Skip to main content
SpringerLink
Log in

The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Disruption of CB1 receptor signaling through the use of CB1 (−/−) mice or the CB1 receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB1 (−/−) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task.

Objectives

The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks.

Materials and methods

Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session.

Results

Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task.

Conclusions

These results support the hypothesis that the CB1 receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  • Brodkin J, Moerschbaecher JM (1997) SR141716A antagonizes the disruptive effects of cannabinoid ligands on learning in rats. J Pharmacol Exp Ther 282:1522–1526

    Google Scholar 

  • Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281

    Article  PubMed  CAS  Google Scholar 

  • Chait LD, Pierri J (1992) Effects of smoked marijuana on human performance: a critical review. In: Murphy L, Bartke A (eds) Marijuana/cannabinoids: neurobiology and neurophysiology. CRC Press, Boca Raton, FL, pp 387–423

    Google Scholar 

  • da Silva GE, Takahashi RN (2002) SR 141716A prevents delta 9-tetrahydrocannabinol-induced spatial learning deficit in a Morris-type water maze in mice. Prog Neuro-psychopharmacol Biol Psychiatry 26:321–325

    Article  Google Scholar 

  • de Oliveira Alvares L, de Oliveira LF, Camboim C, Diehl F, Genro BP, Lanziotti VB, Quillfeldt JA (2005) Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats. Neurobiol Learn Mem 83:119–124

    Article  PubMed  CAS  Google Scholar 

  • De Vry J, Schreiber R, Eckel G, Jentzsch KR (2004) Behavioral mechanisms underlying inhibition of food-maintained responding by the cannabinoid receptor antagonist/inverse agonist SR141716A. Eur J Pharmacol 483:55–63

    Article  PubMed  CAS  Google Scholar 

  • Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825

    Article  PubMed  Google Scholar 

  • Freedland CS, Poston JS, Porrino LJ (2000) Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding. Pharmacol Biochem Behav 67:265–270

    Article  PubMed  CAS  Google Scholar 

  • Hampson RE, Deadwyler SA (2000) Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats. J Neurosci 20:8932–8942

    PubMed  CAS  Google Scholar 

  • Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583

    PubMed  CAS  Google Scholar 

  • Higgs S, Williams CM, Kirkham TC (2003) Cannabinoid influences on palatability: microstructural analysis of sucrose drinking after delta(9)-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716. Psychopharmacology (Berl) 165:370–377

    CAS  Google Scholar 

  • Holter SM, Kallnik M, Wurst W, Marsicano G, Lutz B, Wotjak CT (2005) Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task. Eur J Pharmacol 510:69–74

    Article  PubMed  CAS  Google Scholar 

  • Kamprath K, Marsicano G, Tang J, Monory K, Bisogno T, Di Marzo V, Lutz B, Wotjak CT (2006) Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J Neurosci 26:6677–6686

    Article  PubMed  CAS  Google Scholar 

  • Landsman RS, Burkey TH, Consroe P, Roeske WR, Yamamura HI (1997) SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur J Pharmacol 334:R1–R2

    Article  PubMed  CAS  Google Scholar 

  • Lerman DC, Iwata BA (1996) Developing a technology for the use of operant extinction in clinical settings: an examination of basic and applied research. J Appl Behav Anal 29:345–382; discussion 383–385

    Article  PubMed  CAS  Google Scholar 

  • Lichtman AH (2000) SR 141716A enhances spatial memory as assessed in a radial-arm maze task in rats. Eur J Pharmacol 404:175–179

    Article  PubMed  CAS  Google Scholar 

  • Lichtman AH, Martin BR (1996) D9-Tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. Psychopharmacology 126:125–131

    Article  PubMed  CAS  Google Scholar 

  • Lichtman AH, Varvel SA, Martin BR (2002) Endocannabinoids in cognition and dependence. Prostaglandins Leukot Essent Fat Acids 66:269–285

    Article  CAS  Google Scholar 

  • Lin HC, Mao SC, Gean PW (2006) Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle. Learn Mem 13:316–321

    Article  PubMed  CAS  Google Scholar 

  • Mallet PE, Beninger RJ (1998) The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by delta-9-tetrahydrocannabinol or anandamide. Psychopharmacology 140:11–19

