Self-administration of edible Δ9-tetrahydrocannabinol and associated behavioral effects in mice

Abstract

Background: With increasing access to legal cannabis across the globe, it is imperative to more closely study its behavioral and physiological effects. Furthermore, with the proliferation of cannabis use, modes of consumption are changing, with edible formulations becoming increasingly popular. Nevertheless, there are relatively few animal models of self-administration of the primary psychoactive component of cannabis, Δ 9-tetrahydrocannabinol (THC), and almost all incorporate routes of administration other than those used by humans. The aim of the current study was to develop a model of edible THC self-administration and assess its impact on CB1 receptormediated behaviors in female and male mice. Methods: Mice were given limited access to a palatable dough which occasionally contained THC in doses ranging from 1 to 10 mg/kg. Following dough consumption, mice were assessed for home cage locomotor activity, body temperature, or analgesia. Locomotor activity was also assessed in conjunction with the CB1 receptor antagonist SR141716A. Results: Dough was well-consumed, but consumption decreased at the highest THC concentrations. Edible THC produced dose-dependent decreases in locomotor activity and body temperature in both sexes, and these effects were more pronounced in male mice. Hypolocomotion induced by edible THC was attenuated by SR141716A, indicating mediation by CB1 receptor activation. Conclusions: In contrast to other cannabinoid self-administration models, edible THC is relatively low in stress and uses a route of administration analogous to one used by humans. Potential applications include chronic THC self-administration, determining THC reward/ reinforcement, and investigating consequences of oral THC use.

Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆9‐Tetrahydrocannabinol in Adolescent Male Mice

“…Increased activity following repeated periods of voluntary EtOH intake in adolescent mice has been previously reported (Quoilin and Boehm, ) and appears to be an age‐related phenomenon, as adult mice show a decrease in activity to EtOH intake over days (Linsenbardt et al., ; Quoilin and Boehm, ). Administration of THC typically decreases activity (Lichtman et al., ; McMahon and Koek, ), except at low doses in novel environments (Kruse et al., ; Sañudo‐Peña et al., ), and although there is evidence for age‐related differences in the locomotor response to THC (Kasten et al., ; Schramm‐Sapyta et al., ), the decreases in activity seen here in adolescent mice are similar to those seen in adult mice following edible THC consumption (Smoker et al., ). While these EtOH‐ and THC‐induced locomotor effects were most pronounced during the 2 hours of DID, the effect of THC persisted post‐DID on some days, consistent with the extended duration of action of THC following oral administration (Grotenhermen, ; Hložek et al., ).…”

“…Reduction in consumption of THC dough was likely not due to taste factors, as the highest THC concentration provided was consumed at levels similar to control dough (days 8 to 9) until the dose was increased by doubling the volume provided (days 10 to 11). Rather, this reduction is likely due to the association of THC's postingestive psychoactive effects with dough consumption (Smoker et al., ). Of note is that when provided double the volume of edible THC, consumption was higher in mice receiving dough after DID.…”

“…190‐proof EtOH was purchased from Pharmco, Inc. (Brookfield, CT). Edible dough was created as previously described (Smoker et al., ). Briefly, the THC‐EtOH solution, or 95% EtOH alone, was dissolved in glycerol and combined with flour, sugar, and salt to produce THC dough or control dough, respectively.…”

“…Furthermore, in individuals with an alcohol use disorder, co‐use of cannabis is highest among all illicit drugs (Falk et al., ). While there are many models of alcohol self‐administration in animals (Bell et al., ; Rhodes et al., ; Samson, ), models of cannabinoid self‐administration have only more recently been established (Barrus et al., ; Justinova et al., ; Kruse et al., ; Melis et al., ; Panagis et al., ; Smoker et al., ; Spencer et al., ; Wakeford et al., ), and models of alcohol‐cannabinoid coadministration are sparse (Nelson et al., ).…”

“…Edible THC products are becoming increasingly popular (Giombi et al., ; Wang et al., ), and, given their formulations (e.g., cookies, candies), are likely appealing to adolescents. Although viewed as safer by adolescents (Friese et al., ), edible THC administration in rodents induces CB1R‐mediated effects similar to those produced by other routes of administration (Kruse et al., ; Nelson et al., ; Smoker et al., ), and high doses are known to produce adverse reactions in humans (Benjamin and Fossler, ; Bui et al., ; Favrat et al., ; Monte et al., ). It is still unclear to what degree use of edible THC might induce facets of substance use disorder, such as craving or tolerance, but it has been shown to impact CB1R expression in drug reward‐related circuitry (Kruse et al., ).…”