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Cannabinoid-induced lower lip retraction in rats

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Abstract

Rationale

Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists.

Objectives

To pharmacologically characterize cannabinoid-induced LLR in rats.

Methods

Lower lip retraction was scored using a 3-point scale for up to 6 h after injection of the cannabinoid agonists Δ9-tetrahydrocannabinol (Δ9-THC, 1–10 mg/kg), AM7499 (0.01–1.0 mg/kg), or AM2389 (0.003–0.1 mg/kg), or, for comparison, the 5-HT1A agonist 8-OH-DPAT (0.01–0.3 mg/kg). Next, antagonist effects of rimonabant (1–10 mg/kg) and WAY100635 (0.3 mg/kg) on LLR produced by cannabinoid or 5-HT1A agonists were evaluated. Lastly, effects of 8-OH-DPAT were determined following pretreatment with AM2389 (0.003–0.01 mg/kg) or Δ9-THC (1 mg/kg).

Results

All three cannabinoid agonists produced LLR. Effects of AM2389 were attenuated by both rimonabant and WAY100635 whereas effects of 8-OH-DPAT were antagonized by WAY 100635 but not by rimonabant. Pretreatment with 1 mg/kg Δ9-THC or 0.01 mg/kg AM2389 shifted the 8-OH-DPAT dose-effect function for LLR to the left and isobolographic analysis of the data indicates CB1 and 5-HT1A interactions can be supraadditive.

Conclusions

Cannabinoid agonists produce LLR in rats, an effect heretofore ascribed only to activity at 5-HT1A receptors, via CB1 receptor-mediated actions. Co-administration of a cannabinoid agonist and the 5-HT1A agonist 8-OH-DPAT results in a synergistic effect on LLR.

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Acknowledgments

The authors thank Roger Spealman, Jack Bergman, Brian Kangas, and Fernando de Moura for comments on a previous version of the manuscript.

Funding

This work was supported by the National Institutes of Health [Grants DA023142, DA043700].

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Author notes

  1. Girish R. Chopda

    Present address: Preclinical Development, Dicerna Pharmaceuticals, Cambridge, MA, USA

  2. Rishi Sharma

    Present address: Charles River Laboratories, San Francisco, CA, USA

  3. Shashank Kulkarni

    Present address: EMD Serono R&D Institute, Billerica, MA, USA

  4. Carol A. Paronis

    Present address: Preclinical Pharmacology, McLean Hospital, Belmont, USA

Authors and Affiliations

  1. Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA

    Girish R. Chopda, Spyros P. Nikas, Rishi Sharma, Shashank Kulkarni, Alexandros Makriyannis & Carol A. Paronis

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  1. Girish R. Chopda
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  2. Spyros P. Nikas
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  3. Rishi Sharma
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Correspondence to Carol A. Paronis.

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Portions of this work were presented previously in: Chopda G, Anderson J, Nikas SP, Makriyannis A, Paronis CA. Cannabinoid CB1 and serotonin 5-HT1A agonists mediate lower lip retraction by independent mechanisms, at the 2012 FASEB meeting in San Diego, California; FASEB J (2012) 26:661.8

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Chopda, G.R., Nikas, S.P., Sharma, R. et al. Cannabinoid-induced lower lip retraction in rats. Psychopharmacology 236, 1199–1206 (2019). https://doi.org/10.1007/s00213-018-5125-z

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