Δ⁹-tetrahydrocannabinol (THC) is the primary psychoactive compound found in Cannabis sativa. In mice, intraperitoneal (i.p.) injections of THC, produce a characteristic triad of behavioral responses: hypolocomotion, hypothermia, and analgesia. However, injections of THC do not accurately represent how humans typically administer THC, which primarily consists of inhalation and oral consumption. Thus, we have developed and optimized a paradigm of oral THC consumption in mice to better model a typical route of administration used by humans. Our model balances an acute consummatory window with a highly palatable, chocolate-flavored gelatin. This incentivizes mice to voluntarily consume enough THC to produce measurable cannabimimetic behaviors. Over a 3-day exposure paradigm we habituated mice to the gelatin where they had ad libitum access for 2 hours each day. We introduced THC into the gelatin and measured the triad of behaviors immediately following consumption to determine whether voluntary oral consumption induces the acute cannabimimetic behaviors. We found significant hypolocomotion, hypothermia, and analgesia at our highest concentration. Next, to determine whether these behaviors are caused by THC’s action at the primary endocannabinoid receptor, CB₁R, we treated mice with the inverse agonist SR1 prior to the behavioral tests. SR1 blocked the cannabimimetic behaviors induced by the consumption of THC-gelatin, suggesting the effects are CB₁R-dependent. To finalize this model, we have adapted our oral consumption paradigm to an acoustic startle behavioral model. Following our consumption paradigm, mice are subjected to tones of varying decibels and their startle response is measured. Moving forward we will continue acoustic startle testing to confirm preliminary data and expand the doses tested. Overall, these data verify that our model effectively induces cannabimimetic behaviors and can be used for future behavioral studies investigating a more translational route of administration compared to i.p.

The consumption of Cannabis has increased with legalization, rising 46% from 2019 to 2020 in the US. The primary psychoactive compound in Cannabis, ᐃ9-tetrahydrocannabinol (THC), modifies motivation and induces hypolocomotive effects that cause patients to stop using medical marijuana. Given the increasing frequency of Cannabis use and the unwanted side effects of THC, I sought to decipher the motivational and locomotive effects of THC on prefrontal cortex (PFC) activity during appetitive Pavlovian conditioning. I utilized biological sensors to measure neural activity (CamKIIa-GCaMP6f for calcium in projection neurons (N=3) and eCB2.0 for total endocannabinoid activity (N=6)) in WT mice aged 8-12 weeks. Neural activity (utilizing fiber photometry) and general behavior was recorded during appetitive Pavlovian conditioning. Here, a house light in the behavioral chamber (conditioned stimulus (CS)), initiated 6s before a sipper (sucrose) extended for 20 seconds (unconditioned stimulus (US)). After a random inter-trial interval of 60, 90, 120, or 150s, another event triggered a reward to consolidate an association between the house light (CS) and the reward (US). Mice experienced this conditioning for 25 minutes every day for 5 days. On day 6, I treated mice with either a moderate dose of THC (5 mg/kg) or vehicle to measure changes in neural and endocannabinoid activity during conditioning. I found that both endocannabinoid and calcium signaling were tightly locked to the CS and the US. Interestingly, trials where THC-treated mice did not interact with the sipper (THC-dependent demotivation), neural activity matched the pattern during training days. These data suggest time-locked neural activity linked to stimuli, separate from the locomotor output, to receive the reward. This study contributes to the understanding of THC’s effects on signaling during motivated versus locomotive behaviors to inform future THC-derived treatment paradigms.