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Research Articles, Behavioral/Cognitive

Vaporized Cannabis Extracts Have Reinforcing Properties and Support Conditioned Drug-Seeking Behavior in Rats

Timothy G. Freels, Lydia N. Baxter-Potter, Janelle M. Lugo, Nicholas C. Glodosky, Hayden R. Wright, Samantha L. Baglot, Gavin N. Petrie, Zhihao Yu, Brian H. Clowers, Carrie Cuttler, Rita A. Fuchs, Matthew N. Hill and Ryan J. McLaughlin
Journal of Neuroscience 26 February 2020, 40 (9) 1897-1908; DOI: https://doi.org/10.1523/JNEUROSCI.2416-19.2020
Timothy G. Freels
1Departments of Integrative Physiology and Neuroscience,
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Lydia N. Baxter-Potter
1Departments of Integrative Physiology and Neuroscience,
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Janelle M. Lugo
1Departments of Integrative Physiology and Neuroscience,
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Nicholas C. Glodosky
2Psychology,
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Hayden R. Wright
1Departments of Integrative Physiology and Neuroscience,
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Samantha L. Baglot
4Departments of Cell Biology and Anatomy and Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Gavin N. Petrie
4Departments of Cell Biology and Anatomy and Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Zhihao Yu
3Chemistry, Washington State University, Pullman, Washington 99164, and
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Brian H. Clowers
3Chemistry, Washington State University, Pullman, Washington 99164, and
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Carrie Cuttler
2Psychology,
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Rita A. Fuchs
1Departments of Integrative Physiology and Neuroscience,
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Matthew N. Hill
4Departments of Cell Biology and Anatomy and Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Ryan J. McLaughlin
1Departments of Integrative Physiology and Neuroscience,
2Psychology,
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  • Figure 1.
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    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.
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    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.
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    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.
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    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.

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    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.
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    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.

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    Table 1.

    Assignment of animals and experimental parameters

    ProcedureCANTHC (n)CANCBD (n)VEH (n)SA daysVapor system
    FR/PR11127222nd GEN
    Plasma CB400 mg/ml = 8400 mg/ml = 812–161st GEN
    Quantification200 mg/ml = 17200 mg/ml = 1712–161st GEN
    Brain CB quantification1111192nd GEN
    CB1R binding444222nd GEN
    Radio telemetry332191st GEN
    Metabolic phenotyping665222nd GEN
    CB1R antagonism88271st GEN
    EPM131311191st GEN
    Extinction/reinstatement131111191st 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.

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    Table 2.

    EPM behavior following acute forced abstinence from vapor

    Treatment groupnOpen arm time, %Open arm entriesRearing eventsStretch-attend postures
    VEH1116.32 ± 4.863.09 ± 0.7322.45 ± 1.2010.93 ± 1.03
    CANTHC1311.04 ± 2.182.00 ± 0.3522.55 ± 1.228.47 ± 0.71
    CANCBD1312.80 ± 4.193.07 ± 0.6723.32 ± 1.628.15 ± 0.85
    • Values for EPM measures represent mean ± SEM.

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  • Movie 1.

    Movie clip of a male Sprague Dawley rat responding for CANTHC vapor on a progressive ratio reinforcement schedule.

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The Journal of Neuroscience: 40 (9)
Journal of Neuroscience
Vol. 40, Issue 9
26 Feb 2020
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Vaporized Cannabis Extracts Have Reinforcing Properties and Support Conditioned Drug-Seeking Behavior in Rats
Timothy G. Freels, Lydia N. Baxter-Potter, Janelle M. Lugo, Nicholas C. Glodosky, Hayden R. Wright, Samantha L. Baglot, Gavin N. Petrie, Zhihao Yu, Brian H. Clowers, Carrie Cuttler, Rita A. Fuchs, Matthew N. Hill, Ryan J. McLaughlin
Journal of Neuroscience 26 February 2020, 40 (9) 1897-1908; DOI: 10.1523/JNEUROSCI.2416-19.2020

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Vaporized Cannabis Extracts Have Reinforcing Properties and Support Conditioned Drug-Seeking Behavior in Rats
Timothy G. Freels, Lydia N. Baxter-Potter, Janelle M. Lugo, Nicholas C. Glodosky, Hayden R. Wright, Samantha L. Baglot, Gavin N. Petrie, Zhihao Yu, Brian H. Clowers, Carrie Cuttler, Rita A. Fuchs, Matthew N. Hill, Ryan J. McLaughlin
Journal of Neuroscience 26 February 2020, 40 (9) 1897-1908; DOI: 10.1523/JNEUROSCI.2416-19.2020
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Keywords

