Effects of sex and pre-exposure on Δ9-tetrahydrocannabinol (THC) vapor self-administration in rats

Rationale: Animal models of cannabinoid self-administration are critical for advancing our understanding of the neurobiology of cannabis use and for developing medications for Cannabis Use Disorder. Use of vapor inhalation models have translational relevance, as the majority of human cannabis user do so by inhalation (e.g., smoking, vaporization). Methods: Adult male and female Sprague Dawley rats (N=96, 6-12 per sex/group) were pre-exposed to vaporized THC or vehicle (Veh; 100% propylene glycol). Rats were then trained to self-administer vapor puffs of either THC (50 mg/ml training dose) or Veh under a fixed ratio (FR) 1 schedule. Responding was then assessed under increasing response costs (FR1-5) and different doses (50-200 mg/ml) of THC. As a secondary study aim, we assessed the effects of pre-exposure to THC (or Veh) on self-administration of THC vapor or Veh vapor. Results: There were no differences in responding for THC and Veh vapor under an FR1 schedule. As the FR increased, rats increased their responses for THC, and female rats in the THC group responded more than female rats in the Veh vapor group under FR4-5 schedules. When THC concentration was varied, rats titrated their intake in a predictable U-shaped pattern. THC vapor pre-exposure significantly increased self-administration of THC vapor, but not Veh vapor. Conclusions: Male and female rats voluntarily administered THC vapor in a sustained manner across several months, replicating what has been shown with vaporized cannabis extracts male rats. This study is the first to demonstrate that THC vapor has reinforcing properties in female rats and that pre-exposure is critical for engendering higher intake. This is a promising model of voluntary THC vapor administration.