9–12 The PFC is responsible for higher order cognitive function such as executive function,13–15 and disruption of maturation PFC can be expected to have long-lasting adverse consequences.
Because of the prominent role of endocannabinoids in neurodevelopment,16 cannabis exposure during adolescence might perturb PFC neurodevelopment and cause long-term cognitive, emotional, and behavioral impairments. Supporting this hypothesis, many studies indicate a positive correlation between adolescent cannabis use and aspects of schizophrenia (age of first psychotic episode, severity).17–22 Factors such as onset of use, frequency of use, and the THC/CBD ratio in cannabis consumed have been shown to modulate this risk.17,23,24 For instance, after controlling for confounding variables (e.g., IQ, psychiatric illness in family members), a large population-based study found a dose-dependent relationship of adolescent cannabis use and the development of schizophrenia.19 In addition, the risk of developing a psychotic disorder was shown to increase threefold among users of high-potency cannabis compared with subjects who never used cannabis.25 In this study, daily use of high-potency cannabis conferred an even higher (>fivefold) risk for developing schizophrenia.25
A causal relationship between adolescent cannabis use and an increased risk for schizophrenia is unlikely to be proven given ethical constraints. Thus, research utilizing animal models, rigorously controlled experimental design, and examination of specific cannabis components can identify potential mechanisms linking frequent adolescent cannabis use and an increased risk for schizophrenia. Furthermore, examining the variables involved in producing schizophrenia-associated phenotypes—such as impairment of working and object recognition memory, anxiety, and repetitive and compulsive behaviors—might provide valuable insight into schizophrenia’s etiology. Working26–29 and object recognition memory30–32 deficits are frequent in schizophrenia. Furthermore, repetitive and compulsive behaviors33,34 as well as anxiety35,36 are common in schizophrenia.
This study examined the immediate and long-term effects of chronic cannabinoid exposure on object recognition/working memory, repetitive and compulsive behaviors, and anxiety in adolescent and adult mice. We found that adolescent THC impaired selected behavioral domains and that this impairment was prevented by concurrent CBD treatment.