Abstract
Aim: Δ9-Tetrahydrocannabinol (Δ9-THC) is a potentially addictive cannabinoid. Its impact on the activity of liver arylamine N-Acetyltransferase (NAT) has not been reported. This study investigated the rewarding effects of Δ9-THC in mice and whether Δ9-THC had any impact ex-vivo and in-vitro on NAT activity. Methods: Thirty-six Swiss albinomice randomly assigned to six groups (n = 6) completed a biased, 8-week Conditioned Place Preference (CPP) paradigm. Mice exhibiting ~80% preference for the black chamber at pre-conditioning were selected. Treatment groups were administered Δ9-THC (0.10, 0.50 or 2.0 mg/kg/mL, ip) or amphetamine (AMP, 5.0 mg/kg/mL, ip); while untreated groups (controls) received vehicle solutions (coconut oil or 0.9% saline). Entries and time spent in the white, drug-paired chamber during a 15-min post-conditioning exploration of the CPP apparatus were compared with the pre-conditioning exploratory scores. Livers from Δ9-THC treated and untreated mice were excised and NAT enzyme activity determined ex-vivo using a spectrophotometric assay with p-anisidine as substrate. The impact of varying concentrations of Δ9-THC (0.00 - 162 μM) on the activities of NAT from untreated mice livers were also investigated in-vitro. Results: Δ9-THC treated mice entered and spent significantly more time in the drug-paired CPP chamber (p ≤ 0.05) at post-conditioning vs pre-conditioning (F = 11.22). Mice treated with 2.0 mg/kg Δ9-THC made significantly more entries into the drug-paired chamber (p ≤ 0.05) as compared with their vehicle controls. AMP-treated mice displayed significant (p In-vitro NAT evaluations revealed a dose-dependent inhibitory impact of Δ9-THC on NAT activity with an IC50 value of 34.97 ±1.58 μM. Ex-vivo evaluations of livers from Δ9-THC treated mice showed no significant impact on liver NAT enzyme activity. Conclusion: Δ9-THC induced significant conditioned place preference (drug reward) and produced a moderate dose-dependent inhibition on NAT activity in-vitro, but not ex-vivo.
Highlights
Delta-9-tetrahydrocannabinol (∆9-THC) is the principal psychoactive component of the Cannabis plant, popularly known as marijuana. It is often introduced by smoking marijuana and the plant is being increasingly bred to avail higher ∆9-THC to the user [1] [2]. ∆9-THC is a partial agonist at endocannabinoid receptor subtypes CB1 and CB2 which are abundant in the brains of humans and rodents
Additional comparisons revealed that the 2.0 mg/kg ∆9-THC treated mice made significantly (p < 0.01) more entries into the white chamber post-conditioning as compared with their oil vehicle treated controls
At all three relatively low doses of Δ9-THC (0.1-2.0 mg/kg), mice spent significantly more time in the drug-paired chamber post-conditioning; and at the highest dose investigated in this study, (2 mg/kg Δ9-THC), mice made significantly more frequent entries (Figure 1, Figure 2)
Summary
Delta-9-tetrahydrocannabinol (∆9-THC) is the principal psychoactive component of the Cannabis plant, popularly known as marijuana It is often introduced by smoking marijuana and the plant is being increasingly bred to avail higher ∆9-THC to the user [1] [2]. Et al (2017) [4] attributed cannabis reward to activation of cannabinoid CB1 receptors on GABAergic neurons which disinhibit dopaminergic neurons in the ventral tegmental area of the brain; and activation of CB1 receptors in glutamatergic neurons to aversion in rodents They extrapolated that such neural interactions may explain the variety of reported hedonistic effects in humans [4]. There is contradicting evidence to support and refute the addictive liability of ∆9-THC from animal studies, due to reported aversive and rewarding drug effects [5] [6] [7]
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