Acute Cannabinoids Produce Robust Anxiety-Like and Locomotor Effects in Mice, but Long-Term Consequences Are Age- and Sex-Dependent

Abstract

The rise in cannabinoid legalization and decriminalization in the US has been paired with an increase in adolescents that perceive marijuana as a “no risk” drug. However, a comprehensive review of human literature indicates that cannabinoid usage may have both beneficial and detrimental effects, with adolescent exposure being a critical window for harming cognitive development. Although the cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are often used together for recreational and medical purposes, no study has previously observed the acute and long-lasting effects of THC+CBD in a battery of behavioral assays analogous to subjective human reports. The current study observed the acute and long-term effects of THC, CBD, and THC+CBD on object recognition memory, anxiety-like behavior, and activity levels in adolescent and adult mice of both sexes. Acute THC alone and in combination with CBD resulted in robust effects on anxiety-like and locomotor behavior. A history of repeated cannabinoid treatment followed by a period without drug administration resulted in minimal effects in these behavioral assays. Most notably, the strongest effects of repeated cannabinoid treatment were seen in adult females administered THC+CBD, which significantly impaired their object recognition. No effects of repeated cannabinoid history were present on hippocampal protein expression. These studies represent a detailed examination of age- and sex-effects of acute and repeated cannabinoid administration. However, the acute and long-term effects of THC with and without CBD on additional behaviors in adolescents and adults will need to be examined for a more complete picture of these drug effects.

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

“…1C). This dose was based on previous studies using low to high ranges of THC in mice (Trexler et al, 2018;Kasten et al, 2019). Moreover, this dose used has been shown to elevate plasma levels of THC in rodents (> 100 ng/mL) similar to those found in humans smoking cannabis (Huestis, 2007;Zuurman et al, 2008;Nguyen et al, 2016).…”

Cannabis, a cause for anxiety? A critical appraisal of the anxiogenic and anxiolytic properties

“…Kasten et al (2019) [72] found that 5 and 10 mg/kg doses of THC in adult mice reduced total locomotion. In the 5 mg/kg adult group this was significantly correlated with reduced time in the centre of the open field indicating an anxiogenic-like response.…”

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

“…26 Initial response to cannabis, THC, and other cannabinoid receptor 1 (CB1R) agonists has been measured across a range of doses among several inbred and outbred mouse strains (Table 1). [27][28][29][30][31][32][33][34][35] However, few of these studies have directly compared strain differences in response and most do not include females, thus preventing analysis of sex differences. Despite marked variation among individuals in the acute response to cannabis in humans, 36 little is known about the genetic factors mediating differential response or how initial sensitivity and tolerance may contribute to risk of CUD.…”