Psychopharmacology

, Volume 192, Issue 1, pp 61–70

Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality

  • Pattipati S. Naidu
  • Stephen A. Varvel
  • Kyunghye Ahn
  • Benjamin F. Cravatt
  • Billy R. Martin
  • Aron H. Lichtman
Original Investigation

Abstract

Rationale

Manipulations of the endocannabinoid/fatty acid amide hydrolase (FAAH) signaling systems result in conflicting and paradoxical effects in rodent models of emotional reactivity.

Objectives

In the present study, we tested the hypothesis that the inhibition of FAAH would elicit significant effects in murine models used to screen anxiolytic and antidepressant drugs.

Materials and methods

FAAH (−/−) mice and wild-type mice treated with FAAH inhibitors (URB597 and OL-135) were evaluated in standard behavioral screening models for antidepressant (i.e., tail suspension and forced-swim tests) and anxiolytic (i.e., elevated plus maze) agents. The doses of URB597 and OL-135 selected were based on their ability to augment the pharmacological effects (i.e., analgesia, catalepsy, and hypothermia) of exogenously administered anandamide.

Results

FAAH (−/−) mice, anandamide-injected FAAH (−/−) mice, or wild-type mice injected with FAAH inhibitors or anandamide failed to exhibit significant effects in standard tests of emotional reactivity, although the antidepressant desipramine and the anxiolytic agent midazolam were active in the appropriate assays. FAAH- (−/−) and URB597-treated mice finally displayed significant effects in the tail suspension test when substantial methodological changes were made (i.e., altered ambient light and increased sample sizes).

Conclusions

Although FAAH suppression can elicit significant effects under some instances in which consequential procedural modifications are made, the present results indicate that the pharmacological inhibition or genetic deletion of FAAH is ineffective in standard mouse models of emotional reactivity. It remains to be established whether the effects of FAAH inhibition in these modified tasks are predictive of their efficacy in treating emotional disorders.

Keywords

Antidepressant Anandamide Emotion Depression Cannabinoids Anxiolytic Anxiety Fatty acid amide hydrolase URB597 OL135 

