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Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats

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Abstract

Rationale

The “subjective high” from marijuana ingestion is likely due to Δ9-tetrahydrocannabinol (THC) activating the central cannabinoid receptor type 1 (CB1R) of the endocannabinoid signaling system. THC is a weak partial agonist according to in vitro assays, yet THC mimics the behavioral effects induced by more efficacious cannabinergics. This distinction may be important for understanding similarities and differences in the dose–effect spectra produced by marijuana/THC and designer cannabimimetics (“synthetic marijuana”).

Objective

We evaluated if drug discrimination is able to functionally detect/differentiate between a full, high-efficacy CB1R agonist [(±)AM5983] and the low-efficacy agonist THC in vivo.

Materials and methods

Rats were trained to discriminate between four different doses of AM5983 (0.10 to 0.56 mg/kg), and vehicle and dose generalization curves were determined for both ligands at all four training doses of AM5983. The high-efficacy WIN55,212-2 and the lower-efficacy (R)-(+)-methanandamide were examined at some AM5983 training conditions. Antagonism tests involved rimonabant and WIN55,212-2 and AM5983. The separate (S)- and (R)-isomers of (±)AM5983 were tested at one AM5983 training dose (0.30 mg/kg). The in vitro cyclic adenosine monophosphate (cAMP) assay examined AM5983 and the known CB1R agonist CP55,940.

Results

Dose generalization ed50 values increased as a function of the training dose of AM5983, but more so for the partial agonists. The order of potency was (R)-isomer > (±)AM5983 > (S)-isomer and AM5983 > WIN55,212-2 ≥ THC > (R)-(+)-methanandamide. Surmountable antagonism of AM5983 and WIN55,212-2 occurred with rimonabant. The cAMP assay confirmed the cannabinergic nature of AM5983 and CP55,940.

Conclusions

Drug discrimination using different training doses of a high-efficacy, full CB1R agonist differentiated between low- and high-efficacy CB1R agonists.

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Acknowledgments

This work was supported by the United States Public Health Service grants 5RO1DA 009064–19, 5R37DA 023142–5, 5PO1DA 009158–14, and 5RO1DA 007215–18 from the National Institute on Drug Abuse (NIDA). We thank R. Gifford and three anonymous reviewers for their thoughtful comments on earlier drafts of the manuscript and Dr. Ken Mackie (Indiana University) for generously providing rat CB1R-transfected HEK cells. We thank NIDA for supplies of (−)-Δ9-THC, (−)-CP55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol) and rimonabant.

Conflict of interest

All authors declare that there is no actual or potential conflict of interest related to this manuscript. Authors declare that the study sponsor did not have any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Authors and Affiliations

  1. Center for Drug Discovery (CDD), Department of Pharmaceutical Sciences, Northeastern University, 116 Mugar Hall, 360 Huntington Ave, Boston, MA, 02115, USA

    Torbjörn U. C. Järbe, Brian J. LeMay, Aneetha Halikhedkar, JodiAnne Wood, Subramanian K. Vadivel, Alexander Zvonok & Alexandros Makriyannis

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  1. Torbjörn U. C. Järbe
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  2. Brian J. LeMay
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  3. Aneetha Halikhedkar
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  4. JodiAnne Wood
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  5. Subramanian K. Vadivel
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  6. Alexander Zvonok
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  7. Alexandros Makriyannis
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Corresponding author

Correspondence to Torbjörn U. C. Järbe.

Additional information

Parts of these data were presented at the annual meeting of the International Cannabinoid Research Society symposium held last June 25 to 29, 2008, at the MacDonald Aviemore Highland Resort, Aviemore, Scotland (Tai et al. 2008).

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Järbe, T.U.C., LeMay, B.J., Halikhedkar, A. et al. Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats. Psychopharmacology 231, 489–500 (2014). https://doi.org/10.1007/s00213-013-3257-8

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