Chronic adolescent exposure to cannabis in mice leads to long-term sex-biased changes in gene expression networks across brain regions

Background: The molecular mechanisms underlying the long-lasting behavioral changes associated with adolescent cannabis use are poorly understood. To this end, we performed gene network analyses of multiple brain regions in adult mice exposed during the entire adolescence to Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: Two weeks after the last exposure to THC (10 mg/kg) or vehicle, we measured cognitive behaviors and profiled the transcriptomes of 5 brain regions from 12 female and 12 male mice. We performed differential gene expression analysis and constructed gene coexpression networks (modules) to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, and biological pathways. We integrated the THC-correlated modules with human traits from genome-wide association studies to identify potential regulators of disease-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females than males, which coincided with larger transcriptional changes in the female brain. Modules involved in endocannabinoid signaling and inflammation were correlated with memory deficits in the female dorsal medial striatum and ventral tegmental area, respectively. Converging pathways related to dopamine signaling and addiction were altered in the female amygdala and male nucleus accumbens. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, modules altered by THC were enriched in genes relevant for human cognition and neuropsychiatric disorders. Conclusions: These findings provide novel insights concerning the genes, pathways and brain regions underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner.

Chronic exposure to ∆9-tetrahydrocannabinol in adolescence decreases social play behaviours

Background: Cannabis use remains a major public health concern, and its use typically begins in adolescence. Chronic administration of ∆9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, during adolescence can produce deficits in adult learning and memory, stress reactivity and anxiety. One possible mechanism behind the disruptions in adulthood from adolescent exposure to THC includes changes in social behaviours, such as social play, which has been shown to be critical to socio-cognitive development. Methods: Here, using an established animal model of adolescent THC exposure in male and female Long–Evans rats, we explored the effects of THC on play behaviour during the chronic administration period. Following puberty onset, as indicated by external changes to the genitalia, THC (5mg/kg) was administered for 14 days. Play behaviour was assessed seven days following the onset of the injection period at approximately 1 hour post treatment. The frequency of nape attacks, the likelihood and tactics of defensive behaviour, and pins were scored and analyzed. Results: THC exposure decreased playfulness in adolescent rats including the number of attacks, likelihood of defense and pins compared to control and vehicle treated rats. Conclusion: This suggests that THC suppresses both the attack and defense components of social play. This is an important finding because there is evidence that attack and defense may be mediated by different mechanisms. Furthermore, the effect of THC exposure decreasing playfulness occurred similarly in males and females.

National Trends of Adolescent Exposure to Tobacco Advertisements: 2012–2020

BACKGROUND AND OBJECTIVES The objective of the current study is to evaluate the temporal trends in the prevalence of cigarette and electronic cigarette (e-cigarette) advertisement exposure by venue and sociodemographic correlates among US adolescents from 2012 to 2020. METHODS We conducted a serial cross-sectional analysis of nationally representative samples of middle and high school youth from the 2012–2020 National Youth Tobacco Survey. Advertisement exposure was defined as self-report of seeing advertisements “sometimes,” “most of the time,” and “always.” The prevalence of cigarette (and other tobacco products) and e-cigarette advertisement exposure, including overall and at specific venues (Internet, press, screen, and retail stores), was estimated by survey year. RESULTS A total of 139 795 adolescents aged 11 to 19 years old were included in the analysis. The prevalence of exposure to combustible cigarette marketing remained high across all years (any venue ranging from 77.0% [2018] to 91.1% [2014]). An increasing trend for cigarette advertisement exposure was observed from 2017 to 2020 after a drop in 2015 (β2012–2015 = 2.8, P for trend < .001; β2017–2020 = .7, P for trend = .03), driven by retail store–based and Internet-based exposure. A similar increasing pattern in the estimated prevalence of e-cigarette marketing was observed (β2014–2016 = 4.6, P for trend < .001; β2017–2020 = 5.1, P for trend < .001). CONCLUSIONS Given the high estimated prevalence of cigarette and e-cigarette marketing exposure among US adolescents, further regulation efforts for both off-line and online tobacco marketing are needed to mitigate adolescent exposure to content regarding these products, reducing susceptibility to uptake.

Long-Term Consequences of Adolescent Exposure to THC-Rich/CBD-Poor and CBD-Rich/THC-Poor Combinations: A Comparison with Pure THC Treatment in Female Rats

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.