Article Figures & Data
- Figure 1.
Cannabis vapor supports stable rates of active responding in male rats. A, Schematic illustration of the vapor self-administration apparatus (adapted from Fuchs et al., 2018), and (B) real-life depiction of a Long–Evans rat responding for cannabis vapor (not from the current experiments). C, Mean active (colored symbols) and inactive (open symbols) nose-poke responding for vapor containing high concentrations of CANTHC, CANCBD, or VEH across increasing fixed ratio schedules of reinforcement. D, Mean number of CANTHC, CANCBD, or VEH vapor deliveries earned across increasing fixed ratio schedules of reinforcement. E–G, Mean number of vapor deliveries earned organized by 15 min bins within (E) FR-1, (F) FR-2, and (G) FR-4 schedules of reinforcement. H, Nose-poke operanda discrimination index for CANTHC, CANCBD, and VEH vapor across increasing fixed schedules of reinforcement. The dotted line represents a discrimination index of 0.33, which indicates a 2:1 rate of active–inactive nose-poke responding. n = 7–12/group, p ≤ 0.05. *Significant differences between CANTHC and VEH groups. #Significant differences between CANTHC and CANCBD groups. †Denotes significant differences between CANCBD and VEH groups.
- Figure 2.
Vaporized delivery of THC-dominant cannabis extracts exhibits motivational properties. A, Mean cumulative number of active responses for CANTHC, CANCBD, and VEH vapor during a 180 min progressive ratio challenge. Data are tallied and organized into 15 min bins. B, Mean break points for CANTHC, CANCBD, and VEH vapor during the progressive ratio challenge (defined as an absence of active nose-poke responding for period of 15 min. C, Mean latency to initiate active nose-poke responding for CANTHC, CANCBD, or VEH vapor relative to the immediately preceding vapor delivery. n = 7–12/group. p ≤ 0.05. *Significant differences between CANTHC and VEH groups. #Significant differences between CANTHC and CANCBD groups.
- Figure 3.
Cannabis vapor self-administration produces physiologically relevant cannabinoid concentrations and alterations in CB1R binding. Correlations between the number of cannabis vapor deliveries (200 or 400 mg/ml) earned and plasma concentrations of (A) THC (CANTHC-200: r = 0.51, p = 0.03; CANTHC-400: r = 0.86, p < 0.001) and (B) CBD (CANCBD-200: r = 0.58, p = 0.01; CANCBD-400: r = 0.51, p = 0.18) at the end of the 1 h self-administration session (n = 8–17/group). Brain tissue concentration of (C) THC and (D) CBD measured 24 h after the final self-administration session in rats trained to self-administer CANTHC or CANCBD vapor (n = 11/group). E, Hippocampal CB1R binding site density (pmol/mg protein) and (F) CB1R binding affinity (nm) in rats trained to self-administer CANTHC, CANCBD, or VEH. Tissue was analyzed 24 h after the final self-administration session. n = 4/group. p ≤ 0.05. *Significant differences between CANTHC and VEH groups. #Significant differences between CANTHC and CANCBD groups.
- Figure 4.
Self-administration of THC-rich cannabis vapor produces locomotor and metabolic alterations. A, Radio telemetry recordings of within-session locomotor activity (counts/min) over the final 10 d of self-administration in a subset of CANTHC, CANCBD, and VEH self-administering rats (n = 2–3/group). B, Home cage activity measured as total time spent inactive during the 3 h immediately following CANTHC, CANCBD, or VEH vapor self-administration. C, Total daily inactivity time in CANTHC, CANCBD, and VEH vapor self-administering rats. D, Mean daily distance traveled in the home cage during the active and inactive phases in CANTHC, CANCBD, or VEH vapor self-administering rats. E, Mean daily food consumption (grams) in CANTHC, CANCBD, or VEH vapor self-administering rats. F, Mean oxygen consumption (VO2) and (G) mean carbon dioxide consumption (VCO2) during the active and inactive phase in CANTHC, CANCBD, and VEH self-administering rats. H, Mean energy expenditure (kcal/h) during active and inactive phases of rats trained to self-administer CANTHC, CANCBD, or VEH vapor. All values are presented as averages over the final 10 d of self-administration training. n = 5–6/group. p ≤ 0.05. *Significant differences between CANTHC and VEH groups. #Significant differences between CANTHC and CANCBD groups.
- Figure 5.
The reinforcing effects of vaporized CANTHC require CB1 receptor stimulation. Mean (A) active nose-poke responses for CANTHC and (B) CANTHC vapor deliveries following systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.). Mean (C) active nose-poke responses for CANCBD and (D) CANCBD vapor deliveries following systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.). Data are depicted as a percentage of baseline from the preceding mock injection day. p ≤ 0.05. *Significant differences between CANTHC and VEH groups.
- Figure 6.
Cannabis vapor supports conditioned drug seeking in the absence of drug availability or in the presence of drug-related cues. A, Active (colored symbols) and inactive (open symbols) responding for CANTHC, CANCBD, or VEH vapor on the final day of self-administration training (left) and during the first 7 d of extinction training (right). B, Number of trials required to meet extinction criterion (i.e., ≥50% decrease in active nose-poke responses relative to the final self-administration day during the final two extinction sessions). C, Number of nose-poke responses made on the active operanda for CANTHC, CANCBD, or VEH vapor on the final day of extinction (left) and during a cue-induced reinstatement test (left). n = 11–13/group. p ≤ 0.05. ‡Significant difference in responding relative to the final day of (A) self-administration or (C) extinction training. *Significant differences between CANTHC and VEH groups. †Significant differences between CANCBD and VEH groups.
Procedure CANTHC (n) CANCBD (n) VEH (n) SA days Vapor system FR/PR 11 12 7 22 2nd GEN Plasma CB 400 mg/ml = 8 400 mg/ml = 8 12–16 1st GEN Quantification 200 mg/ml = 17 200 mg/ml = 17 12–16 1st GEN Brain CB quantification 11 11 19 2nd GEN CB1R binding 4 4 4 22 2nd GEN Radio telemetry 3 3 2 19 1st GEN Metabolic phenotyping 6 6 5 22 2nd GEN CB1R antagonism 8 8 27 1st GEN EPM 13 13 11 19 1st GEN Extinction/reinstatement 13 11 11 19 1st GEN SA, self-administration; GEN, generation. Doses for CANTHC and CANCBD are 400 mg/ml unless otherwise specified. Studies involving FR/PR responding, brain CB quantification, CB1R binding, and metabolic phenotyping were conducted in the same cohort of rats. Studies involving radio telemetry, EPM testing, and extinction/reinstatement were conducted in the same cohort of rats. Studies involving plasma CB quantification and CB1R antagonism were each conducted in independent cohorts of rats that were not used for any other experiments.
Treatment group n Open arm time, % Open arm entries Rearing events Stretch-attend postures VEH 11 16.32 ± 4.86 3.09 ± 0.73 22.45 ± 1.20 10.93 ± 1.03 CANTHC 13 11.04 ± 2.18 2.00 ± 0.35 22.55 ± 1.22 8.47 ± 0.71 CANCBD 13 12.80 ± 4.19 3.07 ± 0.67 23.32 ± 1.62 8.15 ± 0.85 Values for EPM measures represent mean ± SEM.
