Pharmacokinetic, behavioral, and brain activity effects of Δ9-tetrahydrocannabinol in adolescent male and female rats

Abstract

Δ 9 -tetrahydrocannabinol (THC) is the intoxicating constituent of cannabis and is responsible for the drug's reinforcing effects. Retrospective human studies suggest that cannabis use during adolescence is linked to long-term negative psychological outcomes, but in such studies it is difficult to distinguish the effects of THC from those of coexisting factors. Therefore, translationally relevant animal models are required to properly investigate THC effects in adolescents. However, though the relevance of these studies depends upon human-relevant dosing, surprisingly little is known about THC pharmacology and its effects on behavior and brain activity in adolescent rodents-especially in females. Here, we conducted a systematic investigation of THC pharmacokinetics, metabolism and distribution in blood and brain, and of THC effects upon behavior and neural activity in adolescent Long Evans rats of both sexes. We administered THC during an early-middle adolescent window (postnatal days 27-45) in which the brain may be particularly sensitive to developmental perturbation by THC. We determined the pharmacokinetic profile of THC and its main first-pass metabolites (11-hydroxy-THC and 11-nor-9-carboxy-THC) in blood and brain following acute injection (0.5 or 5 mg/kg, intraperitoneal). We also evaluated THC effects on behavioral assays of anxiety, locomotion, and place conditioning, as well as c-Fos expression in 14 brain regions. Confirming previous work, we find marked sex differences in THC metabolism, including a female-specific elevation in the bioactive metabolite 11-hydroxy-THC. Furthermore, we find dose-dependent and sexdependent effects on behavior, neural activity, and functional connectivity across multiple nodes of brain stress and reward networks. Our findings are relevant for interpreting results of rat adolescent THC exposure studies, and may lend new insights into how THC impacts the brain in a sex-dependent manner.

Unexpected Role of Physiological Estrogen in Acute Stress-Induced Memory Deficits

“…Specifically, MAS, in contrast to a simple acute stress, reduced cross-correlation between the hippocampal formation and the septum and thalamus, regions involved in sensory processing, and enhanced coactivation of the hippocampus to the amygdala and extended amygdala, regions of the salience network. Using the same approach employed successfully by other groups ( Wiersielis et al, 2016 ; Salvatore et al, 2018 ; Ruiz et al, 2020 ), we identified key differences between functional networks of high E2 and low E2 female mice both at baseline and in response to MAS. As previously established in males, augmented cross corelated activation of extended amygdala and the hippocampus was identified in high E2 MAS females ( Fig.…”

“…We employed Spearman correlation matrices of fos+ cell numbers across all measured regions to identify coactivation between two given regions. Spearman correlation coefficients close to 1 indicated a positive relationship of activation between the two regions whereas values near -1 identified negative (anticorrelated) relations (Maras et al, 2014;Wiersielis et al, 2016;Salvatore et al, 2018;Ruiz et al, 2020). Correlation matrices were computed for each condition ("High E2" Control, "High E2" MAS, "Low E2" Control, and "Low E2" MAS, Fig 6A-D).…”

Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses

“…Cannabis-induced adverse effects may be influenced by other several factors such as genetic variation, age, sex, ethnicity, and duration and frequency of cannabis use [ 119 , 120 , 121 ]. Significant toxicity from cannabis and cannabinoid-containing substances is uncommon in adults, unlike children, who may develop significant symptoms.…”

A low repeated dose of Δ9-tetrahydrocannabinol affects memory performance through serotonergic signalling in mice

“…We also explored whether brain tissues would be affected with regard to their c-Fos responsiveness. Acute high and low doses of THC (10, 5 and 0.5 mg/kg) were previously found to induce the expression of the immediate-early gene c-Fos in diverse brain regions (Valjent et al, 2002;Flores et al, 2016;Ruiz et al, 2021). However, the effects of THC in c-Fos expression after a sub-chronic low dose administration has not been determined yet.…”

“…Acute high and low doses of THC (10, 5 and 0.5 mg/kg) were previously found to induce the expression of the immediate-early gene c-Fos in diverse brain regions (Valjent et al, 2002;Flores et al, 2016;Ruiz et al, 2021). Acute THC exposure also altered functional connectivity as measured by c-Fos expression analysis between brain regions involved in reward and stress responses (Ruiz et al, 2021). We hypothesized that, after the sub-chronic exposure to THC 1, neuronal activity, measured by c-Fos expression analysis, and connectivity, measured by the correlation analysis of c-Fos expression between memory-related brain regions, could be disturbed.…”