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Lack of hippocampal CB1 receptor desensitization by Δ9-tetrahydrocannabinol in aged mice and by low doses of JZL 184

Abstract

Activation of cannabinoid CB1 receptors may offer new therapeutic strategies, but the efficiency of CB1 receptor agonists may be impaired by tolerance development upon prolonged administration. We compared the influence of repeated administration of Δ9-tetrahydrocannabinol (THC) 10 mg/kg on the motility and on basal and CB1 receptor-stimulated 35S-GTPγS binding of adolescent and aged mice. Moreover, we determined the influence of JZL 184 (which inhibits the 2-arachidonoylglycerol, 2-AG, degrading enzyme monoacylglycerol lipase, MAGL) on 35S-GTPγS binding and 2-AG levels of young adult mice. Mouse motility was tested in the open field. 35S-GTPγS binding was studied in hippocampal membranes. THC and CP 55,940 were used as cannabinoid agonists in the behavioural and biochemical studies, respectively. 2-AG levels were quantified by liquid chromatography-multiple reaction monitoring. The THC (10 mg/kg)-induced hypomotility was stronger in untreated than in THC-pretreated adolescent mice but similar in both treatment groups of aged mice. Basal and stimulated 35S-GTPγS binding was decreased in membranes from THC-pretreated adolescent but not affected in membranes from aged mice. Treatment of young adult mice with JZL 184 (4, 10 and 40 mg/kg) for 14 days did not affect basal binding. Stimulated binding tended to be decreased by 25 % only in mice treated with JZL 184 (40 mg/kg). Hippocampal 2-AG level was increased by JZL 184 at 40 and 10 but not affected at 4 mg/kg. In conclusion, CB1 receptor tolerance does not occur in aged mice pretreated with THC and in young adult mice treated with a low dose of the MAGL inhibitor JZL 184.

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Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft to Andras Bilkei-Gorzo, Beat Lutz, Eberhard Schlicker and Andreas Zimmer within the Forschergruppe 926. We are grateful to Kerstin Michel, Doris Petri, Ildiko Racz and Claudia Schwitter for their assistance.

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Correspondence to Eberhard Schlicker.

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All applicable international, national and institutional guidelines for the care and use of animals were followed. For the experiments, a permit (Az 87–51.04.2011.A038) was obtained from the local ethical committee (Bezirksregierung Köln, Köln, Germany).

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A. Bilkei-Gorzo and E. Schlicker share senior authorship

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Feliszek, M., Bindila, L., Lutz, B. et al. Lack of hippocampal CB1 receptor desensitization by Δ9-tetrahydrocannabinol in aged mice and by low doses of JZL 184. Naunyn-Schmiedeberg's Arch Pharmacol 389, 603–612 (2016). https://doi.org/10.1007/s00210-016-1226-6

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Keywords

  • Hippocampus
  • Open-field activity
  • 35S-GTPγS binding
  • Δ9-Tetrahydrocannabinol (THC)
  • JZL 184
  • 2-Arachidonoylglycerol (2-AG)