Tolerance to hypothermic and antinoceptive effects of δ9-tetrahydrocannabinol (THC) vapor inhalation in rats

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Rationale:A reduced effect of a given dose of δ9-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 three 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.HighlightsAn e-cigarette based THC inhalation system produces hypothermia and antinociception in rats.Tolerance to THC emerges with repeated exposure.Repeated daily THC inhalation induces tolerance in female and male rats.This further validates vapor inhalation of THC in rats as a model of human consumption.

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