Sex and Strain Variation in Initial Sensitivity and Rapid Tolerance to Δ9–Tetrahydrocannabinol

Abstract

Background and Objectives: For cannabis and other drugs of abuse, initial response and/or tolerance to drug effects can predict later dependence and problematic use. Our objective is to identify sex and genetic (strain) differences in initial response and rapid tolerance to D9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, between highly genetically divergent inbred mouse strains-C57BL/6J (B6) and DBA/2J (D2). Experimental Approach: Sex and strain responses relative to baseline were quantified following daily exposure (i.p.) to 10 mg/kg THC or vehicle (VEH) over the course of 5 days. Dependent measures included hypothermia (decreased body temperature) and ataxia (decreased spontaneous activity in the open field), and antinociception (increase in tail withdrawal latency to a thermal stimulus). Initial sensitivity to THC was defined as the difference in response between baseline and day 1. Rapid tolerance to THC was defined as the difference in response between days 1 and 2. Results: B6 exhibited greater THC-induced motor activity suppression and initial sensitivity to ataxia relative to the D2 strain. Females demonstrated greater levels of THC-induced hypothermia and initial sensitivity relative to males. Higher levels of THC-induced antinociception and initial sensitivity were observed for D2 relative to B6. Rapid tolerance to THC was observed for hypothermia and antinociception. Much less tolerance was observed for THC-induced ataxia. D2 exhibited rapid tolerance to THC-induced hypothermia and antinociception at time points associated with peak THC initial response. Likewise, at the peak initial THC response time point, females demonstrated greater levels of rapid tolerance to hypothermic effects relative to males. Conclusions: Both sex and genetic factors drive variation in initial response and rapid tolerance to the ataxic, antinociceptive, and hypothermic effects of THC. As these traits directly result from THC activation of the cannabinoid receptor 1, gene variants between B6 and D2 in cannabinoid signaling pathways are likely to mediate strain differences in response to THC.

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

“…[60] in ABH mice. The relatively smaller hypothermic effect observed here (Figure 3G-I) could represent a difference in mouse strain (ABH vs. C57BL/6J) [58,61]. Interestingly, in our study tolerance developed differently between behaviors, as 10 mg/kg of CB-13 continued to produce catalepsy but not tail-flick antinociception on day 3 of dosing (Figure 3B,E).…”

Genetic modulation of initial sensitivity to Δ9-tetrahydrocannabinol (THC) among the BXD family of mice

“…Previously, we identified putative heritable strain differences in acute response to a single THC injection (10 mg/kg) in the parents of the BXD family—B6 and D2 (Parks et al 2020). Here we test the hypothesis that polymorphic variants between these strains segregate among the BXD progeny and cause variation in THC initial responses.…”

“…Each formulation was used for the entire testing schedule of each cohort (see details below). Previously we demonstrated that each THC formulation contains 95.2% of the initial amount of THC when measured eight days after preparation (Parks et al 2020).…”

“…Variation in initial responses to THC are heritable among BXDs. Previously, we identified putative heritable strain differences in acute response to a single THC injection (10 mg/kg) in the parents of the BXD family-B6 and D2 (Parks et al 2020).…”

“…Previously, we established that the parents of the BXDs (strains B6 and D2) differ greatly in their initial responses to a single dose (10 mg/kg, i.p .) of THC, the major psychoactive component in cultivars of cannabis (Parks et al 2020). We have also demonstrated that striatal protein levels of the primary target of THC, the cannabinoid receptor 1 (CB1R), are significantly higher in B6 compared to D2 mice (Parks et al 2019).…”