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

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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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References

  • Albayram O, Alferink J, Pitsch J, Piyanova A, Neitzert K, Poppensieker K, Mauer D, Michel K, Legler A, Becker A, Monory K, Lutz B, Zimmer A, Bilkei-Gorzo A (2011) Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. Proc Natl Acad Sci 108:11256–11261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Albayram O, Bilkei-Gorzo A, Zimmer A (2012) Loss of CB1 receptors leads to differential age-related changes in reward-driven learning and memory. Front Aging Neurosci 4:34

    Article  PubMed  PubMed Central  Google Scholar 

  • Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ, Collaborators CGTP (2013) The concise guide to pharmacology 2013/14: G protein-coupled receptors. Br J Pharmacol 170:1459–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker D, Pryce G, Giovannoni G, Thompson AJ (2003) The therapeutic potential of cannabis. Lancet Neurol 2:291–298

    Article  CAS  PubMed  Google Scholar 

  • Bass CE, Martin BR (2000) Time course for the induction and maintenance of tolerance to Δ9-tetrahydrocannabinol in mice. Drug Alcohol Depend 60:113–119

    Article  CAS  PubMed  Google Scholar 

  • Bilkei-Gorzo A (2012) The endocannabinoid system in normal and pathological brain ageing. Phil Trans R Soc B 367:3326–3341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bilkei-Gorzo A, Racz I, Valverde O, Otto M, Michel K, Sarstre M, Zimmer A (2005) Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc Natl Acad Sci 102:15670–15675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bilkei-Gorzo A, Drews E, Albayram O, Piyanova A, Gaffal E, Tueting T, Michel K, Mauer D, Maier W, Zimmer A (2012) Early onset of aging-like changes is restricted to cognitive abilities and skin structure in CNR1−/− mice. Neurobiol Aging 33:200.e11–22

  • Blankman JL, Cravatt BF (2013) Chemical probes of endocannabinoid metabolism. Pharmacol Rev 65:849–871

    Article  PubMed  PubMed Central  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantitites of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Breivogel CS, Griffin G, Di Marzo V, Martin BR (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163

    CAS  PubMed  Google Scholar 

  • Buczynski MW, Parsons LH (2010) Quantification of brain endocannabinoid levels: methods, interpretations and pitfalls. Brit J Pharmacol 160:423–442

    Article  CAS  Google Scholar 

  • Buntin-Mushock C, Phillip L, Moriyama K, Palmer PP (2005) Age-dependent opioid escalation in chronic pain patients. Anesth Analg 100:1740–1745

    Article  PubMed  Google Scholar 

  • Di Marzo V, Stella N, Zimmer A (2015) Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16:30–42

    Article  PubMed  PubMed Central  Google Scholar 

  • Feliszek M, Bilkei-Gorzo A, Schlicker E (2014) Does aging influence the tolerance development after chronic Δ9-tetrahydrocannabinol treatment in mice? Naunyn-Schmiedeberg's Arch Pharmacol 387(Suppl 1):S39

    Google Scholar 

  • Ghosh S, Wise L, Chen Y, Gujjar R, Mahadevan A, Cravatt BF, Lichtman AH (2013) The monoacylglycerol lipase inhibitor JZL 184 suppresses inflammatory pain in the mouse carrageenan model. Life Sci 92:498–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • González S, Cebeira M, Fernández-Ruiz J (2005) Cannabinoid tolerance and dependence: a review of studies in laboratory animals. Pharmacol Biochem Behav 81:300–318

    Article  PubMed  Google Scholar 

  • González-Maeso J, Torre I, Rodríguez-Puertas R, García-Sevilla JA, Guimón J, Meana JJ (2002) Effects of age, postmortem delay and storage time on receptor-mediated activation of G-proteins in human brain. Neuropsychopharmacology 26:468–478

    Article  PubMed  Google Scholar 

  • Grotenhermen F (2003) Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42:327–360

