Tolerance to hypothermic and antinoceptive effects of Δ9-tetrahydrocannabinol (THC) vapor inhalation in rats

Rationale: A reduced effect of a given dose of Delta(9)-tetrahydrocannabinol (THC) emerges with repeated exposure to the drug. This tolerance can vary depending on THC dose, exposure chronicity and the behavioral or physiological measure of interest. A novel THC inhalation system based on e-cigarette technology has been recently shown to produce the hypothermic and antinociceptive effects of THC in rats. Objective: To determine if tolerance to these effects can be produced with repeated vapor inhalation. Methods: Groups of male and female Wistar rats were exposed to 30 min of inhalation of the propylene glycol (PG) vehicle or THC (200 mg/mL in PG) two or time times per day for four days. Rectal temperature changes and nociception were assessed after the first exposure on the first and fourth days of repeated inhalation. Results: Female, but not male, rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of twice-daily THC vapor inhalation. Thrice daily inhalation for four days resulted in tolerance in both male and female rats. The plasma THC levels reached after a 30 min inhalation session did not differ between the male and female rats. Conclusions: Repeated daily THC inhalation induces tolerance in female and male rats, providing further validation of the vapor inhalation method for preclinical studies.