    Article  PubMed  CAS  Google Scholar 

  • Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534

    Article  PubMed  CAS  Google Scholar 

  • Matsuda LA, Bonner TI, Lolait SJ (1993) Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 327:535–550

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski N, Schatz A, Gopher A, Almog S, Martin B, Compton D, Pertwee R, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    Article  PubMed  CAS  Google Scholar 

  • Miller LL, Branconnier RJ (1983) Cannabis: effects on memory and the cholinergic limbic system. Psychol Bull 93:441–456

    Article  PubMed  CAS  Google Scholar 

  • Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G (2005) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115:1298–12305

    Article  PubMed  CAS  Google Scholar 

  • Shiflett MW, Rankin AZ, Tomaszycki ML, DeVoogd TJ (2004) Cannabinoid inhibition improves memory in food-storing birds, but with a cost. Proc Biol Sci 271:2043–2048

    Article  PubMed  CAS  Google Scholar 

  • Sim-Selley LJ, Brunk LK, Selley DE (2001) Inhibitory effects of SR141716A on G-protein activation in rat brain. Eur J Pharmacol 414:135–143

    Article  PubMed  CAS  Google Scholar 

  • Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoyglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    Article  PubMed  CAS  Google Scholar 

  • Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24:4787–4795

    Article  PubMed  CAS  Google Scholar 

  • Takahashi RN, Pamplona FA, Fernandes MS (2005) The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze. Neurosci Lett 380:270–275

    Article  PubMed  CAS  Google Scholar 

  • Terranova J-P, Michaud J-C, Le Fur G, Soubrie P (1995) Inhibition of long-term potentiation in rat hippocampal slices by anandamide and WIN55212-2: reversal by SR141716A, a selective antagonist of CB1 cannabinoid receptors. Nauyn-Schmiedeberg’s Arch Pharmacol 352:576–579

    CAS  Google Scholar 

  • Terranova JP, Storme JJ, Lafon N, Perio A, Rinaldi-Carmona M, Le Fur G, Soubrie P (1996) Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacology 126:165–172

    Article  PubMed  CAS  Google Scholar 

  • Varvel SA, Lichtman AH (2002) Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 301:915–924

    Article  PubMed  CAS  Google Scholar 

  • Varvel SA, Hamm RJ, Martin BR, Lichtman AH (2001) Differential effects of delta9-THC on spatial reference and working memory in mice. Psychopharmacology (Berl) 157:142–150

    Article  CAS  Google Scholar 

  • Varvel SA, Anum EA, Lichtman AH (2005) Disruption of CB(1) receptor signaling impairs extinction of spatial memory in mice. Psychopharmacology (Berl) 179:863–872

    Article  CAS  Google Scholar 

  • Ward SJ, Dykstra LA (2005) The role of CB1 receptors in sweet versus fat reinforcement: effect of CB1 receptor deletion, CB1 receptor antagonism (SR141716A) and CB1 receptor agonism (CP-55940). Behav Pharmacol 16:381–388

    Article  PubMed  CAS  Google Scholar 

  • Winsauer PJ, Lambert P, Moerschbaecher JM (1999) Cannabinoid ligands and their effects on learning and performance in rhesus monkeys. Behav Pharmacol 10:497–511

    Article  PubMed  CAS  Google Scholar 

  • Wolff MC, Leander JD (2003) SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task. Eur J Pharmacol 477:213–217

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the National Institute on Drug Abuse grants DA015683, DA03672, and DA09789.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA

    Floride Niyuhire, Stephen A. Varvel, Andrew J. Thorpe, Rene J. Stokes, Jenny L. Wiley & Aron H. Lichtman

Authors
  1. Floride Niyuhire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen A. Varvel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew J. Thorpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rene J. Stokes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jenny L. Wiley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aron H. Lichtman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aron H. Lichtman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niyuhire, F., Varvel, S.A., Thorpe, A.J. et al. The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific. Psychopharmacology 191, 223–231 (2007). https://doi.org/10.1007/s00213-006-0650-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0650-6

Keywords

Search

Navigation