Cannabidiol attenuates methamphetamine-induced conditioned place preference in male rats and viability in PC12 cells through the Sigma1R/AKT/GSK3β/CREB signaling pathway

ABSTRACT

Background: Methamphetamine use is associated with several negative consequences, including neurotoxicity and greater probability of exhibiting a substance use disorder. Sigma1 receptor is involved in the neurobiological basis of several drug use disorders. Cannabidiol has received attention in the treatment of drug use disorders and neurotoxicity.

Objectives: To investigate the effects of cannabidiol on methamphetamine-induced conditioned place preference (CPP) and the viability of PC12 cells.

Methods: Adult male rats (n = 70) underwent methamphetamine (2 mg/kg, IP) induced CPP, and were administered cannabidiol (10, 20, 40, or 80 mg/kg, IP) during the methamphetamine withdrawal period for five consecutive days. Methamphetamine (0.5 mg/kg) was then injected to reactivate CPP. Four brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, and hippocampus) were extracted after the last test. PC12 cells were treated with cannabidiol, Sigma1R-siRNA, or BD1047 before methamphetamine exposure.

Results: Administration of 20, 40, or 80 mg/kg cannabidiol facilitated CPP extinction (80 mg/kg, p < .001) and prevented CPP development (80 mg/kg, p < .0001). This was associated with changes in the expression of Sigma1R (ventral tegmental area, 80 mg/kg, p < .0001) in the four brain regions. Cannabidiol protected the PC12 cell’s viability (10 μM, p = .0008) and inhibited the methamphetamine-induced activation of the AKT/GSK3β/CREB signaling pathway by mediating Sigma1R (10 μM, p < .0001).

Conclusions: Cannabidiol seems to inhibit the rewarding effects of methamphetamine and the effects of this drug on cell viability. Sigma1R should be given further consideration as a potential target for cannabidiol.

KEYWORDS:

• Cannabidiol
• methamphetamine
• CPP
• extinction
• cell viability
• Sigma1R

This article is referred to by:

Cannabidiol as a pharmacotherapy tool for attenuating methamphetamine effects

Acknowledgments

We acknowledge Liu L, Li J., Wang C., Xu Y., Leung C.K., Yang G.M., Lin S.C., Zhang S.W., Tan Y., Zhang H.J., and Wang H.W. for their participation in this work literature search, experimental validation, data analysis, and manuscript writing. Liu J.X., Li M., and Zeng X.F. supervised the study design and critically read and edited the manuscript. All the authors approved the final version for publication.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

All animal procedures were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Kunming Medical University (No. kmmu202100001426).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/00952990.2022.2073450

Additional information

Funding

This work was supported by the National Nature Science Foundation of China [81960340 and 82060382], the Yunnan Applied Basic Research Projects Joint Special Project [202001AY070001-015], the Basic Research Program of Yunnan Province [202001AT070098], and Ten Thousand People Plan of Yunnan Province [2020-60121160304].