  • cannabinoid
  • cannabis
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  • Habitual behaviors and addiction
    Jeff D Correa
    Published on: 08 February 2021
  • Published on: (8 February 2021)
    Page navigation anchor for Habitual behaviors and addiction
    Habitual behaviors and addiction
    • Jeff D Correa, Masters Student, Research Assistant, Carleton University

    This paper creates a good foundation in introducing the effects of vaporized cannabis on reinforcing drug-seeking behaviours. The authors focus on the motivational component of reward-oriented behaviours to habitual drug-seeking behaviours. The study introduces different fixed ratios to determine the effects of motivation, and their results demonstrate that effort influences increased self-administration of illicit drugs. However, motivation is only one aspect of this transition. Therefore, future studies should investigate the genomic changes, the second aspect of the transition from reward-oriented behaviours to habitual drug-seeking behaviours.

    Investigating the effects of THC exposure on the genes Cnr1, Grin1, Gin2a, and Gria2 of the dorsal striatum will help consolidate the transition from reward-oriented behaviours to habitual drug-seeking behaviours. These mRNA levels, if affected by THC administration, will demonstrate the progression from recreational drug use to addiction disorder [4].

    The Cnr1 gene encodes for the CB1 receptor, a direct target of THC, and is critical to forming striatal long-term depression (LTD) and synaptic plasticity [1] [2] [4]. The activity of the medium spiny neurons in the striatum regulates glutamatergic inputs and LTD [3]. Striatal LTD is closely associated with habitual behaviours and reinforcement learning [4] [5] [6]. With the investigation of Cnr1 and NMDA receptors in the striatum, you will be able to consolidate you...

    Show More

    This paper creates a good foundation in introducing the effects of vaporized cannabis on reinforcing drug-seeking behaviours. The authors focus on the motivational component of reward-oriented behaviours to habitual drug-seeking behaviours. The study introduces different fixed ratios to determine the effects of motivation, and their results demonstrate that effort influences increased self-administration of illicit drugs. However, motivation is only one aspect of this transition. Therefore, future studies should investigate the genomic changes, the second aspect of the transition from reward-oriented behaviours to habitual drug-seeking behaviours.

    Investigating the effects of THC exposure on the genes Cnr1, Grin1, Gin2a, and Gria2 of the dorsal striatum will help consolidate the transition from reward-oriented behaviours to habitual drug-seeking behaviours. These mRNA levels, if affected by THC administration, will demonstrate the progression from recreational drug use to addiction disorder [4].

    The Cnr1 gene encodes for the CB1 receptor, a direct target of THC, and is critical to forming striatal long-term depression (LTD) and synaptic plasticity [1] [2] [4]. The activity of the medium spiny neurons in the striatum regulates glutamatergic inputs and LTD [3]. Striatal LTD is closely associated with habitual behaviours and reinforcement learning [4] [5] [6]. With the investigation of Cnr1 and NMDA receptors in the striatum, you will be able to consolidate your findings and determine that THC affects the transition from reward-oriented to habitual compulsive drug-taking.

    Reference
    [1] Gerdeman GL, Ronesi J, Lovinger DM (2002). Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci, 5, 446–451. doi:10.1038/nn832
    [2] Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM (2003). It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends in neurosciences, 26, 184–192. doi: 10.1016/S0166-2236(03)00065-1
    [3] Grueter, B., Rothwell, P. and Malenka, R. (2012). Integrating synaptic plasticity and striatal circuit function in addiction. Current Opinion in Neurobiology, 22(3), 545-551. doi: 10.1016/j.conb.2011.09.009
    [4] Szutorisz, H., Dinieri, J. A., Sweet, E., Egervari, G., Michaelides, M., Carter, J. M., . . . Hurd, Y. L. (2014). Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent Generation. Neuropsychopharmacology, 39(6), 1315-1323. doi: 10.1038/npp.2013.352
    [5] Szutorisz, H., Egervári, G., Sperry, J., Carter, J. and Hurd, Y. (2016). Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring. Neurotoxicology and Teratology, 58, 107-114. doi: 10.1016/j.ntt.2016.05.005
    [6] Yager, L., Garcia, A., Wunsch, A., & Ferguson, S. (2015). The ins and outs of the striatum: Role in drug addiction. Neuroscience, 301, 529-541. doi: 10.1016/j.neuroscience.2015.06.033

    Show Less
    Competing Interests: None declared.

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