Effects of Δ⁹-tetrahydrocannabinol (THC) vapor inhalation in Sprague-Dawley and Wistar rats

Abstract

An inhalation system based on e-cigarette technology produces hypothermic and antinociceptive effects of Δ⁹-tetrahydrocannabinol (THC) in rats. Indirect comparison of some prior investigations suggested differential impact of inhaled THC between Wistar (WI) and Sprague-Dawley (SD) rats; thus, this study was conducted to directly compare the strains across inhaled and injected routes of administration. Groups (N = 8 per strain) of age-matched male SD and WI rats were prepared with radiotelemetry devices to measure temperature and then exposed to vapor from the propylene glycol (PG) vehicle or THC (25-200 mg/mL of PG) for 30 or 40 min. Additional studies evaluated effects of THC inhalation on plasma THC (50-200 mg/mL) and nociception (100-200 mg/mL) as well as the thermoregulatory effect of intraperitoneal injection of THC (5-30 mg/kg). Hypothermic effects of THC were more pronounced in SD rats, where plasma levels of THC were identical across strains, under either fixed inhalation conditions or injection of a mg/kg equivalent dose. Strain differences in hypothermia were largest after i.p. injection of THC, with SD rats exhibiting dose-dependent temperature reduction after 5 or 10 mg/kg, i.p. and the WI rats only exhibiting significant hypothermia after 20 mg/kg, i.p. The antinociceptive effects of inhaled THC (100, 200 mg/mL) did not differ significantly across the strains. These studies confirm an insensitivity of WI rats, compared with SD rats, to hypothermia induced by THC following inhalation conditions that produced identical plasma THC and antinociception. Thus, quantitative, albeit not qualitative, strain differences may be obtained when studying thermoregulatory effects of THC. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Figure 1:

Mean (N=8 / group; SEM) body weight of the Wistar and Sprague-Dawley rats from 11 to 57 weeks of age. The approximate experimental timeline is also outlined, refer to Methods for full specification. PK indicates timing of blood draws for plasma assessment.

Figure 2:

Mean (N=8 / group; SEM) body temperature (A, B) and activity rates (C, D) following vapor inhalation of the PG vehicle or A,C) THC (25 mg/mL in the PG) or B, D) THC (100 mg/mL), for 30 minutes. The PG data are duplicated on the dose graphs for clarity. Base=baseline. Open symbols indicate a significant difference from both vehicle at a given time-point and the within-treatment baseline, while shaded symbols indicate a significant difference from the baseline only. A significant difference from the THC 25 mg/mL at a given time is indicated by # and between strains at a given time for the same dose by *.

Figure 3:

Plasma THC concentrations for Wistar and Sprague-Dawley rats (N=8 / group) following vapor inhalation of the THC (100 mg/mL) for 30 minutes at A) 13 and B) 25 weeks of age. Box plots depict median and interquartile range and the bars indicate the range. Individual subject values are also plotted.

Figure 4:

Mean (N=8 / group; SEM) body temperature (A, B, C) and activity rate (D, E, F) following i.p. injection with THC. A,D) Sprague-Dawley and B,E) Wistar groups after injection with THC (0.0, 5.0, 10.0 mg/kg) and C,F) both groups after injection with THC (0.0, 20.0 mg/kg). Base=baseline. Open symbols indicate a significant difference from both vehicle at a given time-point and the within-treatment baseline, while shaded symbols indicate a significant difference from the baseline only. A significant difference from the 5.0 dose at a given time is indicated by # and between strains at a given time for the same dose by *.

Figure 5:

Mean (N=7 / group; SEM) body temperature following vapor inhalation of the PG vehicle or THC (100 mg/mL in the PG) for 30 minutes. Treatment conditions included an injection of vehicle or SR141716 (SR; 4 mg/kg, i.p.) 15 minutes prior to vapor initiation. Open symbols indicate a significant difference from both PG (within respective pre-treatment) at a given time-point and the within-treatment baseline, while shaded symbols indicate a significant difference from the baseline only. A difference from the PG condition (within respective pre-treatment, but not the baseline, is indicated by *. Base: Baseline 30 minutes prior to vapor initiation. SR: SR141716; Veh: Vehicle.

Figure 6:

Mean (N= 8 / group; SEM) tail withdrawal latency following vapor inhalation of the PG vehicle or THC (100, 200 mg/mL in the PG) for 30 minutes. A significant difference between vapor conditions, collapsed across strain, is indicated by *.

Figure 7:

Plasma THC concentrations for Wistar (WI) and Sprague-Dawley (SD) rats (N=10 / group) following A) vapor inhalation of the THC (50, 200 mg/mL) for 30 minutes or B) THC injection (10, 20 mg/kg, i.p.). Box plots depict median and interquartile range and the bars indicate the range. Individual subject values are also plotted.

Figure 8:

Mean (N= 6 / group; SEM) body temperature following injection of THC in A) Wistar (0, 30 mg/kg, i.p.) or B) Sprague-Dawley (0, 20 mg/kg, i.p.) rats. Treatment conditions included an injection of vehicle or SR141716 (SR; 4 mg/kg, i.p.) 15 minutes prior to the THC injection. Open symbols indicate a significant difference from both vehicle (within respective pre-treatment) at a given time-point and the within-treatment baseline, while shaded symbols indicate a significant difference from the baseline only. A significant difference from all other treatment conditions is indicated with &. A significant difference from the vehicle condition (within respective pre-treatment), only, is indicated by *. Base: Baseline 30 minutes prior to vapor initiation. SR: SR141716; Veh: Vehicle.

Figure 9:

Mean (N= 6 / group; ±SEM) A) body temperature, and B) activity rate, after vapor inhalation of THC (100 mg/mL) for 40 minutes. C) mean (N=5 per strain / dose combination; ±SEM) plasma THC concentrations after vapor inhalation of THC (50, 100 mg/mL) for 40 minutes. Open symbols indicate a significant difference from both PG (within respective pre-treatment) at a given time-point and the within-treatment baseline, while shaded symbols indicate a significant difference from the baseline only. A significant difference from all other treatment conditions at a given time point is indicated with &, a difference between strains for a given time and inhalation condition with *, a difference between inhalation concentrations collapsed across strain with $ and a difference across time, collapsed across strain, with #.