    Article  CAS  PubMed  Google Scholar 

  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. classification of cannabinoid receptors. Pharmacol Rev 54:161–202

    Article  CAS  PubMed  Google Scholar 

  • Irie T, Kikura-Hanajiri R, Usami M, Uchiyama N, Goda Y, Sekino Y (2015) MAM-2201, a synthetic cannabinoid drug of abuse, suppresses the synaptic input to cerebellar Purkinje cells via activation of presynaptic CB1 receptors. Neuropharmacology 95:479–491

    Article  CAS  PubMed  Google Scholar 

  • Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, Starowicz K, Steuder R, Schlicker E, Cravatt B, Mechoulam R, Buettner R, Werner S, Di Marzo V, Tüting T, Zimmer A (2007) Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316:1494–1497

    Article  CAS  PubMed  Google Scholar 

  • Kinsey SG, Wise LE, Ramesh D, Abdullah R, Selley DE, Cravatt BF, Lichtman AH (2013) Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects. J Pharmacol Exp Ther 345:492–501

  • Lazenka MF, Selley DE, Sim-Selley LJ (2013) Brain regional differences in CB1 receptor adaptation and regulation of transcription. Life Sci 92:446–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee TT, Hill MN, Hillard CJ, Gorzalka BB (2013) Temporal changes in N-acylethanolamine content and metabolism throughout the periadolescent period. Synapse 67:4–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5:37–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long LE, Lind J, Webster M, Weickert CS (2012) Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex. BMC Neurosci 13:87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin BR, Sim-Selley L, Selley DE (2004) Signaling pathways involved in the development of cannabinoid tolerance. Trends Pharmacol Sci 25:325–330

    Article  CAS  PubMed  Google Scholar 

  • Mato S, Pazos A (2004) Influence of age, postmortem delay and freezing storage period on cannabinoid receptor density and functionality in human brain. Neuropharmacology 46:716–726

    Article  CAS  PubMed  Google Scholar 

  • McKinney DL, Cassidy MP, Collier LM, Martin BR, Wiley JL, Selley DE, Sim-Selley LJ (2008) Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vitro tolerance development to Δ9-tetrahydrocannabinol. J Pharmacol Exp Ther 324:664–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47

    Article  PubMed  Google Scholar 

  • Moore RJ, Xiao R, Sim-Selley LJ, Childers SR (2000) Agonist-stimulated [35S]GTPγS binding in brain: modulation by endogenous adenosine. Neuropharmacology 39:282–289

    Article  CAS  PubMed  Google Scholar 

  • Moore NLT, Greenleaf ALR, Acheson SK, Wilson WA, Swartzwelder HS, Kuhn CM (2010) Role of cannabinoid receptor type 1 desensitization in greater tetrahydrocannabinol impairment of memory in adolescent rats. J Pharmacol Exp Ther 335:294–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morena M, Patel S, Bains JS, Hill MN (2016) Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology 41:80–102

    Article  CAS  PubMed  Google Scholar 

  • Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ (2012) ß-Arrestin2 regulates cannabinoid CB1 receptor signalling and adaptation in a central nervous system region-dependent manner. Biol Psychiat 71:714–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohno-Shosaku T, Tanimura A, Hashimotodani Y, Kano M (2012) Endocannabinoids and retrograde modulation of synaptic transmission. Neuroscientist 18:119–132

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 76:1307–1324

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piomelli D (2014) More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology 76:228–234

    Article  CAS  PubMed  Google Scholar 

  • Piyanova A, Albayram O, Rossi CA, Farwanah H, Michel K, Nicotera P, Sandhoff K, Bilkei-Gorzo A (2013) Loss of CB1 receptors leads to decreased cathepsin D levels and accelerated lipofuscin accumulation in the hippocampus. Mech Ageing Dev 134:391–399

    Article  CAS  PubMed  Google Scholar 

  • Piyanova A, Lomazzo E, Bindila L, Lerner R, Albayram O, Ruhl T, Lutz B, Zimmer A, Bilkei-Gorzo A (2015) Age-related changes in the endocannabinoid system in the mouse hippocampus. Mech Ageing Dev 150:55–64

