Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.
- Authors
- Wiley, Jenny L; Walentiny, D Matthew; Wright, M Jerry; Beardsley, Patrick M; Burston, James J; Poklis, Justin L; Lichtman, Aron H; Vann, Robert E
- Year
- 2014
- Journal
- European journal of pharmacology
- PMID
- 24858366
- DOI
- 10.1016/j.ejphar.2014.05.013
- PMCID
- PMC4110679
The mechanism through which marijuana produces its psychoactive effects is Δ(9)-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC׳s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects.
Effects of THC (filled squares) on % THC-lever responding (upper panels) and response rate (lower panels) in two groups of mice trained to discriminate 5.6 mg/kg THC vs. vehicle. Left panels (A and C) show the effects of anandamide in combination with vehicle (unfilled circles) and in combination with 0.3 mg/kg URB-597 (filled circles) on % THC-lever responding and response rate, respectively. Right panels (B and D) show the effects of 2-AG in combination with vehicle (unfilled circles) and in combination with 1 mg/kg NAM (filled circles) on % THC-lever responding and response rate, respectively. Points above V and T represent the results of control tests with vehicle conducted prior to the dose-effect curve determination for the endocannabinoid (unfilled triangles) and for THC (unfilled squares), respectively. Filled squares above T represent the results of control tests with 5.6 mg/kg THC. Unfilled circles above U (left panels) and N (right panels) represent results of tests with 0.3 mg/kg URB597 and 1 mg/kg NAM, respectively (each in combination with vehicle). All compounds were administered i.p. Values represent the mean (±S.E.M.) of data from 7–10 male mice in each group of discriminators unless indicated otherwise on the figure (numbers in parentheses). Asterisks (*) designate a significant (P < 0.05) decrease in response rate compared to mean rate of responding during the control test with vehicle.
Effects of THC (filled squares) on % THC-lever responding (upper panels) and response rate (lower panels) in two groups of mice trained to discriminate 5.6 mg/kg THC vs. vehicle. Left panels (A and C) also show the effects of the FAAH inhibitor PF3845 alone (unfilled squares) and the effects of 10 mg/kg PF3845 in combination with anandamide (unfilled circles) or THC (filled circles) on % THC-lever responding and response rate, respectively. Right panels (B and D) also show the effects of the MAGL inhibitor JZL184 alone (unfilled squares) on % THC-lever responding and response rate, respectively. In addition, the effects of 30 mg/kg JZL184 and 0.1 or 0.3 mg/kg rimonabant (unfilled and filled circle, respectively) are shown. Points above V and T represent the results of control tests with vehicle and 5.6 mg/kg THC conducted prior to each dose-effect curve determination. THC and anandamide were administered s.c. JZL184 and PF3845 were administered i.p. Values represent the mean (+S.E.M.) of data from 6–9 male mice in each group of discriminators unless indicated otherwise on the figure (numbers in parentheses). Asterisks (*) designate a significant (P < 0.05) decrease in response rates compared to mean rates of responding during the control test with vehicle.
Effects of THC (filled triangles) on % THC-lever responding (upper panels) and response rate (lower panels) in rats trained to discriminate 3 mg/kg THC vs. vehicle (left panels) and re-trained to discriminate 1 mg/kg THC vs. vehicle (right panels). Left panels (A and C) show the effects of URB597 (filled circles) on % THC-lever responding and response rate, respectively. The right side of the panel shows the effects of 30 mg/kg URB597 (unfilled diamond), 16 mg/kg JZL184 (filled square) and its vehicle (unfilled square), and dual inhibition of FAAH and MAGL with 30 mg/kg URB597 and 16 mg/kg JZL184 (filled diamond). Right panels (B and D) show the effects of THC (filled triangles) and URB597 (filled circles) in rats after the THC training dose was decreased to 1 mg/kg. Points above U and T at the left side of each panel represent the results of control tests with vehicle conducted prior to the URB597 and THC dose-effect curve determinations, respectively. All compounds were administered i.p. Values on the left panels (A and C) represent the mean (±S.E.M.) of data from 8 male rats for THC and URB597 dose-effect curves, with the exception that n=6 for % drug-lever responding at the 30 mg/kg dose of THC in panel A and n=5 for the URB597 and JZL184 combination tests (panels A and C). Values on the right panels (B and D) represent the mean (±S.E.M.) of data from 6 male rats for THC and URB597 dose-effect curves. Asterisks (*) designate a significant (P < 0.05) decrease in response rates compared to mean rates of responding during the control test with vehicle.
Top panel: Endocannabinoid concentrations in the cerebellum of male ICR mice following i.p. injection with vehicle, 5 mg/kg NAM, 1 mg/kg URB597 or 16 mg/kg JZL184. Bottom panel: Concentration effect curves for anandamide-stimulated [35S]GTPγS binding with and without addition of 50 nM URB597 in tissues from cerebellum of adult male ICR mice.
No entities extracted from this document yet.
No uploaded files.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Acute Cardiovascular and Cardiorespiratory Effects of JWH-018 in Awake and Freely Moving Mice: Mechanism of Action and Possible Antidotal Interventions? | Marchetti B et al. | — | 2023 | → |
| The endocannabinoid system - current implications for drug development. | Fowler CJ | — | 2021 | → |
| Sex and Gender Differences in the Effects of Novel Psychoactive Substances. | Fattore L et al. | — | 2020 | → |
| Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. | Galaj E et al. | — | 2019 | → |
| Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids. | Wiley JL et al. | — | 2018 | → |
| Effects of Cannabinoid Drugs on Aversive or Rewarding Drug-Associated Memory Extinction and Reconsolidation. | Stern CAJ et al. | — | 2018 | → |
| Loren Parsons' contribution to addiction neurobiology. | De Luca MA et al. | — | 2018 | → |
| Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke. | Choi SH et al. | — | 2018 | → |
| Cannabinoid CB<sub>1</sub> Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors. | Leonard MZ et al. | — | 2017 | → |
| Comparison of the discriminative stimulus and response rate effects of <sup>Δ9</sup>-tetrahydrocannabinol and synthetic cannabinoids in female and male rats. | Wiley JL et al. | — | 2017 | → |
| Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB<sub>1</sub> receptor-mediated discriminative stimulus in mice. | Owens RA et al. | — | 2017 | → |
| Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice. | Owens RA et al. | — | 2016 | → |
| Just add water: cannabinoid discrimination in a water T-maze with FAAH(-/-) and FAAH(+/+) mice. | Wiley JL et al. | — | 2016 | → |
| Endocannabinoid signalling in reward and addiction. | Parsons LH et al. | — | 2015 | → |
| Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. | Ghosh S et al. | — | 2015 | → |
| Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis. | Carey CE et al. | — | 2015 | → |
| Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice. | Walentiny DM et al. | — | 2015 | → |
| Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies. | Gauvin DV et al. | — | 2015 | → |
| Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice. | Ignatowska-Jankowska B et al. | — | 2015 | → |
| Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with Δ9-tetrahydrocannabinol in mice. | Hruba L et al. | — | 2015 | → |
| The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs--A practical view. | Fowler CJ | — | 2015 | → |