References

  1. Akinshola BE, Chakrabarti A, Onaivi ES (1999) In-vitro and in-vivo action of cannabinoids. Neurochem Res 24:1233–1240PubMedCrossRefGoogle Scholar
  2. Alexander JP, Cravatt BF (2005) Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes. Chem Biol 12:1179–1187PubMedCrossRefGoogle Scholar
  3. Arevalo C, de Miguel R, Hernandez-Tristan R (2001) Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters. Pharmacol Biochem Behav 70:123–131PubMedCrossRefGoogle Scholar
  4. Boger DL, Miyauchi H, Du W, Hardouin C, Fecik RA, Cheng H, Hwang I, Hedrick MP, Leung D, Acevedo O, Guimaraes CR, Jorgensen WL, Cravatt BF (2005) Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. J Med Chem 48:1849–1856PubMedCrossRefGoogle Scholar
  5. Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V, La Rana G, Russo R, Calignano A, Gessa GL, Cuomo V, Piomelli D (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31(12):2652–2659PubMedCrossRefGoogle Scholar
  6. Colquhoun D (1997) Lectures on biostatistics: an introduction to statistics with applications in biology and medicine. Clarendon Press, Oxford, pp 327–332Google Scholar
  7. Cravatt B, Prospero-Garcia O, Siuzdak G, Gilula N, Henriksen S, Boger D, Lerner R (1995) Chemical characterization of a family of brain lipids that induce sleep. Science 268:1506–1509PubMedCrossRefGoogle Scholar
  8. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376PubMedCrossRefGoogle Scholar
  9. Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH (2004) Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci USA 101:10821–10826PubMedCrossRefGoogle Scholar
  10. Crawley J, Corwin R, Robinson J, Felder C, Devane W, Axelrod J (1993) Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. Pharmacol Biochem Behav 46(4):967–972PubMedCrossRefGoogle Scholar
  11. Despres JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134PubMedCrossRefGoogle Scholar
  12. Fabre LF, McLendon D (1981) The efficacy and safety of nabilone (a synthetic cannabinoid) in the treatment of anxiety. J Clin Pharmacol 21:377S–382SPubMedGoogle Scholar
  13. Fegley D, Gaetani S, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther 313:352–358PubMedCrossRefGoogle Scholar
  14. Fride E, Mechoulam R (1993) Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 231:313–314PubMedCrossRefGoogle Scholar
  15. Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano T, Morgese MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625PubMedCrossRefGoogle Scholar
  16. Griebel G, Stemmelin J, Scatton B (2005) Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol Psychiatry 57:261–267PubMedCrossRefGoogle Scholar
  17. Haller J, Bakos N, Szirmay M, Ledent C, Freund TF (2002) The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci 16:1395–1398PubMedCrossRefGoogle Scholar
  18. Hollister LE (1986) Health aspects of cannabis. Pharmacol Rev 38:1–20PubMedGoogle Scholar
  19. Holt S, Comelli F, Costa B, Fowler CJ (2005) Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br J Pharmacol 146:467–476PubMedCrossRefGoogle Scholar
  20. Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, Rana GL, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedCrossRefGoogle Scholar
  21. Lichtman AH, Leung D, Shelton CC, Saghatelian A, Hardouin C, Boger DL, Cravatt BF (2004a) Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 311:441–448PubMedCrossRefGoogle Scholar
  22. Lichtman AH, Shelton CC, Advani T, Cravatt BF (2004b) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327PubMedCrossRefGoogle Scholar
  23. Maccarrone M, Valverde O, Barbaccia ML, Castane A, Maldonado R, Ledent C, Parmentier M, Finazzi-Agro A (2002) Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour. Eur J Neurosci 15:1178–1186PubMedCrossRefGoogle Scholar
  24. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl) 159:379–387CrossRefGoogle Scholar
  25. Navarro M, Hernandez E, Munoz RM, del Arco I, Villanua MA, Carrera MR, Rodriguez de Fonseca F (1997) Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport 8:491–496PubMedCrossRefGoogle Scholar
  26. Nielsen DM, Carey GJ, Gold LH (2004) Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice. Eur J Pharmacol 499:135–146PubMedCrossRefGoogle Scholar
  27. Nunes-de-Souza RL, Canto-de-Souza A, da-Costa M, Fornari RV, Graeff FG, Pela IR (2000) Anxiety-induced antinociception in mice: effects of systemic and intra-amygdala administration of 8-OH-DPAT and midazolam. Psychopharmacology (Berl) 150:300–310CrossRefGoogle Scholar
  28. Onaivi ES, Green MR, Martin BR (1990) Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther 253:1002–1009PubMedGoogle Scholar
  29. Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318(1):304–311PubMedCrossRefGoogle Scholar
  30. Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  31. Rodgers RJ, Evans PM, Murphy A (2005) Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice. Behav Pharmacol 16:405–413PubMedCrossRefGoogle Scholar
  32. Rodgers RJ, Haller J, Halasz J, Mikics E (2003) ‘One-trial sensitization’ to the anxiolytic-like effects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze. Eur J Neurosci 17:1279–1286PubMedCrossRefGoogle Scholar
  33. Rodriguez de Fonseca F, Rubio P, Menzaghi F, Merlo-Pich E, Rivier J, Koob G, Navarro M (1996) Corticotropin-releasing factor (crf) antagonist [D-Phe12, Nle21,38, CaMeLeu37]. J Pharmacol Exp Ther 276:56–64PubMedGoogle Scholar
  34. Rutkowska M, Jamontt J, Gliniak H (2006) Effects of cannabinoids on the anxiety-like response in mice. Pharmacol Rep 58:200–206PubMedGoogle Scholar
  35. Shearman LP, Rosko KM, Fleischer R, Wang J, Xu S, Tong XS, Rocha BA (2003) Antidepressant-like and anorectic effects of the cannabinoid CB1 receptor inverse agonist AM251 in mice. Behav Pharmacol 14:573–582PubMedCrossRefGoogle Scholar
  36. Steru L, Chermat R, Thierry B, Mico JA, Lenegre A, Steru M, Simon P, Porsolt RD (1987) The automated tail suspension test: a computerized device which differentiates psychotropic drugs. Prog Neuropsychopharmacol Biol Psychiatry 11:659–671PubMedCrossRefGoogle Scholar
  37. Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 138:544–553PubMedCrossRefGoogle Scholar
  38. Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R (2002) Behavioural and biochemical evidence for interactions between delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578PubMedCrossRefGoogle Scholar
  39. Valverde O, Karsak M, Zimmer A (2005) Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice. Handb Exp Pharmacol 117–145Google Scholar
  40. Varvel SA, Cravatt BF, Engram AE, Lichtman AH (2006) Fatty acid amide hydrolase (−/−) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task. J Pharmacol Exp Ther 317:251–257PubMedCrossRefGoogle Scholar
  41. Viveros MP, Marco EM, File SE (2005) Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81:331–342PubMedCrossRefGoogle Scholar
  42. Wiley JL, Martin BR (2003) Cannabinoid pharmacological properties common to other centrally acting drugs. Eur J Pharmacol 471:185–193PubMedCrossRefGoogle Scholar
  43. Willoughby KA, Moore SF, Martin BR, Ellis EF (1997) The biodisposition and metabolism of anandamide in mice. J Pharmacol Exp Ther 282:243–247PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Pattipati S. Naidu
    • 1
  • Stephen A. Varvel
    • 1
  • Kyunghye Ahn
    • 2
  • Benjamin F. Cravatt
    • 3
  • Billy R. Martin
    • 1
  • Aron H. Lichtman
    • 1
  1. 1.Department of Pharmacology and ToxicologyMedical College of Virginia Campus, Virginia Commonwealth UniversityRichmondUSA
  2. 2.Pfizer Global Research and Development, Molecular PharmacologyAnn ArborUSA
  3. 3.The Skaggs Institute for Chemical Biology and Departments of Cell Biology and ChemistryThe Scripps Research InstituteLa JollaUSA

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