    Article  CAS  PubMed  Google Scholar 

  • Puighermanal E, Busquets-Garcia A, Maldonado R, Ozaita A (2012) Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids. Phil Trans R Soc B 367:3254–3263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A (2013) Dissociation of the pharmacological effects of THC by mTOR blockade. Neuropsychopharmacology 38:1334–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruehle S, Rey AA, Remmers F, Lutz B (2012) The endocannabinoid system in anxiety, fear memory and habituation. J Psychopharmacol 26:23–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scherma M, Fattore L, Castelli MP, Fratta W, Fadda P (2014) The role of the endocannabinoid system in eating disorders: neurochemical and behavioural preclinical evidence. Curr Pharm Des 20:2089–2099

    Article  CAS  PubMed  Google Scholar 

  • Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, Lichtman AH, Cravatt BF (2010) Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 13:1113–1119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sim LJ, Hampson RE, Deadwyler SA, Childers SR (1996) Effects of chronic treatment with Δ9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPγS autoradiography in rat brain. J Neurosci 16:8057–8066

    CAS  PubMed  Google Scholar 

  • Sim-Selley LJ (2003) Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 15:91–119

    Article  CAS  PubMed  Google Scholar 

  • Sim-Selley LJ, Schechter NS, Rorrer WK, Dalton GD, Hernandez J, Martin BR, Selley DE (2006) Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term cannabinoid administration. Mol Pharmacol 70:986–996

    Article  CAS  PubMed  Google Scholar 

  • Strange PG (2010) Use of the GTPγS ([35S]GTPγS and Eu-GTPγS) binding assay for analysis of ligand potency and efficacy at G protein-coupled receptors. Br J Pharmacol 161:1238–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo B, Schlicker E (2005) Effects of cannabinoids on neurotransmission. Handb Exp Pharmacol 168:327–365

    Article  CAS  PubMed  Google Scholar 

  • Tai S, Hyatt WS, Gu C, Franks LN, Vasiljevik T, Brents LK, Prather PL, Fantegrossi WE (2015) Repeated administration of phytocannabinoid Δ9-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. Pharmacol Res 102:22–32

    Article  CAS  PubMed  Google Scholar 

  • Vlachou S, Panagis G (2014) Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals. Curr Pharm Des 20:2072–2088

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Liu J, Harvey-White J, Zimmer A, Kunos A (2003) Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci 100:1393–1398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Mitchell J, Moriyama K, Kim KJ, Sharma M, Xie GX, Palmer PP (2005) Age-dependent morphine tolerance development in the rat. Anesth Analg 100:1733–1739

    Article  CAS  PubMed  Google Scholar 

  • Wenzel D, Matthey M, Bindila L, Lerner R, Lutz B, Zimmer A, BK F (2013) Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci 110:18710–18715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu DF, Yang LQ, Goschke A, Stumm R, Brandenburg LO, Liang YJ, Höllt V, Koch T (2008) Role of receptor internalization in the agonist-induced desensitization of cannabinoid type 1 receptors. J Neurochem 104:1132–1143

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Xin X, Xie GX, Palmer PP, Huang YG (2012) Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance. Mol Pain 10:38

    Article  Google Scholar 

  • Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci 96:5780–5785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zogopoulos P, Vasileiou I, Patsouris E, Theocharis SE (2013) The role of endocannabinoids in pain modulation. Fundam Clin Pharmacol 27:64–80

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Monika Feliszek & Eberhard Schlicker

  2. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany

    Laura Bindila & Beat Lutz

  3. Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Andreas Zimmer & Andras Bilkei-Gorzo

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  1. Monika Feliszek
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  2. Laura Bindila
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  3. Beat Lutz
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  4. Andreas Zimmer
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  5. Andras Bilkei-Gorzo
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  6. Eberhard Schlicker
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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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