RT Journal Article SR Electronic T1 Repeated vapor inhalation of Δ9-tetrahydrocannabinol induces tolerance to hypothermia in female rats JF bioRxiv FD Cold Spring Harbor Laboratory SP 172759 DO 10.1101/172759 A1 Jacques D. Nguyen A1 K. M. Creehan A1 Yanabel Grant A1 Sophia A. Vandewater A1 Maury Cole A1 Michael A. Taffe YR 2017 UL http://biorxiv.org/content/early/2017/08/04/172759.abstract AB Background and Purpose Tolerance to the effects of Δ9-tetrahydrocannabinol (THC) emerges with repeated exposure, although it varies with dose, chronicity and the measure of interest. THC inhalation via an e-cigarette based system induces hypothermic and antinociceptive effects in rats. This study was conducted to determine if tolerance to these effects could be produced with repeated vapor inhalation.Experimental Approaches Wistar rats were exposed to 30 minutes of vapor inhalation of the propylene glycol (PG) vehicle and then THC (200 mg/mL in PG) twice per day for four days. Female and male groups were compared for rectal temperature changes and tail-withdrawal latency from a noxious stimulus. A second female group was prepared with radiotelemetry devices for temperature and activity and then exposed to 30 minutes of PG (b.i.d., 4 days) and then THC (100 mg/mL; b.i.d., 5 days). Additional studies evaluated the effects of 4 mg/kg SR141716, AM251 or AM630 i.p. to determine CB1 and CB2 receptor contributions.Key Results Female, but not male rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of THC vapor inhalation. The antagonist SR141716 blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. Initial hypothermia was not prevented by SR141716 or AM251 but the restoration of normal temperature was accelerated.Conclusions and Implications Twice daily THC inhalation induces tolerance in female rats, providing further validation of the method. Blockade of the CB1 receptor shortens the maintenance of hypothermia and blocks antinociception after THC inhalation.Abbreviations PG, propylene glycol; SR141716 (SR), 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide; AM251, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM630, 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone; THC; Δ9tetrahydrocannabinol;