Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats

Abstract

Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component of cannabis and its effects have been well-studied. However, cannabis contains many other cannabinoids that affect brain function. Therefore, these studies investigated the effect of cannabis smoke exposure on locomotor activity, rearing, anxiety-like behavior, and the development of dependence in rats. It was also investigated if cannabis smoke exposure leads to tolerance to the locomotor-suppressant effects of the endogenous cannabinoid anandamide. Cannabis smoke was generated by burning 5.7% Δ9-THC cannabis cigarettes in a smoking machine. The effect of cannabis smoke on the behavior of rats in a small and large open field and an elevated plus maze was evaluated. Cannabis smoke exposure induced a brief increase in locomotor activity followed by a prolonged decrease in locomotor activity and rearing in the 30-min small open field test. The cannabinoid receptor type 1 (CB1) receptor antagonist rimonabant increased locomotor activity and prevented the smoke-induced decrease in rearing. Smoke exposure also increased locomotor activity in the 5-min large open field test and the elevated plus maze test. The smoke exposed rats spent more time in the center zone of the large open field, which is indicative of a decrease in anxiety-like behavior. A high dose of anandamide decreased locomotor activity and rearing in the small open field and this was not prevented by rimonabant or pre-exposure to cannabis smoke. Serum Δ9-THC levels were 225 ng/ml after smoke exposure, which is similar to levels in humans after smoking cannabis. Exposure to cannabis smoke led to dependence as indicated by more rimonabant-precipitated somatic withdrawal signs in the cannabis smoke exposed rats than in the air-control rats. In conclusion, chronic cannabis smoke exposure in rats leads to clinically relevant Δ9-THC levels, dependence, and has a biphasic effect on locomotor activity.

Tolerance to hypothermic and antinoceptive effects of Δ9-tetrahydrocannabinol (THC) vapor inhalation in rats

“…Similar effects have also been demonstrated following inhalation of THC (or cannabis smoke) but efficacy may be more variable. SR blocked hypolocomotive effects of marijuana smoke inhalation in rats (Bruijnzeel et al, 2016) and fully blocked antinociception caused by aerosolized THC, but only partially blocked the antinociceptive effects of cannabis smoke inhalation, in male ICR mice (Lichtman et al, 2000;Lichtman, Poklis, Poklis, Wilson & Martin, 2001). Catalepsy caused by marijuana smoke inhlation was not blocked by SR pretreatment in the latter study.…”

Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood

“…However, contradictory findings have also been published, with either no change 54 or even a decrease 55 in anxiety-like behavior after cannabinoid exposure in adolescence. Rats that were exposed to cannabis smoke were also reported to exhibit a decrease in anxiety-like behavior 56 . Interestingly, a previous study also demonstrated that long-term cognitive and behavioral dysfunction that was induced by adolescent THC exposure could be prevented by concurrent cannabidiol treatment 57 .…”

Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

“…Our prior work found female adult rats became tolerant after a repeated THC vapor inhalation regimen that did not produce tolerance in male adults (Nguyen, J. D. et al, 2018a). Adult male rats (females were not assessed) exposed to repeated marijuana smoke did not exhibit cross-tolerance to the locomotor suppressing effects of the endogenous cannabinoid agonist anandamide (Bruijnzeel et al, 2016). The finding of significantly lower bodyweight in the males during the second treatment week (Figure S3) is similar to evidence that repeated THC injections during adolescence reduced weight gain in male and female Wistar and Long-Evans rats in a 14 day treatment interval (Keeley et al, 2015) and in male Wistar rats during an 8 day repeated-injection study (Sofia and Barry, 1974).…”