PT  - JOURNAL ARTICLE
AU  - English, Anthony
AU  - Uittenbogaard, Fleur
AU  - Torrens, Alexa
AU  - Sarroza, Dennis
AU  - Slaven, Anna
AU  - Piomelli, Danielle
AU  - Bruchas, Michael
AU  - Stella, Nephi
AU  - Land, Benjamin
TI  - A preclinical model of THC edibles that produces high-dose cannabimimetic responses
AID  - 10.1101/2022.11.23.517743
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.23.517743
4099  - http://biorxiv.org/content/early/2022/11/24/2022.11.23.517743.short
4100  - http://biorxiv.org/content/early/2022/11/24/2022.11.23.517743.full
AB  - Background No preclinical approach enables the study of voluntary oral consumption of high dose Δ9-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here we developed a palatable THC formulation and an optimized access paradigm in mice.Methods THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowed ad libitum access for 2 h. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain samples. Acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior.Results Access to high-dose THC-E-gel (≈30 mg/kg over 2 h) resulted in robust consumption and CB1 receptor-dependent behavioral responses. High-dose THC-E-gel consumption resulted in parallel accumulation of THC and its psychoactive metabolite 11-OH-THC in brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following intraperitoneal THC injections. High-dose THC-E-gel consumption increased the acoustic startle response preferentially in males, and this psychotomimetic response was remarkably different from the response triggered by intraperitoneal contingent administration of THC. Comparing cannabimimetic responses elicited by intraperitoneal versus oral administration enabled us to model a “predicted dose” of THC that triggers these responses.Conclusion Voluntary consumption of high-dose THC-E-gel triggered equivalent cannabimimetic responses in male and female mice but an increased acoustic startle response preferentially in males. These findings indicate that THC-E-gel offers a robust preclinical consumption model to study cannabimimetic responses in mice, including sex-dependent psychotomimetic responses.Competing Interest StatementThe authors have declared no competing interest.