Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.
S Tai, William S Hyatt, C Gu, Lirit N Franks, T Vasiljevik, Lisa K Brents, Paul L Prather, William E Fantegrossi
Pharmacological Research December 2015 DOI: 10.1016/j.phrs.2015.09.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | JWH-018 JWH-073 |
| Dose | JWH-018 3.0 mg/kg; JWH-073 10.0 mg/kg; delta-9-THC 30.0 mg/kg |
| Duration | 5 consecutive days of daily dosing (or 4 days of delta-9-THC followed by testing on day 5), with follow-up testing 14 days after the last drug administration |
| Topics | Cannabis |
| Keywords | Cb1r Cannabinoid Cross-tolerance Desensitization Downregulation |
| Key findings | Repeated administration of delta-9-THC, JWH-018, or JWH-073 produced tolerance to hypothermic effects but not locomotor effects, persisting 14 days after the last dose, and delta-9-THC pretreatment produced cross-tolerance to both synthetic cannabinoids. The authors propose this long-lasting tolerance is likely mediated by region-specific downregulation and desensitization of CB1 receptors, observed in the hypothalamus but not the cortex. |
Abstract
These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 7
- Repeated Exposure to the “Spice” Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats Frontiers in Psychiatry February 27, 2018
- The Sigma1 receptor antagonist CM304 potentiates the antinociceptive effects of the cannabinoid receptor agonist delta9-tetrahydrocannabinol in rats and mice. Pharmacological Reports April 1, 2026
- Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice. British Journal of Pharmacology July 13, 2023
- Reduced Tolerance and Asymmetrical Crosstolerance to Effects of the Indole Quinuclidinone Analog PNR-4-20, a G Protein-Biased Cannabinoid 1 Receptor Agonist in Mice: Comparisons with Δ9-Tetrahydrocannabinol and JWH-018. Journal of Pharmacology and Experimental Therapeutics May 2019
- Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Drug and Alcohol Dependence October 1, 2017
and 2 more in the library
Cites 6
- Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users Psychopharmacology October 30, 2010
- A survey study to characterize use of Spice products (synthetic cannabinoids). Drug and Alcohol Dependence August 10, 2011
- Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers Molecular Psychiatry July 12, 2011
- Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 2011
- Withdrawal phenomena and dependence syndrome after the consumption of "spice gold". Deutsches Arzteblatt international July 3, 2009
and 1 more in the library